2024/01/31 更新

写真a

キノシタ リエ
木下 理恵
KINOSHITA Rie
所属
医歯薬学域 助教
職名
助教
外部リンク

学位

  • 博士(工学) ( 岡山大学 )

研究キーワード

  • 細胞生物学

  • Cell biology

  • 抗体医薬品

研究分野

  • ライフサイエンス / 細胞生物学

学歴

  • 岡山大学   Graduate School, Division of Engineering  

    - 2015年

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  • 岡山大学    

    - 2015年

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    国名: 日本国

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  • 岡山大学   Faculty of Engineering   Department of Bioscience and Biotechnology

    - 2000年

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    国名: 日本国

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  • 岡山大学   Faculty of Engineering  

    - 2000年

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経歴

  • - 岡山大学医歯薬学総合研究科機能再生・再建科学専攻 助教

    2015年

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  • - Assistant Professor,Science of Functional Recovery and Reconstruction,Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,Okayama University

    2015年

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所属学協会

  • 日本組織培養学会

    2017年4月 - 現在

  • 日本癌学会

    2015年4月 - 現在

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  • 日本組織培養学会

    2015年4月 - 現在

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論文

  • Phosphorylated SARM1 is involved in the pathological process of rotenone-induced neurodegeneration. 国際誌

    Hitoshi Murata, May Tha Zin Phoo, Toshiki Ochi, Nahoko Tomonobu, Ken-Ichi Yamamoto, Rie Kinoshita, Ikuko Miyazaki, Masahiro Nishibori, Masato Asanuma, Masakiyo Sakaguchi

    Journal of biochemistry   2023年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Sterile alpha and Toll/interleukin receptor motif-containing protein 1 (SARM1) is a NAD+ hydrolase that plays a key role in axonal degeneration and neuronal cell death. We reported that c-Jun N-terminal kinase (JNK) activates SARM1 through phosphorylation at Ser-548. The importance of SARM1 phosphorylation in the pathological process of Parkinson's disease (PD) has not been determined. We thus conducted the present study by using rotenone (an inducer of PD-like pathology) and neurons derived from induced pluripotent stem cells (iPSCs) from healthy donors and a patient with familial PD PARK2 (FPD2). The results showed that compared to the healthy neurons, FPD2 neurons were more vulnerable to rotenone-induced stress and had higher levels of SARM1 phosphorylation. Similar cellular events were obtained when we used PARK2-knockdown neurons derived from healthy donor iPSCs. These events in both types of PD-model neurons were suppressed in neurons treated with JNK inhibitors, Ca2+-signal inhibitors, or by a SARM1-knockdown procedure. The degenerative events were enhanced in neurons overexpressing wild-type SARM1 and conversely suppressed in neurons overexpressing the SARM1-S548A mutant. We also detected elevated SARM1 phosphorylation in the midbrain of PD-model mice. The results indicate that phosphorylated SARM1 plays an important role in the pathological process of rotenone-induced neurodegeneration.

    DOI: 10.1093/jb/mvad068

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  • β3インテグリン遺伝子導入ヒト表皮角化細胞を用いた難治性潰瘍に対する新規再生医療の開発

    久保 美代子, 山本 健一, 木下 理恵, 米澤 朋子, 大橋 俊孝, 阪口 政清

    日本結合組織学会学術大会プログラム・抄録集   55回   134 - 134   2023年6月

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    記述言語:日本語   出版者・発行元:日本結合組織学会  

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  • STAT1/3 signaling suppresses axon degeneration and neuronal cell death through regulation of NAD+-biosynthetic and consuming enzymes. 国際誌

    Hitoshi Murata, Yu Yasui, Kazuma Oiso, Toshiki Ochi, Nahoko Tomonobu, Ken-Ichi Yamamoto, Rie Kinoshita, Masakiyo Sakaguchi

    Cellular signalling   108   110717 - 110717   2023年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Nicotinamide adenine dinucleotide (NAD)+-biosynthetic and consuming enzymes are involved in various intracellular events through the regulation of NAD+ metabolism. Recently, it has become clear that alterations in the expression of NAD+-biosynthetic and consuming enzymes contribute to the axonal stability of neurons. We explored soluble bioactive factor(s) that alter the expression of NAD+-metabolizing enzymes and found that cytokine interferon (IFN)-γ increased the expression of nicotinamide nucleotide adenylyltransferase 2 (NMNAT2), an NAD+-biosynthetic enzyme. IFN-γ activated signal transducers and activators of transcription 1 and 3 (STAT1/3) followed by c-Jun N-terminal kinase (JNK) suppression. As a result, STAT1/3 increased the expression of NMNAT2 at both mRNA and protein levels in a dose- and time-dependent manner and, at the same time, suppressed activation of sterile alpha and Toll/interleukin receptor motif-containing 1 (SARM1), an NAD+-consuming enzyme, and increased intracellular NAD+ levels. We examined the protective effect of STAT1/3 signaling against vincristine-mediated cell injury as a model of chemotherapy-induced peripheral neuropathy (CIPN), in which axonal degeneration is involved in disease progression. We found that IFN-γ-mediated STAT1/3 activation inhibited vincristine-induced downregulation of NMNAT2 and upregulation of SARM1 phosphorylation, resulting in modest suppression of subsequent neurite degradation and cell death. These results indicate that STAT1/3 signaling induces NMNAT2 expression while simultaneously suppressing SARM1 phosphorylation, and that both these actions contribute to suppression of axonal degeneration and cell death.

    DOI: 10.1016/j.cellsig.2023.110717

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  • Novel extracellular role of REIC/Dkk-3 protein in PD-L1 regulation in cancer cells. 国際誌

    Yuma Gohara, Nahoko Tomonobu, Rie Kinoshita, Junichiro Futami, Léna Audebert, Youyi Chen, Ni Luh Gede Yoni Komalasari, Fan Jiang, Chikako Yoshizawa, Hitoshi Murata, Ken-Ichi Yamamoto, Masami Watanabe, Hiromi Kumon, Masakiyo Sakaguchi

    Journal of molecular medicine (Berlin, Germany)   101 ( 4 )   431 - 447   2023年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The adenovirus-REIC/Dkk-3 expression vector (Ad-REIC) has been the focus of numerous clinical studies due to its potential for the quenching of cancers. The cancer-suppressing mechanisms of the REIC/DKK-3 gene depend on multiple pathways that exert both direct and indirect effects on cancers. The direct effect is triggered by REIC/Dkk-3-mediated ER stress that causes cancer-selective apoptosis, and the indirect effect can be classified in two ways: (i) induction, by Ad-REIC-mis-infected cancer-associated fibroblasts, of the production of IL-7, an important activator of T cells and NK cells, and (ii) promotion, by the secretory REIC/Dkk-3 protein, of dendritic cell polarization from monocytes. These unique features allow Ad-REIC to exert effective and selective cancer-preventative effects in the manner of an anticancer vaccine. However, the question of how the REIC/Dkk-3 protein leverages anticancer immunity has remained to be answered. We herein report a novel function of the extracellular REIC/Dkk-3-namely, regulation of an immune checkpoint via modulation of PD-L1 on the cancer-cell surface. First, we identified novel interactions of REIC/Dkk-3 with the membrane proteins C5aR, CXCR2, CXCR6, and CMTM6. These proteins all functioned to stabilize PD-L1 on the cell surface. Due to the dominant expression of CMTM6 among the proteins in cancer cells, we next focused on CMTM6 and observed that REIC/Dkk-3 competed with CMTM6 for PD-L1, thereby liberating PD-L1 from its complexation with CMTM6. The released PD-L1 immediately underwent endocytosis-mediated degradation. These results will enhance our understanding of not only the physiological nature of the extracellular REIC/Dkk-3 protein but also the Ad-REIC-mediated anticancer effects. KEY MESSAGES: • REIC/Dkk-3 protein effectively suppresses breast cancer progression through an acceleration of PD-L1 degradation. • PD-L1 stability on the cancer cell membrane is kept high by binding with mainly CMTM6. • Competitive binding of REIC/Dkk-3 protein with CMTM6 liberates PD-L1, leading to PD-L1 degradation.

    DOI: 10.1007/s00109-023-02292-w

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  • LOXL1 and LOXL4 are novel target genes of the Zn2+-bound form of ZEB1 and play a crucial role in the acceleration of invasive events in triple-negative breast cancer cells

    Daisuke Hirabayashi, Ken-ichi Yamamoto, Akihiro Maruyama, Nahoko Tomonobu, Rie Kinoshita, Youyi Chen, Ni Luh Gede Yoni Komalasari, Hitoshi Murata, Yuma Gohara, Fan Jiang, Jin Zhou, I Made Winarsa Ruma, I Wayan Sumardika, Akira Yamauchi, Futoshi Kuribayashi, Shinichi Toyooka, Yusuke Inoue, Masakiyo Sakaguchi

    Frontiers in Oncology   13   2023年2月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Frontiers Media SA  

    Background

    EMT has been proposed to be a crucial early event in cancer metastasis. EMT is rigidly regulated by the action of several EMT-core transcription factors, particularly ZEB1. We previously revealed an unusual role of ZEB1 in the S100A8/A9-mediated metastasis in breast cancer cells that expressed ZEB1 at a significant level and showed that the ZEB1 was activated on the MCAM-downstream pathway upon S100A8/A9 binding. ZEB1 is well known to require Zn2+ for its activation based on the presence of several Zn-finger motifs in the transcription factor. However, how Zn2+-binding works on the pleiotropic role of ZEB1 through cancer progression has not been fully elucidated.

    Methods

    We established the engineered cells, MDA-MB-231 MutZEB1 (MDA-MutZEB1), that stably express MutZEB1 (ΔZn). The cells were then evaluated in vitro for their invasion activities. Finally, an RNA-Seq analysis was performed to compare the gene alteration profiles of the established cells comprehensively.

    Results

    MDA-MutZEB1 showed a significant loss of the EMT, ultimately stalling the invasion. Inclusive analysis of the transcription changes after the expression of MutZEB1 (ΔZn) in MDA-MB-231 cells revealed the significant downregulation of LOX family genes, which are known to play a critical role in cancer metastasis. We found that LOXL1 and LOXL4 remarkably enhanced cancer invasiveness among the LOX family genes with altered expression.

    Conclusions

    These findings indicate that ZEB1 potentiates Zn2+-mediated transcription of plural EMT-relevant factors, including LOXL1 and LOXL4, whose upregulation plays a critical role in the invasive dissemination of breast cancer cells.

    DOI: 10.3389/fonc.2023.1142886

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  • Lysyl oxidase-like 4 exerts an atypical role in breast cancer progression that is dependent on the enzymatic activity that targets the cell-surface annexin A2. 国際誌

    Ni Luh Gede Yoni Komalasari, Nahoko Tomonobu, Rie Kinoshita, Youyi Chen, Yoshihiko Sakaguchi, Yuma Gohara, Fan Jiang, Ken-Ich Yamamoto, Hitoshi Murata, I Made Winarsa Ruma, I Wayan Sumardika, Jin Zhou, Akira Yamauchi, Futoshi Kuribayashi, Yusuke Inoue, Shinichi Toyooka, Masakiyo Sakaguchi

    Frontiers in oncology   13   1142907 - 1142907   2023年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: LOX family members are reported to play pivotal roles in cancer. Unlike their enzymatic activities in collagen cross-linking, their precise cancer functions are unclear. We revealed that LOXL4 is highly upregulated in breast cancer cells, and we thus sought to define an unidentified role of LOXL4 in breast cancer. METHODS: We established the MDA-MB-231 sublines MDA-MB-231-LOXL4 mutCA and -LOXL4 KO, which stably overexpress mutant LOXL4 that loses its catalytic activity and genetically ablates the intrinsic LOXL4 gene, respectively. In vitro and in vivo evaluations of these cells' activities of cancer outgrowth were conducted by cell-based assays in cultures and an orthotopic xenograft model, respectively. The new target (s) of LOXL4 were explored by the MS/MS analytic approach. RESULTS: Our in vitro results revealed that both the overexpression of mutCA and the KO of LOXL4 in cells resulted in a marked reduction of cell growth and invasion. Interestingly, the lowered cellular activities observed in the engineered cells were also reflected in the mouse model. We identified a novel binding partner of LOXL4, i.e., annexin A2. LOXL4 catalyzes cell surface annexin A2 to achieve a cross-linked multimerization of annexin A2, which in turn prevents the internalization of integrin β-1, resulting in the locking of integrin β-1 on the cell surface. These events enhance the promotion of cancer cell outgrowth. CONCLUSIONS: LOXL4 has a new role in breast cancer progression that occurs via an interaction with annexin A2 and integrin β-1 on the cell surface.

    DOI: 10.3389/fonc.2023.1142907

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  • Toll-like receptor 4 promotes bladder cancer progression upon S100A8/A9 binding, which requires TIRAP-mediated TPL2 activation

    Acosta Gonzalez Herik Rodrigo, Nahoko Tomonobu, Haruka Yoneda, Rie Kinoshita, Yosuke Mitsui, Takuya Sadahira, Shin-ichi Terawaki, Yuma Gohara, Ni Luh Gede Yoni Komalasari, Fan Jiang, Hitoshi Murata, Ken-ichi Yamamoto, Junichiro Futami, Akira Yamauchi, Futoshi Kuribayashi, Yusuke Inoue, Eisaku Kondo, Shinichi Toyooka, Masahiro Nishibori, Masami Watanabe, Yasutomo Nasu, Masakiyo Sakaguchi

    Biochemical and Biophysical Research Communications   634   83 - 91   2022年12月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.bbrc.2022.09.116

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  • Functional Blockage of S100A8/A9 Ameliorates Ischemia-Reperfusion Injury in the Lung. 国際誌

    Kentaro Nakata, Mikio Okazaki, Tomohisa Sakaue, Rie Kinoshita, Yuhei Komoda, Dai Shimizu, Haruchika Yamamoto, Shin Tanaka, Ken Suzawa, Kazuhiko Shien, Kentaroh Miyoshi, Hiromasa Yamamoto, Toshiaki Ohara, Seiichiro Sugimoto, Masaomi Yamane, Akihiro Matsukawa, Masakiyo Sakaguchi, Shinichi Toyooka

    Bioengineering (Basel, Switzerland)   9 ( 11 )   2022年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    (1) Background: Lung ischemia-reperfusion (IR) injury increases the mortality and morbidity of patients undergoing lung transplantation. The objective of this study was to identify the key initiator of lung IR injury and to evaluate pharmacological therapeutic approaches using a functional inhibitor against the identified molecule. (2) Methods: Using a mouse hilar clamp model, the combination of RNA sequencing and histological investigations revealed that neutrophil-derived S100A8/A9 plays a central role in inflammatory reactions during lung IR injury. Mice were assigned to sham and IR groups with or without the injection of anti-S100A8/A9 neutralizing monoclonal antibody (mAb). (3) Results: Anti-S100A8/A9 mAb treatment significantly attenuated plasma S100A8/A9 levels compared with control IgG. As evaluated by oxygenation capacity and neutrophil infiltration, the antibody treatment dramatically ameliorated the IR injury. The gene expression levels of cytokines and chemokines induced by IR injury were significantly reduced by the neutralizing antibody. Furthermore, the antibody treatment significantly reduced TUNEL-positive cells, indicating the presence of apoptotic cells. (4) Conclusions: We identified S100A8/A9 as a novel therapeutic target against lung IR injury.

    DOI: 10.3390/bioengineering9110673

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  • Inhibition of pancreatic cancer-cell growth and metastasis in vivo by a pyrazole compound characterized as a cell-migration inhibitor by an in vitro chemotaxis assay

    Shuichiro Okamoto, Kei Miyano, Tominari Choshi, Norihiko Sugisawa, Takashi Nishiyama, Rika Kotouge, Masahiro Yamamura, Masakiyo Sakaguchi, Rie Kinoshita, Nahoko Tomonobu, Naoki Katase, Kyo Sasaki, Sohji Nishina, Keisuke Hino, Koji Kurose, Mikio Oka, Hisako Kubota, Tomio Ueno, Toshihiro Hirai, Hideyo Fujiwara, Chikage Kawai, Masumi Itadani, Aya Morihara, Kouji Matsushima, Shiro Kanegasaki, Robert M. Hoffman, Akira Yamauchi, Futoshi Kuribayashi

    Biomedicine & Pharmacotherapy   155   113733 - 113733   2022年11月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.biopha.2022.113733

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  • がん免疫サイクルのレベルを末梢血で評価する自己抗体バイオマーカー群網羅的測定法の確立

    宮本 愛, 本莊 知子, 益井 実鈴, 木下 理恵, 公文 裕巳, 垣見 和宏, 二見 淳一郎

    日本生物工学会大会講演要旨集   2022年   223 - 223   2022年10月

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    記述言語:日本語   出版者・発行元:(公社)日本生物工学会  

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  • Histidine-Rich Glycoprotein Suppresses the S100A8/A9-Mediated Organotropic Metastasis of Melanoma Cells

    Nahoko Tomonobu, Rie Kinoshita, Hidenori Wake, Yusuke Inoue, I Made Winarsa Ruma, Ken Suzawa, Yuma Gohara, Ni Luh Gede Yoni Komalasari, Fan Jiang, Hitoshi Murata, Ken-ichi Yamamoto, I Wayan Sumardika, Youyi Chen, Junichiro Futami, Akira Yamauchi, Futoshi Kuribayashi, Eisaku Kondo, Shinichi Toyooka, Masahiro Nishibori, Masakiyo Sakaguchi

    International Journal of Molecular Sciences   23 ( 18 )   10300 - 10300   2022年9月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:MDPI AG  

    The dissection of the complex multistep process of metastasis exposes vulnerabilities that could be exploited to prevent metastasis. To search for possible factors that favor metastatic outgrowth, we have been focusing on secretory S100A8/A9. A heterodimer complex of the S100A8 and S100A9 proteins, S100A8/A9 functions as a strong chemoattractant, growth factor, and immune suppressor, both promoting the cancer milieu at the cancer-onset site and cultivating remote, premetastatic cancer sites. We previously reported that melanoma cells show lung-tropic metastasis owing to the abundant expression of S100A8/A9 in the lung. In the present study, we addressed the question of why melanoma cells are not metastasized into the brain at significant levels in mice despite the marked induction of S100A8/A9 in the brain. We discovered the presence of plasma histidine-rich glycoprotein (HRG), a brain-metastasis suppression factor against S100A8/A9. Using S100A8/A9 as an affinity ligand, we searched for and purified the binding plasma proteins of S100A8/A9 and identified HRG as the major protein on mass spectrometric analysis. HRG prevents the binding of S100A8/A9 to the B16-BL6 melanoma cell surface via the formation of the S100A8/A9 complex. HRG also inhibited the S100A8/A9-induced migration and invasion of A375 melanoma cells. When we knocked down HRG in mice bearing skin melanoma, metastasis to both the brain and lungs was significantly enhanced. The clinical examination of plasma S100A8/A9 and HRG levels showed that lung cancer patients with brain metastasis had higher S100A8/A9 and lower HRG levels than nonmetastatic patients. These results suggest that the plasma protein HRG strongly protects the brain and lungs from the threat of melanoma metastasis.

    DOI: 10.3390/ijms231810300

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  • Inhibiting S100A8/A9 attenuates airway obstruction in a mouse model of heterotopic tracheal transplantation. 国際誌

    Dai Shimizu, Mikio Okazaki, Seiichiro Sugimoto, Rie Kinoshita, Kentaro Nakata, Shin Tanaka, Kohei Hashimoto, Kentaroh Miyoshi, Masaomi Yamane, Akihiro Matsukawa, Masakiyo Sakaguchi, Shinichi Toyooka

    Biochemical and biophysical research communications   629   86 - 94   2022年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Although bronchiolitis obliterans syndrome (BOS) is a major cause of death after lung transplantation, an effective drug therapy for BOS has not yet developed. Here, we assessed the effectiveness of a neutralizing anti-S100 calcium binding protein (S100) A8/A9 antibody against BOS. A murine model of heterotopic tracheal transplantation was used. Mice were intraperitoneally administered control IgG or the S100A8/A9 antibody on day 0 and twice per week until they were sacrificed. Tissue sections were used to evaluate the obstruction ratio, epithelium-preservation ratio, α-smooth muscle actin (SMA)-positive myofibroblast infiltration, and luminal cell death. Quantitative reverse transcriptase-polymerase chain reaction analysis was performed to analyze the mRNA-expression levels of collagen, inflammatory cytokines, and chemokines on days 7, 14, and 21. The anti-S100A8/A9 antibody significantly improved the obstruction ratio and epithelium-preservation ratio, with less α-SMA-positive myofibroblast infiltration compared to the control group. Antibody treatment reduced the type-III collagen: type-I collagen gene-expression ratio. The antibody also significantly suppressed the number of dead cells in the graft lumen. The expression levels of tumor growth factor β1 and C-C motif chemokine 2 on day 21, but not those of interleukin-1β, interleukin-6, and tumor necrosis factor α, were significantly suppressed by S100A8/A9 antibody treatment. These findings suggest that S100A8/A9 may be a potential therapeutic target for BOS after lung transplantation.

    DOI: 10.1016/j.bbrc.2022.08.087

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  • がん免疫サイクルを評価する自己抗体バイオマーカー群の精密測定法の開発

    宮本 愛, 本莊 知子, 益井 実鈴, 木下 理恵, 公文 裕巳, 垣見 和宏, 二見 淳一郎

    日本がん免疫学会総会プログラム・抄録集   26回   102 - 102   2022年6月

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    記述言語:日本語   出版者・発行元:日本がん免疫学会  

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  • がん免疫サイクルを評価する自己抗体バイオマーカー群の精密測定法の開発

    宮本 愛, 本莊 知子, 益井 実鈴, 木下 理恵, 公文 裕巳, 垣見 和宏, 二見 淳一郎

    日本がん免疫学会総会プログラム・抄録集   26回   102 - 102   2022年6月

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    記述言語:日本語   出版者・発行元:日本がん免疫学会  

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  • Dkk3/REIC Deficiency Impairs Spermiation, Sperm Fibrous Sheath Integrity and the Sperm Motility of Mice. 国際誌

    Ruizhi Xue, Wenfeng Lin, Hirofumi Fujita, Jingkai Sun, Rie Kinoshita, Kazuhiko Ochiai, Junichiro Futami, Masami Watanabe, Hideyo Ohuchi, Masakiyo Sakaguchi, Zhengyan Tang, Peng Huang, Yasutomo Nasu, Hiromi Kumon

    Genes   13 ( 2 )   2022年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The role of Dickkopf-3 (Dkk3)/REIC (The Reduced Expression in Immortalized Cells), a Wnt-signaling inhibitor, in male reproductive physiology remains unknown thus far. To explore the functional details of Dkk3/REIC in the male reproductive process, we studied the Dkk3/REIC knock-out (KO) mouse model. By examining testicular sections and investigating the sperm characteristics (count, vitality and motility) and ultrastructure, we compared the reproductive features between Dkk3/REIC-KO and wild-type (WT) male mice. To further explore the underlying molecular mechanism, we performed RNA sequencing (RNA-seq) analysis of testicular tissues. Our results showed that spermiation failure existed in seminiferous tubules of Dkk3/REIC-KO mice, and sperm from Dkk3/REIC-KO mice exhibited inferior motility (44.09 ± 8.12% vs. 23.26 ± 10.02%, p < 0.01). The Ultrastructure examination revealed defects in the sperm fibrous sheath of KO mice. Although the average count of Dkk3/REIC-KO epididymal sperm was less than that of the wild-types (9.30 ± 0.69 vs. 8.27 ± 0.87, ×106), neither the gap (p > 0.05) nor the difference in the sperm vitality rate (72.83 ± 1.55% vs. 72.50 ± 0.71%, p > 0.05) were statistically significant. The RNA-seq and GO (Gene Oncology) enrichment results indicated that the differential genes were significantly enriched in the GO terms of cytoskeleton function, cAMP signaling and calcium ion binding. Collectively, our research demonstrates that Dkk3/REIC is involved in the process of spermiation, fibrous sheath integrity maintenance and sperm motility of mice.

    DOI: 10.3390/genes13020285

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  • Engineering Cancer/Testis Antigens With Reversible S-Cationization to Evaluate Antigen Spreading. 国際誌

    Ai Miyamoto, Tomoko Honjo, Mirei Masui, Rie Kinoshita, Hiromi Kumon, Kazuhiro Kakimi, Junichiro Futami

    Frontiers in oncology   12   869393 - 869393   2022年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Serum autoantibody to cancer/testis antigens (CTAs) is a critical biomarker that reflects the antitumor immune response. Quantitative and multiplexed anti-CTA detection arrays can assess the immune status in tumors and monitor therapy-induced antitumor immune reactions. Most full-length recombinant CTA proteins tend to aggregate. Cysteine residue-specific S-cationization techniques facilitate the preparation of water-soluble and full-length CTAs. Combined with Luminex technology, we designed a multiple S-cationized antigen-immobilized bead array (MUSCAT) assay system to evaluate multiple serum antibodies to CTAs. Reducible S-alkyl-disulfide-cationized antigens in cytosolic conditions were employed to develop rabbit polyclonal antibodies as positive controls. These control antibodies sensitively detected immobilized antigens on beads and endogenous antigens in human lung cancer-derived cell lines. Rabbit polyclonal antibodies successfully confirmed the dynamic ranges and quantitative MUSCAT assay results. An immune monitoring study was conducted using the serum samples on an adenovirus-mediated REIC/Dkk-3 gene therapy clinical trial that showed a successful clinical response in metastatic castration-resistant prostate cancer. Autoantibody responses were closely related to clinical outcomes. Notably, upregulation of anti-CTA responses was monitored before tumor regression. Thus, quantitative monitoring of anti-CTA antibody biomarkers can be used to evaluate the cancer-immunity cycle. A quality-certified serum autoantibody monitoring system is a powerful tool for developing and evaluating cancer immunotherapy.

    DOI: 10.3389/fonc.2022.869393

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  • マウス異所性気管移植モデルを用いたS100A8/A9抗体の慢性移植肺機能不全に対する効果の検討

    清水 大, 岡崎 幹生, 木下 理恵, 中田 憲太郎, 三好 健太郎, 大谷 真二, 杉本 誠一郎, 山根 正修, 阪口 政清, 豊岡 伸一

    移植   56 ( 総会臨時 )   P2 - 11   2021年9月

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    記述言語:日本語   出版者・発行元:(一社)日本移植学会  

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  • マウス異所性気管移植モデルを用いたS100A8/A9抗体の慢性移植肺機能不全に対する効果の検討

    清水 大, 岡崎 幹生, 木下 理恵, 中田 憲太郎, 三好 健太郎, 大谷 真二, 杉本 誠一郎, 山根 正修, 阪口 政清, 豊岡 伸一

    移植   56 ( 総会臨時 )   P2 - 11   2021年9月

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    記述言語:日本語   出版者・発行元:(一社)日本移植学会  

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  • The heterodimer S100A8/A9 is a potent therapeutic target for idiopathic pulmonary fibrosis. 査読 国際誌

    Kota Araki, Rie Kinoshita, Nahoko Tomonobu, Yuma Gohara, Shuta Tomida, Yuta Takahashi, Satoru Senoo, Akihiko Taniguchi, Junko Itano, Ken-Ichi Yamamoto, Hitoshi Murata, Ken Suzawa, Kazuhiko Shien, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Kouichi Ichimura, Masahiro Nishibori, Nobuaki Miyahara, Shinichi Toyooka, Masakiyo Sakaguchi

    Journal of molecular medicine (Berlin, Germany)   99 ( 1 )   131 - 145   2021年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    In patients with interstitial pneumonia, pulmonary fibrosis is an irreversible condition that can cause respiratory failure. Novel treatments for pulmonary fibrosis are necessary. Inflammation is thought to activate lung fibroblasts, resulting in pulmonary fibrosis. Of the known inflammatory molecules, we have focused on S100A8/A9 from the onset of inflammation to the subsequent progression of inflammation. Our findings confirmed the high expression of S100A8/A9 in specimens from patients with pulmonary fibrosis. An active role of S100A8/A9 was demonstrated not only in the proliferation of fibroblasts but also in the fibroblasts' differentiation to myofibroblasts (the active form of fibroblasts). S100A8/A9 also forced fibroblasts to upregulate the production of collagen. These effects were induced via the receptor of S100A8/A9, i.e., the receptor for advanced glycation end products (RAGE), on fibroblasts. The anti-S100A8/A9 neutralizing antibody inhibited the effects of S100A8/A9 on fibroblasts and suppressed the progression of fibrosis in bleomycin (BLM)-induced pulmonary fibrosis mouse model. Our findings strongly suggest a crucial role of S100A8/A9 in pulmonary fibrosis and the usefulness of S100A8/A9-targeting therapy for fibrosis interstitial pneumonia. HIGHLIGHTS: S100A8/A9 level is highly upregulated in the IPF patients' lungs as well as the blood. S100A8/A9 promotes not only the growth of fibroblasts but also differentiation to myofibroblasts. The cell surface RAGE acts as a crucial receptor to the extracellular S100A8/A9 in fibroblasts. The anti-S100A8/A9 antibody effectively suppresses the progression of IPF in a mouse model. In idiopathic pulmonary fibrosis (IPF), S100A8/A9, a heterodimer composed of S100A8 and S100A9 proteins, plays a crucial role in the onset of inflammation and the subsequent formation of a feed-forward inflammatory loop that promotes fibrosis. (1) The local, pronounced increase in S100A8/A9 in the injured inflammatory lung region-which is provided mainly by the activated neutrophils and macrophages-exerts strong inflammatory signals accompanied by dozens of inflammatory soluble factors including cytokines, chemokines, and growth factors that further act to produce and secrete S100A8/A9, eventually making a sustainable inflammatory circuit that supplies an indefinite presence of S100A8/A9 in the extracellular space with a mal-increased level. (2) The elevated S100A8/A9 compels fibroblasts to activate through receptor for advanced glycation end products (RAGE), one of the major S100A8/A9 receptors, resulting in the activation of NFκB, leading to fibroblast mal-events (e.g., elevated cell proliferation and transdifferentiation to myofibroblasts) that actively produce not only inflammatory cytokines but also collagen matrices. (3) Finally, the S100A8/A9-derived activation of lung fibroblasts under a chronic inflammation state leads to fibrosis events and constantly worsens fibrosis in the lung. Taken together, these findings suggest that the extracellular S100A8/A9 heterodimer protein is a novel mainstay soluble factor for IPF that exerts many functions as described above (1-3). Against this background, we herein applied the developed S100A8/A9 neutralizing antibody to prevent IPF. The IPF imitating lung fibrosis in an IPF mouse model was effectively blocked by treatment with the antibody, leading to enhanced survival. The developed S100A8/A9 antibody, as an innovative novel biologic, may help shed light on the difficulties encountered with IPF therapy in clinical settings.

    DOI: 10.1007/s00109-020-02001-x

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  • Neuroplastinβ-mediated upregulation of solute carrier family 22 member 18 antisense (SLC22A18AS) plays a crucial role in the epithelial-mesenchymal transition, leading to lung cancer cells' enhanced motility. 査読 国際誌

    Karolina Bajkowska, I Wayan Sumardika, Nahoko Tomonobu, Youyi Chen, Ken-Ichi Yamamoto, Rie Kinoshita, Hitoshi Murata, Ni Luh Gede Yoni Komalasari, Fan Jiang, Akira Yamauchi, I Made Winarsa Ruma, Carlos Ichiro Kasano-Camones, Yusuke Inoue, Masakiyo Sakaguchi

    Biochemistry and biophysics reports   22   100768 - 100768   2020年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Our recent study revealed an important role of the neuroplastin (NPTN)β downstream signal in lung cancer dissemination in the lung. The molecular mechanism of the signal pathway downstream of NPTNβ is a serial activation of the key molecules we identified: tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) adaptor, nuclear factor (NF)IA/NFIB heterodimer transcription factor, and SAM pointed-domain containing ETS transcription factor (SPDEF). The question of how dissemination is controlled by SPDEF under the activated NPTNβ has not been answered. Here, we show that the NPTNβ-SPDEF-mediated induction of solute carrier family 22 member 18 antisense (SLC22A18AS) is definitely required for the epithelial-mesenchymal transition (EMT) through the NPTNβ pathway in lung cancer cells. In vitro, the induced EMT is linked to the acquisition of active cellular motility but not growth, and this is correlated with highly disseminative tumor progression in vivo. The publicly available data also show the poor survival of SLC22A18AS-overexpressing lung cancer patients. Taken together, these data highlight a crucial role of SLC22A18AS in lung cancer dissemination, which provides novel input of this molecule to the signal cascade of NPTNβ. Our findings contribute to a better understanding of NPTNβ-mediated lung cancer metastasis.

    DOI: 10.1016/j.bbrep.2020.100768

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  • Xylitol acts as an anticancer monosaccharide to induce selective cancer death via regulation of the glutathione level. 査読 国際誌

    Nahoko Tomonobu, Ni Luh Gede Yoni Komalasari, I Wayan Sumardika, Fan Jiang, Youyi Chen, Ken-Ichi Yamamoto, Rie Kinoshita, Hitoshi Murata, Yusuke Inoue, Masakiyo Sakaguchi

    Chemico-biological interactions   324   109085 - 109085   2020年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Herbal medicines and their bioactive compounds are increasingly being recognized as useful drugs for cancer treatments. The parasitic fungus Cordyceps militaris is an attractive anticancer herbal since it shows very powerful anticancer activity due to its phytocompound cordycepin. We previously discovered and reported that a high amount of xylitol is present in Cordyceps militaris extract, and that xylitol unexpectedly showed anticancer activity in a cancer-selective manner. We thus hypothesized that xylitol could become a useful supplement to help prevent various cancers, if we can clarify the specific machinery by which xylitol induces cancer cell death. It is also unclear whether xylitol acts on cancer suppression in vivo as well as in vitro. Here we show for the first time that induction of the glutathione-degrading enzyme CHAC1 is the main cause of xylitol-induced apoptotic cell death in cancer cells. The induction of CHAC1 is required for the endoplasmic reticulum (ER) stress that is triggered by xylitol in cancer cells, and is linked to a second induction of oxidative stress in the treated cells, and eventually leads to apoptotic cell death. Our in vivo approach also demonstrated that an intravenous injection of xylitol had a tumor-suppressing effect in mice, to which the xylitol-triggered ER stress also greatly contributed. We also observed that xylitol efficiently sensitized cancer cells to chemotherapeutic drugs. Based on our findings, a chemotherapeutic strategy combined with xylitol might improve the outcomes of patients facing cancer.

    DOI: 10.1016/j.cbi.2020.109085

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  • exMCAM-Fc, an S100A8/A9-mediated-metastasis blocker, efficiently reduced the number of circulating tumor cells that appeared in the blood flow. 査読 国際誌

    Nahoko Tomonobu, Rie Kinoshita, Masakiyo Sakaguchi

    Molecular biology reports   47 ( 6 )   4879 - 4883   2020年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Metastasis is the major cause of treatment failure in cancer patients and of cancer-associated death so that therapeutic regulation of metastasis is very important subject for the cancer treatment. We have been reported that S100A8/A9, a heterodimer complex of S100A8 and S100A9, and its receptors play a crucial role in the lung tropic cancer metastasis, i.e., S100A8/A9 is actively secreted from the lung when cancer mass exists even at remote area from the lung and then functions to attract the distant cancer cells to the lung since cancer cells own the S100A8/A9 receptor(s) on their cell surface. Interestingly, one of the newly developed decoys, exMCAM-Fc, a Fc fusion protein with the extracellular region of melanoma cell adhesion molecule (MCAM), one of the S100A8/A9 receptors, that could prevent the interaction of S100A8/A9 with MCAM, efficiently suppressed the lung tropic cancer metastasis through exerting the several inhibitory effects on the S100A8/A9-mediated cancer cell events including enhanced mobility, invasion and attachment to the endothelial cells. However, it still remains to clarify if the decoy will reduce the number of circulating tumor cells (CTCs) that are defined as substantial cells in the context of organ tropic cancer metastasis. Here, we first show that exMCAM-Fc effectively reduces the number of CTCs in the blood flow of the melanoma bearing mice. The novel finding reinforces the suppressive role of exMCAM-Fc on the cancer metastasis. We therefore expect that exMCAM-Fc may greatly contribute to reduce treatment failure by the efficient blocking of the life threatening cancer metastasis.

    DOI: 10.1007/s11033-020-05495-3

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  • S100 Soil Sensor Receptors and Molecular Targeting Therapy Against Them in Cancer Metastasis. 査読 国際誌

    Nahoko Tomonobu, Rie Kinoshita, Masakiyo Sakaguchi

    Translational oncology   13 ( 4 )   100753 - 100753   2020年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The molecular mechanisms underlying the 'seed and soil' theory are unknown. S100A8/A9 (a heterodimer complex of S100A8 and S100A9 proteins that exhibits a 'soil signal') is a ligand for Toll-like receptor 4, causing distant melanoma cells to approach the lung as a 'seeding' site. Unknown soil sensors for S100A8/A9 may exist, e.g., extracellular matrix metalloproteinase inducer, neuroplastin, activated leukocyte cell adhesion molecule, and melanoma cell adhesion molecule. We call these receptor proteins 'novel S100 soil sensor receptors (novel SSSRs).' Here we review and summarize a crucial role of the S100A8/A9-novel SSSRs' axis in cancer metastasis. The binding of S100A8/A9 to individual SSSRs is important in cancer metastasis via upregulations of the epithelial-mesenchymal transition, cellular motility, and cancer cell invasiveness, plus the formation of an inflammatory immune suppressive environment in metastatic organ(s). These metastatic cellular events are caused by the SSSR-featured signal transductions we identified that provide cancer cells a driving force for metastasis. To deprive cancer cells of these metastatic forces, we developed novel biologics that prevent the interaction of S100A8/A9 with SSSRs, followed by the efficient suppression of S100A8/A9-mediated lung-tropic metastasis in vivo.

    DOI: 10.1016/j.tranon.2020.100753

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  • 転移がんに有効なS100A8/A9阻害薬の開発(Novel therapeutic approach based on S100A8/A9-mediated organ tropic cancer metastasis)

    木下 理恵, 友信 奈保子, 山内 明, 枝園 和彦, 冨田 秀太, 村田 等, 二見 淳一郎, 近藤 英作, 豊岡 伸一, 阪口 政清

    日本癌学会総会記事   78回   P - 2252   2019年9月

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    記述言語:英語   出版者・発行元:(一社)日本癌学会  

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  • Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11 Through Activation of Surrounding Fibroblasts. 査読 国際誌

    Yosuke Mitsui, Nahoko Tomonobu, Masami Watanabe, Rie Kinoshita, I Wayan Sumardika, Chen Youyi, Hitoshi Murata, Ken-Ichi Yamamoto, Takuya Sadahira, Acosta Gonzalez Herik Rodrigo, Hitoshi Takamatsu, Kota Araki, Akira Yamauchi, Masahiro Yamamura, Hideyo Fujiwara, Yusuke Inoue, Junichiro Futami, Ken Saito, Hidekazu Iioka, Eisaku Kondo, Masahiro Nishibori, Shinichi Toyooka, Yasuhiko Yamamoto, Yasutomo Nasu, Masakiyo Sakaguchi

    Oncology research   27 ( 8 )   945 - 956   2019年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    S100A11, a member of the S100 family of proteins, is actively secreted from pancreatic ductal adenocarcinoma (PDAC) cells. However, the role of the extracellular S100A11 in PDAC progression remains unclear. In the present study, we investigated the extracellular role of S100A11 in crosstalking between PDAC cells and surrounding fibroblasts in PDAC progression. An abundant S100A11 secreted from pancreatic cancer cells stimulated neighboring fibroblasts through receptor for advanced glycation end products (RAGE) upon S100A11 binding and was followed by not only an enhanced cancer cell motility in vitro but also an increased number of the PDAC-derived circulating tumor cells (CTCs) in vivo. Mechanistic investigation of RAGE downstream in fibroblasts revealed a novel contribution of a mitogen-activated protein kinase kinase kinase (MAPKKK), tumor progression locus 2 (TPL2), which is required for positive regulation of PDAC cell motility through induction of cyclooxygenase 2 (COX2) and its catalyzed production of prostaglandin E2 (PGE2), a strong chemoattractive fatty acid. The extracellularly released PGE2 from fibroblasts was required for the rise in cellular migration as well as infiltration of their adjacent PDAC cells in a coculture setting. Taken together, our data reveal a novel role of the secretory S100A11 in PDAC disseminative progression through activation of surrounding fibroblasts triggered by the S100A11-RAGE-TPL2-COX2 pathway. The findings of this study will contribute to the establishment of a novel therapeutic antidote to PDACs that are difficult to treat by regulating cancer-associated fibroblasts (CAFs) through targeting the identified pathway.

    DOI: 10.3727/096504019X15555408784978

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  • Newly developed anti-S100A8/A9 monoclonal antibody efficiently prevents lung tropic cancer metastasis. 査読 国際誌

    Rie Kinoshita, Hiroki Sato, Akira Yamauchi, Yuta Takahashi, Yusuke Inoue, I Wayan Sumardika, Youyi Chen, Nahoko Tomonobu, Kota Araki, Kazuhiko Shien, Shuta Tomida, Hidejiro Torigoe, Kei Namba, Eisuke Kurihara, Yusuke Ogoshi, Hitoshi Murata, Ken-Ichi Yamamoto, Junichiro Futami, Endy Widya Putranto, I Made Winarsa Ruma, Hiromasa Yamamoto, Junichi Soh, Toshihiko Hibino, Masahiro Nishibori, Eisaku Kondo, Shinichi Toyooka, Masakiyo Sakaguchi

    International journal of cancer   145 ( 2 )   569 - 575   2019年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The metastatic dissemination of cancer cells to remote areas of the body is the most problematic aspect in cancer patients. Among cancers, melanomas are notoriously difficult to treat due to their significantly high metastatic potential even during early stages. Hence, the establishment of advanced therapeutic approaches to regulate metastasis is required to overcome the melanoma disease. An accumulating mass of evidence has indicated a critical role of extracellular S100A8/A9 in melanoma distant metastasis. Lung S100A8/A9 is induced by melanoma cells from distant organs and it attracts these cells to its enriched lung environment since melanoma cells possess several receptors that sense the S100A8/A9 ligand. We hence aimed to develop a neutralizing antibody against S100A8/A9 that would efficiently block melanoma lung metastasis. Our protocol provided us with one prominent antibody, Ab45 that efficiently suppressed not only S100A8/A9-mediated melanoma mobility but also lung tropic melanoma metastasis in a mouse model. This prompted us to make chimeric Ab45, a chimera antibody consisting of mouse Ab45-Fab and human IgG2-Fc. Chimeric Ab45 also showed significant inhibition of the lung metastasis of melanoma. From these results, we have high hopes that the newly produced antibody will become a potential biological tool to block melanoma metastasis in future clinical settings.

    DOI: 10.1002/ijc.31982

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  • Critical role of the MCAM-ETV4 axis triggered by extracellular S100A8/A9 in breast cancer aggressiveness. 査読 国際誌

    Youyi Chen, I Wayan Sumardika, Nahoko Tomonobu, Rie Kinoshita, Yusuke Inoue, Hidekazu Iioka, Yosuke Mitsui, Ken Saito, I Made Winarsa Ruma, Hiroki Sato, Akira Yamauchi, Hitoshi Murata, Ken-Ichi Yamamoto, Shuta Tomida, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Junichiro Futami, Miyoko Kubo, Endy Widya Putranto, Takashi Murakami, Ming Liu, Toshihiko Hibino, Masahiro Nishibori, Eisaku Kondo, Shinichi Toyooka, Masakiyo Sakaguchi

    Neoplasia (New York, N.Y.)   21 ( 7 )   627 - 640   2019年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Metastatic breast cancer is the leading cause of cancer-associated death in women. The progression of this fatal disease is associated with inflammatory responses that promote cancer cell growth and dissemination, eventually leading to a reduction of overall survival. However, the mechanism(s) of the inflammation-boosted cancer progression remains unclear. In this study, we found for the first time that an extracellular cytokine, S100A8/A9, accelerates breast cancer growth and metastasis upon binding to a cell surface receptor, melanoma cell adhesion molecule (MCAM). Our molecular analyses revealed an important role of ETS translocation variant 4 (ETV4), which is significantly activated in the region downstream of MCAM upon S100A8/A9 stimulation, in breast cancer progression in vitro as well as in vivo. The MCAM-mediated activation of ETV4 induced a mobile phenotype called epithelial-mesenchymal transition (EMT) in cells, since we found that ETV4 transcriptionally upregulates ZEB1, a strong EMT inducer, at a very high level. In contrast, downregulation of either MCAM or ETV4 repressed EMT, resulting in greatly weakened tumor growth and lung metastasis. Overall, our results revealed that ETV4 is a novel transcription factor regulated by the S100A8/A9-MCAM axis, which leads to EMT through ZEB1 and thereby to metastasis in breast cancer cells. Thus, therapeutic strategies based on our findings might improve patient outcomes.

    DOI: 10.1016/j.neo.2019.04.006

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  • Convenient methodology for extraction and subsequent selective propagation of mouse melanocytes in culture from adult mouse skin tissue. 査読 国際誌

    Nahoko Tomonobu, Rie Kinoshita, I Wayan Sumardika, Youyi Chen, Yusuke Inoue, Akira Yamauchi, Ken-Ichi Yamamoto, Hitoshi Murata, Masakiyo Sakaguchi

    Biochemistry and biophysics reports   18   100619 - 100619   2019年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Mouse melanoma B16-BL6 cells are useful cells for cancer metastatic studies. To understand the metastatic principle at molecular levels, it is necessary to carry out experiments in which cancer cells and their normal counterparts are compared. However, unlike normal human melanocytes, preparation of normal mouse melanocytes is quite difficult due to the lack of marketing and insufficient information on an established protocol for primary culture of mouse melanocytes. In this study, we aimed to establish a convenient method for primary culture of mouse melanocytes on the basis of the protocol for human melanocytes. The main obstacles to preparing pure mouse melanocytes are how to digest mouse skin tissue and how to reduce the contamination of keratinocytes and fibroblasts. The obstacles were overcome by collagenase digestion for skin specimens, short time trypsinization for separating melanocytes and keratinocytes, and use of 12-O-Tetradecanoylphorbol 13-acetate (TPA) and cholera toxin in the culture medium. These supplements act to prevent the proliferation of keratinocytes and fibroblasts, respectively. The convenient procedure enabled us to prepare a pure culture of normal mouse melanocytes. Using enriched normal mouse melanocytes and cancerous B16-BL6 cells, we compared the expression levels of melanoma cell adhesion molecule (MCAM), an important membrane protein for melanoma metastasis, in the cells. The results showed markedly higher expression of MCAM in B16-BL6 cells than in normal mouse melanocytes.

    DOI: 10.1016/j.bbrep.2019.100619

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  • MUSCAT-Assay法での自己抗体モニタリングによる腫瘍免疫応答評価

    二見 淳一郎, 本莊 知子, 吉岡 実咲, 勝河 祐希, Ahmadi Hannaneh, 尾崎 龍之介, 木下 理恵, 鵜殿 平一郎, 垣見 和宏

    日本がん免疫学会総会プログラム・抄録集   23回   141 - 141   2019年7月

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    記述言語:日本語   出版者・発行元:日本がん免疫学会  

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  • Melanoma cell adhesion molecule is the driving force behind the dissemination of melanoma upon S100A8/A9 binding in the original skin lesion. 査読 国際誌

    Youyi Chen, I Wayan Sumardika, Nahoko Tomonobu, I Made Winarsa Ruma, Rie Kinoshita, Eisaku Kondo, Yusuke Inoue, Hiroki Sato, Akira Yamauchi, Hitoshi Murata, Ken-Ichi Yamamoto, Shuta Tomida, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Ming Liu, Junichiro Futami, Kaori Sasai, Hiroshi Katayama, Miyoko Kubo, Endy Widya Putranto, Toshihiko Hibino, Bei Sun, Masahiro Nishibori, Shinichi Toyooka, Masakiyo Sakaguchi

    Cancer letters   452   178 - 190   2019年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Since metastasis accounts for the majority of cancer-associated deaths, studies on the mechanisms of metastasis are needed to establish innovative strategies for cancer treatment. We previously reported that melanoma cell adhesion molecule (MCAM) functions as a critical receptor for S100A8/A9, and binding of S100A8/A9 to MCAM results in the migration of melanoma cells to lung tissue. However, the critical role of MCAM in the original melanoma skin lesion is still not clear. In this study, we aimed to determine the importance of the S100A8/A9-MCAM axis in melanoma dissemination in a skin lesion as a critical early step for metastasis. Mechanistic studies revealed the downstream signaling of MCAM that signaled the induction of metastasis. S100A8/A9-MCAM binding activates mitogen-activated protein kinase kinase kinase 8 (MAP3K8), also termed TPL2, leading to strong activation of the transcription factor ETV4 and subsequent induction of matrix metalloproteinase-25 (MMP25), and finally to induction of melanoma lung tropic metastasis. Collectively, our results demonstrate a crucial role of the S100A8/A9-MCAM signaling axis in metastatic onset of melanoma cells and indicate that strategies targeting the identified pathway may be useful for the establishment of innovative anti-cancer therapies.

    DOI: 10.1016/j.canlet.2019.03.023

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  • Extracellular S100A11 Plays a Critical Role in Spread of the Fibroblast Population in Pancreatic Cancers. 査読 国際誌

    Hitoshi Takamatsu, Ken-Ichi Yamamoto, Nahoko Tomonobu, Hitoshi Murata, Yusuke Inoue, Akira Yamauchi, I Wayan Sumardika, Youyi Chen, Rie Kinoshita, Masahiro Yamamura, Hideyo Fujiwara, Yosuke Mitsui, Kota Araki, Junichiro Futami, Ken Saito, Hidekazu Iioka, I Made Winarsa Ruma, Endy Widya Putranto, Masahiro Nishibori, Eisaku Kondo, Yasuhiko Yamamoto, Shinichi Toyooka, Masakiyo Sakaguchi

    Oncology research   27 ( 6 )   713 - 727   2019年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The fertile stroma in pancreatic ductal adenocarcinomas (PDACs) has been suspected to greatly contribute to PDAC progression. Since the main cell constituents of the stroma are fibroblasts, there is crosstalking(s) between PDAC cells and surrounding fibroblasts in the stroma, which induces a fibroblast proliferation burst. We have reported that several malignant cancer cells including PDAC cells secrete a pronounced level of S100A11, which in turn stimulates proliferation of cancer cells via the receptor for advanced glycation end products (RAGE) in an autocrine manner. Owing to the RAGE+ expression in fibroblasts, the extracellular abundant S100A11 will affect adjacent fibroblasts. In this study, we investigated the significance of the paracrine axis of S100A11-RAGE in fibroblasts for their proliferation activity. In in vitro settings, extracellular S100A11 induced upregulation of fibroblast proliferation. Our mechanistic studies revealed that the induction is through RAGE-MyD88-mTOR-p70 S6 kinase upon S100A11 stimulation. The paracrine effect on fibroblasts is linked mainly to triggering growth but not cellular motility. Thus, the identified pathway might become a potential therapeutic target to suppress PDAC progression through preventing PDAC-associated fibroblast proliferation.

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  • exSSSRs (extracellular S100 soil sensor receptors)-Fc fusion proteins work as prominent decoys to S100A8/A9-induced lung tropic cancer metastasis. 査読 国際誌

    Rie Kinoshita, Hiroki Sato, Akira Yamauchi, Yuta Takahashi, Yusuke Inoue, I Wayan Sumardika, Youyi Chen, Nahoko Tomonobu, Kota Araki, Kazuhiko Shien, Shuta Tomida, Hidejiro Torigoe, Kei Namba, Eisuke Kurihara, Yusuke Ogoshi, Hitoshi Murata, Ken-Ichi Yamamoto, Junichiro Futami, Endy Widya Putranto, I Made Winarsa Ruma, Hiromasa Yamamoto, Junichi Soh, Toshihiko Hibino, Masahiro Nishibori, Eisaku Kondo, Shinichi Toyooka, Masakiyo Sakaguchi

    International journal of cancer   144 ( 12 )   3138 - 3145   2019年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Within the "seed and soil" theory of organ tropic cancer metastasis is a growing compilation of evidence that S100A8/A9 functions as a soil signal that attracts cancer cells to certain organs, which prove beneficial to their growth. S100A8/A9-sensing receptors including Toll-like receptor 4 (TLR4), advanced glycation end products (RAGE), and also important receptors we recently succeeded in identifying (EMMPRIN, NPTNβ, MCAM, and ALCAM) have the potential to become promising therapeutic targets. In our study, we prepared extracellular regions of these novel molecules and fused them to human IgG2-Fc to extend half-life expectancy, and we evaluated the anti-metastatic effects of the purified decoy proteins on metastatic cancer cells. The purified proteins markedly suppressed S100A8/A9-mediated lung tropic cancer metastasis. We hence expect that our novel biologics may become a prominent medicine to prevent cancer metastasis in clinical settings through cutting the linkage between "seed and soil".

    DOI: 10.1002/ijc.31945

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  • Neuroplastin-β mediates S100A8/A9-induced lung cancer disseminative progression. 査読 国際誌

    Sumardika IW, Chen Y, Tomonobu N, Kinoshita R, Ruma IMW, Sato H, Kondo E, Inoue Y, Yamauchi A, Murata H, Yamamoto KI, Tomida S, Shien K, Yamamoto H, Soh J, Futami J, Putranto EW, Hibino T, Nishibori M, Toyooka S, Sakaguchi M

    Molecular carcinogenesis   58 ( 6 )   980 - 995   2019年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/mc.22987

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  • NEUROPLASTIN-β MEDIATES S100A8/A9-INDUCED LUNG CANCER DISSEMINATIVE PROGRESSION 査読

    Sumardika IW, Chen Y, Tomonobu N, Kinoshita R, Ruma IMW, Sato H, Kondo E, Inoue Y, Yamauchi A, Murata H, Yamamoto KI, Tomida S, Shien K, Yamamoto H, Soh J, Futami J, Putranto EW, Hibino T, Nishibori M, Toyooka S, Sakaguchi M

    Molecular Carcinogenesis   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Compiling evidence indicates an unusual role of extracellular S100A8/A9 in cancer metastasis. S100A8/A9 secreted from either cancer cells or normal cells including epithelial and inflammatory cells stimulates cancer cells through S100A8/A9 sensor receptors in an autocrine or paracrine manner, leading to cancer cell metastatic progression. We previously reported a novel S100A8/A9 receptor, neuroplastin-β (NPTNβ), which plays a critical role in atopic dermatitis when it is highly activated in keratinocytes by an excess amount of extracellular S100A8/A9 in the inflammatory skin lesion. Interestingly, our expression profiling of NPTNβ showed significantly high expression levels in lung cancer cell lines in a consistent manner. We hence aimed to determine the significance of NPTNβ as an S100A8/A9 receptor in lung cancer. Our results showed that NPTNβ has strong ability to induce cancer-related cellular events, including anchorage-independent growth, motility and invasiveness, in lung cancer cells in response to extracellular S100A8/A9, eventually leading to the expression of a cancer disseminative phenotype in lung tissue in vivo. Mechanistic investigation revealed that binding of S100A8/A9 to NPTNβ mediates activation of NFIA and NFIB and following SPDEF transcription factors through orchestrated upstream signals from TRAF2 and RAS, which is linked to anchorage-independent growth, motility and invasiveness. Overall, our results indicate the importance of the S100A8/A9-NPTNβ axis in lung cancer disseminative progression and reveal a pivotal role of its newly identified downstream signaling, TRAF2/RAS-NFIA/NFIB-SPDEF, in linking to the aggressive development of lung cancers. This article is protected by copyright.

    DOI: 10.1002/mc.22987

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  • c-Jun N-terminal kinase (JNK)-mediated phosphorylation of SARM1 regulates NAD+ cleavage activity to inhibit mitochondrial respiration. 査読 国際誌

    Hitoshi Murata, Cho Cho Khine, Akane Nishikawa, Ken-Ichi Yamamoto, Rie Kinoshita, Masakiyo Sakaguchi

    The Journal of biological chemistry   293 ( 49 )   18933 - 18943   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Mitochondrial dysfunction is a key pathological feature of many different types of neurodegenerative disease. Sterile alpha and Toll/interleukin receptor motif-containing protein 1 (SARM1) has been attracting much attention as an important molecule for inducing axonal degeneration and neuronal cell death by causing loss of NAD (NADH). However, it has remained unclear what exactly regulates the SARM1 activity. Here, we report that NAD+ cleavage activity of SARM1 is regulated by its own phosphorylation at serine 548. The phosphorylation of SARM1 was mediated by c-jun N-terminal kinase (JNK) under oxidative stress conditions, resulting in inhibition of mitochondrial respiration concomitant with enhanced activity of NAD+ cleavage. Nonphosphorylatable mutation of Ser-548 or treatment with a JNK inhibitor decreased SARM1 activity. Furthermore, neuronal cells derived from a familial Parkinson's disease (PD) patient showed a congenitally increased level of SARM1 phosphorylation compared with that in neuronal cells from a healthy person and were highly sensitive to oxidative stress. These results indicate that JNK-mediated phosphorylation of SARM1 at Ser-548 is a regulator of SARM1 leading to inhibition of mitochondrial respiration. These findings suggest that an abnormal regulation of SARM1 phosphorylation is involved in the pathogenesis of Parkinson's disease and possibly other neurodegenerative diseases.

    DOI: 10.1074/jbc.RA118.004578

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  • Embigin Promotes Prostate Cancer Progression by S100A4-Dependent and-Independent Mechanisms. 査読 国際誌

    I Made Winarsa Ruma, Rie Kinoshita, Nahoko Tomonobu, Yusuke Inoue, Eisaku Kondo, Akira Yamauchi, Hiroki Sato, I Wayan Sumardika, Youyi Chen, Ken-Ichi Yamamoto, Hitoshi Murata, Shinichi Toyooka, Masahiro Nishibori, Masakiyo Sakaguchi

    Cancers   10 ( 7 )   2018年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Embigin, a transmembrane glycoprotein belonging to the immunoglobulin superfamily, is involved in prostate and mammary gland development. As embigin's roles in cancer remain elusive, we studied its biological functions and interaction with extracellular S100A4 in prostate cancer progression. We found by a pull-down assay that embigin is a novel receptor for S100A4, which is one of the vital cancer microenvironment milleu. Binding of extracellular S100A4 to embigin mediates prostate cancer progression by inhibition of AMPK activity, activation of NF-κB, MMP9 and mTORC1 signaling, and inhibition of autophagy, which increase prostate cancer cell motility. We also found that embigin promotes prostate cancer growth, spheroid- and colony-forming ability, and survival upon chemotherapy independently of S100A4. An in vivo growth mouse model confirmed the importance of embigin and its cytoplasmic tail in mediating prostate tumor growth. Moreover, embigin and p21WAF1 can be used to predict survival of prostate cancer patients. Our results demonstrated for the first time that the S100A4-embigin/AMPK/mTORC1/p21WAF1 and NF-κB/MMP9 axis is a vital oncogenic molecular cascade for prostate cancer progression. We proposed that embigin and p21WAF1 could be used as prognostic biomarkers and a strategy to inhibit S100A4-embigin binding could be a therapeutic approach for prostate cancer patients.

    DOI: 10.3390/cancers10070239

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  • 分泌性S100A11-受容体RAGEシグナルに着眼した膵がん間質増大のメカニズムの解明

    山本 健一, 高松 仁, 光井 洋介, 木下 理恵, 村田 等, 二見 淳一郎, 山本 靖彦, 西堀 正洋, 豊岡 伸一, 阪口 政清

    日本がん免疫学会総会プログラム・抄録集   22回   117 - 117   2018年7月

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    記述言語:日本語   出版者・発行元:日本がん免疫学会  

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  • 膵がん進展に導く膵がん細胞 間質線維芽細胞クロストークを介在する分泌性S100A11 受容体RAGE連携の役割

    光井 洋介, 山本 健一, Sumardika I Wayan, 木下 理恵, 村田 等, 二見 淳一郎, 高松 仁, 山本 靖彦, 西堀 正洋, 豊岡 伸一, 渡部 昌実, 那須 保友, 阪口 政清

    日本がん免疫学会総会プログラム・抄録集   22回   156 - 156   2018年7月

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    記述言語:日本語   出版者・発行元:日本がん免疫学会  

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  • β-1,3-Galactosyl-O-Glycosyl-Glycoprotein β-1,6-N-Acetylglucosaminyltransferase 3 Increases MCAM Stability, Which Enhances S100A8/A9-Mediated Cancer Motility. 査読 国際誌

    Sumardika IW, Youyi C, Kondo E, Inoue Y, Ruma IMW, Murata H, Kinoshita R, Yamamoto KI, Tomida S, Shien K, Sato H, Yamauchi A, Futami J, Putranto EW, Hibino T, Toyooka S, Nishibori M, Sakaguchi M

    Oncology research   26 ( 3 )   431 - 444   2018年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.3727/096504017X15031557924123

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  • Development of novel biologics for cancer metastasis via prevention of extracellular S100A8/A9 function 査読

    Kinoshita Rie, Yamauchi Akira, Shien Kazuhiko, Tomida Shuta, Toyooka Shinichi, Kondo Eisaku, Sakaguchi Masakiyo

    CANCER SCIENCE   109   1017   2018年1月

  • PINK1 Regulation of Mitochondrial Homeostasis and Cell Survival. 査読

    Murata Hitoshi, Yamamoto Ken-ichi, Kinoshita Rie, Kataoka Ken, Huh Nam-ho, Sakaguchi Masakiyo

    IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL   52   S8   2016年6月

  • Sensitive Multiplexed Quantitative Analysis of Autoantibodies to Cancer Antigens with Chemically S-Cationized Full-Length and Water-Soluble Denatured Proteins. 査読

    Futami J, Nonomura H, Kido M, Niidoi N, Fujieda N, Hosoi A, Fujita K, Mandai K, Atago Y, Kinoshita R, Honjo T, Matsushita H, Uenaka A, Nakayama E, Kakimi K

    Bioconjugate chemistry   26 ( 10 )   2076 - 2084   2015年10月

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  • Inhibiting S100A8/A9 Attenuates Airway Obstruction in a Mouse Heterotopic Tracheal Transplantation Model

    D. Shimizu, M. Okazaki, S. Sugimoto, R. Kinoshita, S. Kawana, Y. Kubo, K. Matsubara, K. Nakata, A. Matsukawa, M. Sakaguchi, S. Toyooka

    The Journal of Heart and Lung Transplantation   41 ( 4 )   2022年4月

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    記述言語:英語   出版者・発行元:Elsevier {BV}  

    DOI: 10.1016/j.healun.2022.01.191

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  • NOX4 on lymphatic endothelial cells (LEC) plays an important role on the migration of pancreatic cancer cells.

    Akira Yamauchi, Masahiro Yamamura, Naoki Katase, Nahoko Tomonobu, Rie Kinoshita, Masakiyo Sakaguchi, Shuichiro Okamoto

    CANCER SCIENCE   112   347 - 347   2021年2月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:WILEY  

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  • リンパ内皮細胞上のNOX4は癌細胞のリンパ系への遊走に重要な役割を果たす

    山内明, 山村真弘, 片瀬直樹, 友信奈保子, 木下理恵, 阪口政清, 岡本秀一郎

    日本癌学会学術総会抄録集(Web)   79th   2020年

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  • 細胞外S100A11によりがん間質線維芽細胞が加速する膵がん進展のメカニズムの解明

    合原勇馬, 光井洋介, 友信奈保子, 木下理恵, 山内明, 山村真弘, 近藤英作, 豊岡伸一, 豊岡伸一, 那須保友, 阪口政清

    日本癌学会学術総会抄録集(Web)   79th   2020年

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  • 分泌性S100A11は膵臓癌の細胞運動性を高める腫瘍周囲の線維芽細胞を活性化する

    合原勇馬, 光井洋介, 友信奈保子, 木下理恵, 山本健一, 山内明, 山村真弘, 近藤英作, 豊岡伸一, 那須保友, 村田等, 阪口政清

    日本分子生物学会年会プログラム・要旨集(Web)   43rd   2020年

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  • メラノーマ原発巣における転移機構に関わるMCAM-S100A8/A9シグナル経路の分子学的解析

    友信奈保子, 木下理恵, 近藤英作, 山内明, 二見淳一郎, 豊岡伸一, 阪口政清

    日本癌学会学術総会抄録集(Web)   78th   2019年

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  • 膵がん進展に導く膵がん細胞 間質線維芽細胞クロストークを介在する分泌性S100A11 受容体RAGE連携の役割

    光井 洋介, 山本 健一, Sumardika I Wayan, 木下 理恵, 村田 等, 二見 淳一郎, 高松 仁, 山本 靖彦, 西堀 正洋, 豊岡 伸一, 渡部 昌実, 那須 保友, 阪口 政清

    日本がん免疫学会総会プログラム・抄録集   22回   156 - 156   2018年7月

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    記述言語:日本語   出版者・発行元:日本がん免疫学会  

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  • 分泌性S100A11-受容体RAGEシグナルに着眼した膵がん間質増大のメカニズムの解明

    山本 健一, 高松 仁, 光井 洋介, 木下 理恵, 村田 等, 二見 淳一郎, 山本 靖彦, 西堀 正洋, 豊岡 伸一, 阪口 政清

    日本がん免疫学会総会プログラム・抄録集   22回   117 - 117   2018年7月

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    記述言語:日本語   出版者・発行元:日本がん免疫学会  

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  • 抗がん抗原抗体で腫瘍免疫応答をモニタリングするMUSCAT-Assay

    二見 淳一郎, 本莊 知子, 吉岡 実咲, 勝河 祐希, Hannaneh Ahmadi, 木下 理恵, 藤枝 奈緒, 垣見 和宏

    日本がん免疫学会総会プログラム・抄録集   22回   122 - 122   2018年7月

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    記述言語:日本語   出版者・発行元:日本がん免疫学会  

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  • Signal Diversity of Receptor for Advanced Glycation End Products.

    Masakiyo Sakaguchi, Rie Kinoshita, Endy Widya Putranto, I Made Winarsa Ruma, I Wayan Sumardika, Chen Youyi, Naoko Tomonobu, Ken-Ichi Yamamoto, Hitoshi Murata

    Acta medica Okayama   71 ( 6 )   459 - 465   2017年12月

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    記述言語:英語   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    The receptor for advanced glycation end products (RAGE) is involved in inflammatory pathogenesis. It functions as a receptor to multiple ligands such as AGEs, HMGB1 and S100 proteins, activating multiple intracellular signaling pathways with each ligand binding. The molecular events by which ligand-activated RAGE controls diverse signaling are not well understood, but some progress was made recently. Accumulating evidence revealed that RAGE has multiple binding partners within the cytoplasm and on the plasma membrane. It was first pointed out in 2008 that RAGE's cytoplasmic tail is able to recruit Diaphanous-1 (Dia-1), resulting in the acquisition of increased cellular motility through Rac1/Cdc42 activation. We also observed that within the cytosol, RAGE's cytoplasmic tail behaves similarly to a Toll-like receptor (TLR4)-TIR domain, interacting with TIRAP and MyD88 adaptor molecules that in turn activate multiple downstream signals. Subsequent studies demonstrated the presence of an alternative adaptor molecule, DAP10, on the plasma membrane. The coupling of RAGE with DAP10 is critical for enhancing the RAGE-mediated survival signal. Interestingly, RAGE interaction on the membrane was not restricted to DAP10 alone. The chemotactic G-protein-coupled receptors (GPCRs) formyl peptide receptors1 and 2 (FPR1 and FPR2) also interacted with RAGE on the plasma membrane. Binding interaction between leukotriene B4 receptor 1 (BLT1) and RAGE was also demonstrated. All of the interactions affected the RAGE signal polarity. These findings indicate that functional interactions between RAGE and various molecules within the cytoplasmic area or on the membrane area coordinately regulate multiple ligand-mediated RAGE responses, leading to typical cellular phenotypes in several pathological settings. Here we review RAGE's signaling diversity, to contribute to the understanding of the elaborate functions of RAGE in physiological and pathological contexts.

    DOI: 10.18926/AMO/55582

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  • Exogenous DKK-3/REIC inhibits Wnt/β-catenin signaling and cell proliferation in human kidney cancer KPK1 国際誌

    Jiaqi Xu, Takuya Sadahira, Rie Kinoshita, Shun Ai Li, Peng Huang, Koichiro Wada, Motoo Araki, Kazuhiko Ochiai, Hirofumi Noguchi, Masakiyo Sakaguchi, Yasutomo Nasu, Masami Watanabe

    Oncology Letters   14 ( 5 )   5638 - 5642   2017年11月

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  • Robust cancer-specific gene expression by a novel cassette with hTERT and CMV promoter elements

    Masakiyo Sakaguchi, Takuya Sadahira, Hideo Ueki, Rie Kinoshita, Hitoshi Murata, Ken-Ichi Yamamoto, Junichiro Futami, Yasutomo Nasu, Kazuhiko Ochiai, Hiromi Kumon, Nam-Ho Huh, Masami Watanabe

    ONCOLOGY REPORTS   38 ( 2 )   1108 - 1114   2017年8月

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    記述言語:英語   出版者・発行元:SPANDIDOS PUBL LTD  

    We developed and validated a novel hTERT/CMV promoter element-driven gene expression cassette that can robustly enhance cancer-specific gene expression. The following gene expressional elements were located in tandem within the plasmid construct: [hTERT core promoter, cytomegalovirus (CMV) minimized promoter, RU5' sequence, an inserted gene, BGH polyA, hTERT enhancer]; this is hereafter referred to as the hT/Cm-R-hT construct. Using various human cancer cell lines and normal cells, the cancer-specific transcription of the green fluorescent protein (GFP) gene was examined by western blotting and fluorescence microscopy. Cancer-specific gene expression was robustly achieved in the hT/Cm-R-hT plasmid in comparison to the other control hT/Cm-driven construct. Notably, the expression level of GFP observed in the hT/Cm-RhT-driven construct was superior to that of the control plasmid with the conventional CMV promoter in HEK293 cells, which are known to possess higher hTERT activity than normal cells. We next examined the availability of hT/Cm-R-hT in detecting the target GFP expressing cancer cells from human peripheral blood mononuclear cells (PBMCs). The hT/Cm-R-hT plasmid successfully induced cancer-specific gene expression; the robust expression of GFP was observed in target HeLa cancer cells, whereas GFP was not visibly expressed in normal PBMCs. The plasmid allowed for the selective visualization of viable HeLa cancer cells in mixed cell cultures containing up to 10000-fold more PBMCs. These findings indicate that the hT/Cm-R-hT expressional system is a valuable tool for detecting viable cancer cells mixed with normal cells. The current system can therefore be applied to the in vitro detection of cancer cells that are disseminated in the blood and other types of body fluid in vivo. Since the current system can also be applied to other types of vectors, including virus vectors, this approach using the hTERT promoter-based construct is expected to become a valuable tool for enhancing cancer specific gene expression.

    DOI: 10.3892/or.2017.5710

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  • Expression of tumor suppressor REIC/Dkk-3 by a newly improved adenovirus vector with insertion of a hTERT promoter at the 3'-side of the transgene

    Endy Widya Putranto, Rie Kinoshita, Masami Watanabe, Takuya Sadahira, Hitoshi Murata, Ken-Ichi Yamamoto, Junichiro Futami, Ken Kataoka, Yusuke Inoue, I. Made Winarsa Ruma, I. Wayan Sumardika, Chen Youyi, Miyoko Kubo, Yoshihiko Sakaguchi, Kenji Saito, Yasutomo Nasu, Hiromi Kumon, Nam-Ho Huh, Masakiyo Sakaguchi

    ONCOLOGY LETTERS   14 ( 1 )   1041 - 1048   2017年7月

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    記述言語:英語   出版者・発行元:SPANDIDOS PUBL LTD  

    Reduced expression in immortalized cells (REIC)/Dickkopf-3 (Dkk-3) overexpression, induced using an adenovirus (Ad)-REIC, has been revealed to have a dramatic therapeutic effect on multiple types of cancer. To achieve an improved therapeutic effect from Ad-REIC on cancer, our group previously developed an enhanced gene expression system, the C-TSC cassette [cytomegalovirus (CMV)-RU5' located upstream (C); another promoter unit composed of triple tandem promoters, human telomerase reverse transcriptase (hTERT), simian virus 40 and CMV, located downstream of the cDNA (TSC); plus a polyadenylation (polyA) signal]. When applied to the conventional Ad-REIC, this novel system induced the development of an enhanced product, Ad-C-TSC-REIC, which exhibited a noticeable anticancer effect. However, there were difficulties in terms of Ad-C-TSC-REIC productivity in HEK293 cells, which are a widely used donor cell line for viral production. Productivity of Ad-C-TSC-REIC was significantly reduced compared with the conventional Ad-REIC, as the Ad-C-TSC-REIC had a significantly higher ability to induce apoptotic cell death of not only various types of cancer cell, but also HEK293 cells. The present study aimed to overcome this problem by modifying the C-TSC structure, resulting in an improved candidate: A C-T cassette (C: CMV-RU5' located upstream; T: another promoter unit composed of a single hTERT promoter, located downstream of the cDNA plus a polyA signal), which demonstrated gene expression comparable to that of the C-TSC system. The improved adenovirus REIC/Dkk-3 product with the C-T cassette, named Ad-C-T-REIC, exhibited a higher expression level of REIC/Dkk3, similar to that of Ad-C-TSC-REIC. Notably, the vector mitigated the cell death of donor HEK293 cells, resulting in a higher rate of production of its adenovirus. These results indicated that Ad-C-T-REIC has the potential to be a useful tool for application in cancer gene therapy.

    DOI: 10.3892/ol.2017.6201

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  • Topics from special edition 転移先臓器を感知する受容体群の分子制御機構の解明とその応用

    阪口 政清, 木下 理恵, 村田 等, 山本 健一, 許 南浩, 日比野 利彦

    細胞   49 ( 7 )   359 - 362   2017年6月

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    記述言語:日本語   出版者・発行元:ニューサイエンス社  

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    その他リンク: http://search.jamas.or.jp/link/ui/2017264472

  • Topics from special edition 転移先臓器を感知する受容体群

    阪口 政清, 木下 理恵, 村田 等, 山本 健一, 許 南浩, 日比野 利彦

    細胞   49 ( 3 )   143 - 146   2017年3月

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    記述言語:日本語   出版者・発行元:ニューサイエンス社  

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    その他リンク: http://search.jamas.or.jp/link/ui/2017181594

  • ß-1,3-galactosyl-O-glycosyl-glycoprotein ß-1,6-N-acetylglucosaminyltransferase 3 Increases MCAM Stability, Which Enhances S100A8/A9-Mediated Cancer Motility.

    Sumardika IW, Youyi C, Kondo E, Inoue Y, Ruma IMW, Murata H, Kinoshita R, Yamamoto KI, Tomida S, Shien K, Satoh H, Yamauchi A, Futami J, Putranto EW, Hibino T, Toyooka S, Nishibori M, Sakaguchi M

    Oncol Res   2017年

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  • Neuroplastinβとextracellular matrix metalloprotease inducerはS100A8/A9に対する機能的な受容体であり,ケラチノサイトの増殖とアトピーの皮膚炎症の増強に関与している. Critical role of novel receptors to S100A8/A9, EMMPRIN and NPTNβ, on keratinocyte growth and inflammation in atopic dermatitis.

    阪口政清, 山本真実, 宮井雅史, 松元 有羽子, 木下理恵, 村田 等, 山本健一, 森実 真, 岩月啓氏, 許 南浩, 坪井良治, 日比野 利彦

    臨床免疫   49 ( 6 )   594 - 598   2017年

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    記述言語:日本語   出版者・発行元:科学評論社  

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  • 転移先臓器を感知する受容体群の分子制御機構の解明とその応用. Advanced approach to prevent cancer metastasis based on S100A8/A9-mediated seed and soil theory Innovative approach to prevent cancer metastasis based on S100A8/A9-mediated seed and soil theory.

    阪口政清, 木下理恵, 村田 等, 山本健一, 許 南浩, 日比野 利彦

    月刊「細胞」6月号   49 ( 7 )   43 - 46   2017年

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  • 転移先臓器を感知する受容体群Innovative approach to prevent cancer metastasis based on S100A8/A9-mediated seed and soil theory.

    阪口政清, 木下理恵, 村田 等, 山本健一, 許 南浩, 日比野 利彦

    月刊「細胞」3月号   49 ( 3 )   39 - 42   2017年

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  • 【アトピー性皮膚炎の病態研究】 Neuroplastin βとextracellular matrix metallo-protease inducerはS100A8/A9に対する機能的な受容体であり、ケラチノサイトの増殖とアトピーの皮膚炎症の増強に関与している

    阪口 政清, 山本, 真実, 宮井 雅史, 木下 理恵, 村田 等, 山本 健一, 森実 真, 岩月 啓氏, 許 南浩, 坪井 良治, 日比野 利彦

    臨床免疫・アレルギー科   67 ( 6 )   594 - 598   2017年

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    記述言語:日本語   出版者・発行元:科学評論社  

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    その他リンク: http://search.jamas.or.jp/link/ui/2017265401

  • Active Secretion of Dimerized S100A11 Induced by the Peroxisome in Mesothelioma Cells. 国際誌

    Satomi Saho, Hiroki Satoh, Eisaku Kondo, Yusuke Inoue, Akira Yamauchi, Hitoshi Murata, Rie Kinoshita, Ken-Ichi Yamamoto, Junichiro Futami, Endy Widya Putranto, I Made Winarsa Ruma, I Wayan Sumardika, Chen Youyi, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh, Shuta Tomida, Yoshihiko Sakaguchi, Ken Saito, Hidekazu Iioka, Nam-Ho Huh, Shinichi Toyooka, Masakiyo Sakaguchi

    Cancer microenvironment : official journal of the International Cancer Microenvironment Society   9 ( 2-3 )   93 - 105   2016年12月

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    記述言語:英語  

    S100A11, a small Ca2+ binding protein, acts extracellularly as a mediator of cancer progression. That raises the question of how a protein that lacks the classical secretory signal is able to be secreted outside cells without being damaged. Some insights into this question have been obtained, and there has been accumulating evidence indicating a pivotal role of a non-classical vesicle-mediated pathway using lysosomes or peroxisomes for the protein secretion. To obtain a more precise insight into the secretory mechanism of S100A11, we first screened representative cancer cells exhibiting significantly active secretion of S100A11. From the results of profiling, we turned our attention to aggressive cancer mesothelioma cells. In mesothelioma cells, we found that abundant dimeric S100A11 was produced selectively in the peroxisome after transportation of monomeric S100A11 through an interaction with PEX14, a peroxisome membrane protein, resulting in peroxisomal secretion of dimerized S100A11. In an extracellular environment in vitro, dimerized S100A11 promoted mesothelial cell invasion indirectly with the help of fibroblast cells. Overall, the results indicate that the peroxisome functions as an essential vesicle for the production of dimerized S100A11 and the subsequent secretion of the protein from mesothelioma cells and that peroxisome-mediated secretion of dimerized S100A11 might play a critical role in mesothelioma progression in a tumor microenvironment.

    DOI: 10.1007/s12307-016-0185-2

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  • Identification of an S100A8 Receptor Neuroplastin-β and its Heterodimer Formation with EMMPRIN

    Masakiyo Sakaguchi, Mami Yamamoto, Masashi Miyai, Tatsuo Maeda, Junichiro Hiruma, Hitoshi Murata, Rie Kinoshita, I. Made, Winarsa Ruma, ndy Widya Putranto, Yusuke Inoue, Shin Morizane, Nam Ho Huh, Ryoji Tsuboi, Toshihiko Hibino

    Journal of Investigative Dermatology, Advances in biology of skin   136 ( 11 )   2240 - 2250   2016年11月

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  • MCAM, as a novel receptor for S100A8/A9, mediates progression of malignant melanoma through prominent activation of NF-κB and ROS formation upon ligand binding

    I. Made, Winarsa Ruma, ndy Widya Putranto, Eisaku Kondo, Hitoshi Murata, Masami Watanabe, Peng Huang, Rie Kinoshita, Junichiro Futami, Yusuke Inoue, Akira Yamauchi, I. Wayan, Sumardika,Chen Youyi, Ken Ichi Yamamoto, Yasutomo Nasu, Masahiro Nishibori, Toshihiko H

    Clinical and Experimental Metastasis   33 ( 6 )   609 - 627   2016年8月

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  • An efficient method for the preparation of preferentially heterodimerized recombinant S100A8/A9 coexpressed in Escherichia coli

    Junichiro Futami, Yuki Atago, Akari Azuma, Endy Widya Putranto, Rie Kinoshita, Hitoshi Murata, Masakiyo Sakaguchi

    Biochemistry and Biophysics Reports   6   94 - 100   2016年7月

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    記述言語:英語   出版者・発行元:Elsevier B.V.  

    It is now known that multicomponent protein assemblies strictly regulate many protein functions. The S100 protein family is known to play various physiological roles, which are associated with alternative complex formations. To prepare sufficient amounts of heterodimeric S100A8 and S100A9 proteins, we developed a method for bicistronic coexpression from a single-vector system using Escherichia coli cells as a host. The complex formation between S100A8 and S100A9 appears to be dependent on the thermodynamic stability of the protein during expression. The stable S100A8/A9 heterodimer complex spontaneously formed during coexpression, and biologically active samples were purified by cation-exchange chromatography. Semi-stable homodimers of S100A8 and S100A9 were also formed when expressed individually. These results suggest that the assembly of S100 protein complexes might be regulated by expression levels of partner proteins in vivo. Because protein assembly occurs rapidly after protein synthesis, coexpression of relevant proteins is crucial for the design of multicomponent recombinant protein expression systems.

    DOI: 10.1016/j.bbrep.2016.03.009

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  • S-カチオン化全長・水溶性抗原を用いた高感度抗体技術による腫瘍免疫応答の定量評価

    二見 淳一郎, 野々村 英典, 木戸 桃子, 新土居 奈緒美, 藤枝 奈緒, 細井 亮宏, 藤田 佳那, 万袋 木麻子, 愛宕 祐基, 木下 理恵, 本荘 知子, 松下 博一, 上中 明子, 中山 睿一, 垣見 和宏

    日本生物工学会大会講演要旨集   平成27年度   191 - 191   2015年9月

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    記述言語:日本語   出版者・発行元:(公社)日本生物工学会  

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    その他リンク: http://search.jamas.or.jp/link/ui/2016231959

  • The cysteine-rich core domain of REIC/Dkk-3 is critical for its effect on monocyte differentiation and tumor regression

    Rie Kinoshita, Masami Watanabe, Peng Huang, Shun-Ai Li, Masakiyo Sakaguchi, Hiromi Kumon, Junichiro Futami

    ONCOLOGY REPORTS   33 ( 6 )   2908 - 2914   2015年6月

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    記述言語:英語   出版者・発行元:SPANDIDOS PUBL LTD  

    Reduced expression in immortalized cells (REIC)/Dickkopf (Dkk)-3 is a tumor-suppressor gene and has been studied as a promising therapeutic gene for cancer gene therapy. Intratumoral injection of an adenovirus vector carrying the human REIC/Dkk-3 gene (Ad-REIC) elicits cancer cell-specific apoptosis and anticancer immune responses. The cytokine-like effect of secretory REIC/Dkk-3 on the induction of dendritic cell (DC)-like cell differentiation from monocytes plays a role in systemic anticancer immunity. In the present study, we generated recombinant full-length and N-terminally truncated REIC/Dkk-3 to characterize the biological activity of the protein. During the purification procedure, we identified a 17 kDa cysteine-rich stable product (C17-REIC) showing limited degradation. Further analysis showed that the C17-REIC domain was sufficient for the induction of DC-like cell differentiation from monocytes. Concomitant with the differentiation of DCs, the REIC/Dkk-3 protein induced the phosphorylation of glycogen synthase kinase 3 beta (GSK-3 beta) and signal transducers and activators of transcription (STAT) at a level comparable to that of granulocyte/macrophage colony-stimulating factor. In a mouse model of subcutaneous renal adenocarcinoma, intraperitoneal injection of full-length and C17-REIC proteins exerted anticancer effects in parallel with the activation of immunocompetent cells such as DCs and cytotoxic T lymphocytes in peripheral blood. Taken together, our results indicate that the stable cysteine-rich core region of REIC/Dkk-3 is responsible for the induction of anticancer immune responses. Because REIC/Dkk-3 is a naturally circulating serum protein, the upregulation REIC/Dkk-3 protein expression could be a promising option for cancer therapy.

    DOI: 10.3892/or.2015.3885

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  • The cysteine-rich core domain of REIC/Dkk-3 is critical for its effect on monocyte differentiation and tumor regression

    Rie Kinoshita, Masami Watanabe, Peng Huang, Shun-Ai Li, Masakiyo Sakaguchi, Hiromi Kumon, Junichiro Futami

    ONCOLOGY REPORTS   33 ( 6 )   2908 - 2914   2015年6月

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    記述言語:英語   出版者・発行元:SPANDIDOS PUBL LTD  

    Reduced expression in immortalized cells (REIC)/Dickkopf (Dkk)-3 is a tumor-suppressor gene and has been studied as a promising therapeutic gene for cancer gene therapy. Intratumoral injection of an adenovirus vector carrying the human REIC/Dkk-3 gene (Ad-REIC) elicits cancer cell-specific apoptosis and anticancer immune responses. The cytokine-like effect of secretory REIC/Dkk-3 on the induction of dendritic cell (DC)-like cell differentiation from monocytes plays a role in systemic anticancer immunity. In the present study, we generated recombinant full-length and N-terminally truncated REIC/Dkk-3 to characterize the biological activity of the protein. During the purification procedure, we identified a 17 kDa cysteine-rich stable product (C17-REIC) showing limited degradation. Further analysis showed that the C17-REIC domain was sufficient for the induction of DC-like cell differentiation from monocytes. Concomitant with the differentiation of DCs, the REIC/Dkk-3 protein induced the phosphorylation of glycogen synthase kinase 3 beta (GSK-3 beta) and signal transducers and activators of transcription (STAT) at a level comparable to that of granulocyte/macrophage colony-stimulating factor. In a mouse model of subcutaneous renal adenocarcinoma, intraperitoneal injection of full-length and C17-REIC proteins exerted anticancer effects in parallel with the activation of immunocompetent cells such as DCs and cytotoxic T lymphocytes in peripheral blood. Taken together, our results indicate that the stable cysteine-rich core region of REIC/Dkk-3 is responsible for the induction of anticancer immune responses. Because REIC/Dkk-3 is a naturally circulating serum protein, the upregulation REIC/Dkk-3 protein expression could be a promising option for cancer therapy.

    DOI: 10.3892/or.2015.3885

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  • A vaccine strategy with multiple prostatic acid phosphatase-fused cytokines for prostate cancer treatment

    Kei Fujio, Masami Watanabe, Hideo Ueki, Shun-Ai Li, Rie Kinoshita, Kazuhiko Ochiai, Junichiro Futami, Toyohiko Watanabe, Yasutomo Nasu, Hiromi Kumon

    ONCOLOGY REPORTS   33 ( 4 )   1585 - 1592   2015年4月

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    記述言語:英語   出版者・発行元:SPANDIDOS PUBL LTD  

    Immunotherapy is one of the attractive treatment strategies for advanced prostate cancer. The US Food and Drug Administration (FDA) previously approved the therapeutic vaccine, sipuleucel-T, which is composed of autologous antigen-presenting cells cultured with a fusion protein [prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GMCSF)]. Although sipuleucel-T has been shown to prolong the median survival of patients for 4.1 months, more robust therapeutic effects may be expected by modifying the vaccination protocol. In the present study, we aimed to develop and validate a novel vaccination strategy using multiple PAP-fused cytokines for prostate cancer treatment. Using a super gene expression (SGE) system that we previously established to amplify the production of a recombinant protein, significant amounts of PAP-fused cytokines [human GMCSF, interleukin-2 (IL2), IL4, IL7 and mouse GMCSF and IL4] were obtained. We examined the activity of the fusion proteins in vitro to validate their cytokine functions. A significant upregulation of dendritic cell differentiation from monocytes was achieved by PAP-GMCSF when used with the other PAP-fused cytokines. The PAP-fused human IL2 significantly increased the proliferation of lymphocytes, as determined by flow cytometry. We also investigated the in vivo therapeutic effects of multiple PAP-fused cytokines in a mouse prostate cancer model bearing prostate-specific antigen (PSA)- and PAP-expressing tumors. The simultaneous intraperitoneal administration of PAP-GMCSF, -IL2, -IL4 and -IL7 significantly prevented tumor induction and inhibited the tumor growth in the PAP-expressing tumors, yet not in the PSA-expressing tumors. The in vivo therapeutic effects with the multiple PAP-fused cytokines were superior to the effects of PAP-GMCSF alone. We thus demonstrated the advantages of the combined use of multiple PAP-fused cytokines including PAP-GMCSF, and propose a promising prostatic antigen-vaccination strategy to enhance the therapeutic effects.

    DOI: 10.3892/or.2015.3770

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  • A vaccine strategy with multiple prostatic acid phosphatase-fused cytokines for prostate cancer treatment

    Kei Fujio, Masami Watanabe, Hideo Ueki, Shun-Ai Li, Rie Kinoshita, Kazuhiko Ochiai, Junichiro Futami, Toyohiko Watanabe, Yasutomo Nasu, Hiromi Kumon

    ONCOLOGY REPORTS   33 ( 4 )   1585 - 1592   2015年4月

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    記述言語:英語   出版者・発行元:SPANDIDOS PUBL LTD  

    Immunotherapy is one of the attractive treatment strategies for advanced prostate cancer. The US Food and Drug Administration (FDA) previously approved the therapeutic vaccine, sipuleucel-T, which is composed of autologous antigen-presenting cells cultured with a fusion protein [prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GMCSF)]. Although sipuleucel-T has been shown to prolong the median survival of patients for 4.1 months, more robust therapeutic effects may be expected by modifying the vaccination protocol. In the present study, we aimed to develop and validate a novel vaccination strategy using multiple PAP-fused cytokines for prostate cancer treatment. Using a super gene expression (SGE) system that we previously established to amplify the production of a recombinant protein, significant amounts of PAP-fused cytokines [human GMCSF, interleukin-2 (IL2), IL4, IL7 and mouse GMCSF and IL4] were obtained. We examined the activity of the fusion proteins in vitro to validate their cytokine functions. A significant upregulation of dendritic cell differentiation from monocytes was achieved by PAP-GMCSF when used with the other PAP-fused cytokines. The PAP-fused human IL2 significantly increased the proliferation of lymphocytes, as determined by flow cytometry. We also investigated the in vivo therapeutic effects of multiple PAP-fused cytokines in a mouse prostate cancer model bearing prostate-specific antigen (PSA)- and PAP-expressing tumors. The simultaneous intraperitoneal administration of PAP-GMCSF, -IL2, -IL4 and -IL7 significantly prevented tumor induction and inhibited the tumor growth in the PAP-expressing tumors, yet not in the PSA-expressing tumors. The in vivo therapeutic effects with the multiple PAP-fused cytokines were superior to the effects of PAP-GMCSF alone. We thus demonstrated the advantages of the combined use of multiple PAP-fused cytokines including PAP-GMCSF, and propose a promising prostatic antigen-vaccination strategy to enhance the therapeutic effects.

    DOI: 10.3892/or.2015.3770

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  • Denatured Mammalian Protein Mixtures Exhibit Unusually High Solubility in Nucleic Acid-Free Pure Water

    Junichiro Futami, Haruna Fujiyama, Rie Kinoshita, Hidenori Nonomura, Tomoko Honjo, Hiroko Tada, Hirokazu Matsushita, Yoshito Abe, Kazuhiro Kakimi

    PLOS ONE   9 ( 11 )   e113295-e113295   2014年11月

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    記述言語:英語   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Preventing protein aggregation is a major goal of biotechnology. Since protein aggregates are mainly comprised of unfolded proteins, protecting against denaturation is likely to assist solubility in an aqueous medium. Contrary to this concept, we found denatured total cellular protein mixture from mammalian cell kept high solubility in pure water when the mixture was nucleic acids free. The lysates were prepared from total cellular protein pellet extracted by using guanidinium thiocyanate-phenol-chloroform mixture of TRIzol, denatured and reduced total protein mixtures remained soluble after extensive dialysis against pure water. The total cell protein lysates contained fully disordered proteins that readily formed large aggregates upon contact with nucleic acids or salts. These findings suggested that the highly flexible mixtures of disordered proteins, which have fully ionized side chains, are protected against aggregation. Interestingly, this unusual solubility is characteristic of protein mixtures from higher eukaryotes, whereas most prokaryotic protein mixtures were aggregated under identical conditions. This unusual solubility of unfolded protein mixtures could have implications for the study of intrinsically disordered proteins in a variety of cells.

    DOI: 10.1371/journal.pone.0113295

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  • Denatured Mammalian Protein Mixtures Exhibit Unusually High Solubility in Nucleic Acid-Free Pure Water

    Junichiro Futami, Haruna Fujiyama, Rie Kinoshita, Hidenori Nonomura, Tomoko Honjo, Hiroko Tada, Hirokazu Matsushita, Yoshito Abe, Kazuhiro Kakimi

    PLOS ONE   9 ( 11 )   e113295-e113295   2014年11月

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    記述言語:英語   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Preventing protein aggregation is a major goal of biotechnology. Since protein aggregates are mainly comprised of unfolded proteins, protecting against denaturation is likely to assist solubility in an aqueous medium. Contrary to this concept, we found denatured total cellular protein mixture from mammalian cell kept high solubility in pure water when the mixture was nucleic acids free. The lysates were prepared from total cellular protein pellet extracted by using guanidinium thiocyanate-phenol-chloroform mixture of TRIzol, denatured and reduced total protein mixtures remained soluble after extensive dialysis against pure water. The total cell protein lysates contained fully disordered proteins that readily formed large aggregates upon contact with nucleic acids or salts. These findings suggested that the highly flexible mixtures of disordered proteins, which have fully ionized side chains, are protected against aggregation. Interestingly, this unusual solubility is characteristic of protein mixtures from higher eukaryotes, whereas most prokaryotic protein mixtures were aggregated under identical conditions. This unusual solubility of unfolded protein mixtures could have implications for the study of intrinsically disordered proteins in a variety of cells.

    DOI: 10.1371/journal.pone.0113295

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  • DNAX-activating Protein 10 (DAP10) Membrane Adaptor Associates with Receptor for Advanced Glycation End Products (RAGE) and Modulates the RAGE-triggered Signaling Pathway in Human Keratinocytes

    Masakiyo Sakaguchi, Hitoshi Murata, Yumi Aoyama, Toshihiko Hibino, Endy Widya Putranto, I. Made Winarsa Ruma, Yusuke Inoue, Yoshihiko Sakaguchi, Ken-ichi Yamamoto, Rie Kinoshita, Junichiro Futami, Ken Kataoka, Keiji Iwatsuki, Nam-ho Huh

    JOURNAL OF BIOLOGICAL CHEMISTRY   289 ( 34 )   23389 - 23402   2014年8月

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    記述言語:英語   出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    Background: RAGE receptor plays a critical role in many inflammatory disorders. Results: Functional interaction between RAGE and DAP10 coordinately regulates S100A8/A9-mediated cell survival. Conclusion: DAP10 membrane adaptor is critically involved in RAGE-mediated survival signaling upon S100A8/A9 binding. Significance: This is the first report demonstrating that RAGE-mediated survival signaling is critically regulated by DAP10 interaction.
    The receptor for advanced glycation end products (RAGE) is involved in the pathogenesis of many inflammatory, degenerative, and hyperproliferative diseases, including cancer. Previously, we revealed mechanisms of downstream signaling from ligand-activated RAGE, which recruits TIRAP/MyD88. Here, we showed that DNAX-activating protein 10 (DAP10), a transmembrane adaptor protein, also binds to RAGE. By artificial oligomerization of RAGE alone or RAGE-DAP10, we found that RAGE-DAP10 heterodimer formation resulted in a marked enhancement of Akt activation, whereas homomultimeric interaction of RAGE led to activation of caspase 8. Normal human epidermal keratinocytes exposed to S100A8/A9, a ligand for RAGE, at a nanomolar concentration mimicked the pro-survival response of RAGE-DAP10 interaction, although at a micromolar concentration, the cells mimicked the pro-apoptotic response of RAGE-RAGE. In transformed epithelial cell lines, A431 and HaCaT, in which endogenous DAP10 was overexpressed, and S100A8/A9, even at a micromolar concentration, led to cell growth and survival due to RAGE-DAP10 interaction. Functional blocking of DAP10 in the cell lines abrogated the Akt phosphorylation from S100A8/A9-activated RAGE, eventually leading to an increase in apoptosis. Finally, S100A8/A9, RAGE, and DAP10 were overexpressed in the psoriatic epidermis. Our findings indicate that the functional interaction between RAGE and DAP10 coordinately regulates S100A8/A9-mediated survival and/or apoptotic response of keratinocytes.

    DOI: 10.1074/jbc.M114.573071

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  • DNAX-activating Protein 10 (DAP10) Membrane Adaptor Associates with Receptor for Advanced Glycation End Products (RAGE) and Modulates the RAGE-triggered Signaling Pathway in Human Keratinocytes

    Masakiyo Sakaguchi, Hitoshi Murata, Yumi Aoyama, Toshihiko Hibino, Endy Widya Putranto, I. Made Winarsa Ruma, Yusuke Inoue, Yoshihiko Sakaguchi, Ken-ichi Yamamoto, Rie Kinoshita, Junichiro Futami, Ken Kataoka, Keiji Iwatsuki, Nam-ho Huh

    JOURNAL OF BIOLOGICAL CHEMISTRY   289 ( 34 )   23389 - 23402   2014年8月

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    記述言語:英語   出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    Background: RAGE receptor plays a critical role in many inflammatory disorders. Results: Functional interaction between RAGE and DAP10 coordinately regulates S100A8/A9-mediated cell survival. Conclusion: DAP10 membrane adaptor is critically involved in RAGE-mediated survival signaling upon S100A8/A9 binding. Significance: This is the first report demonstrating that RAGE-mediated survival signaling is critically regulated by DAP10 interaction.
    The receptor for advanced glycation end products (RAGE) is involved in the pathogenesis of many inflammatory, degenerative, and hyperproliferative diseases, including cancer. Previously, we revealed mechanisms of downstream signaling from ligand-activated RAGE, which recruits TIRAP/MyD88. Here, we showed that DNAX-activating protein 10 (DAP10), a transmembrane adaptor protein, also binds to RAGE. By artificial oligomerization of RAGE alone or RAGE-DAP10, we found that RAGE-DAP10 heterodimer formation resulted in a marked enhancement of Akt activation, whereas homomultimeric interaction of RAGE led to activation of caspase 8. Normal human epidermal keratinocytes exposed to S100A8/A9, a ligand for RAGE, at a nanomolar concentration mimicked the pro-survival response of RAGE-DAP10 interaction, although at a micromolar concentration, the cells mimicked the pro-apoptotic response of RAGE-RAGE. In transformed epithelial cell lines, A431 and HaCaT, in which endogenous DAP10 was overexpressed, and S100A8/A9, even at a micromolar concentration, led to cell growth and survival due to RAGE-DAP10 interaction. Functional blocking of DAP10 in the cell lines abrogated the Akt phosphorylation from S100A8/A9-activated RAGE, eventually leading to an increase in apoptosis. Finally, S100A8/A9, RAGE, and DAP10 were overexpressed in the psoriatic epidermis. Our findings indicate that the functional interaction between RAGE and DAP10 coordinately regulates S100A8/A9-mediated survival and/or apoptotic response of keratinocytes.

    DOI: 10.1074/jbc.M114.573071

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  • Dramatic Increase in Expression of a Transgene by Insertion of Promoters Downstream of the Cargo Gene

    Masakiyo Sakaguchi, Masami Watanabe, Rie Kinoshita, Haruki Kaku, Hideo Ueki, Junichiro Futami, Hitoshi Murata, Yusuke Inoue, Shun-Ai Li, Peng Huang, Endy Widya Putranto, I. Made Winarsa Ruma, Yasutomo Nasu, Hiromi Kumon, Nam-ho Huh

    MOLECULAR BIOTECHNOLOGY   56 ( 7 )   621 - 630   2014年7月

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    記述言語:英語   出版者・発行元:HUMANA PRESS INC  

    For expression of genes in mammalian cells, various vectors have been developed using promoters including CMV, EF-1 alpha, and CAG promoters and have been widely used. However, such expression vectors sometimes fail to attain sufficient expression levels depending on the nature of cargo genes and/or on host cell types. In the present study, we aimed to develop a potent promoter system that enables high expression levels of cargo genes ubiquitously in many different cell types. We found that insertion of an additional promoter downstream of a cargo gene greatly enhanced the expression levels. Among the constructs we tested, C-TSC cassette (C: CMV-RU5' located upstream; TSC: another promoter unit composed of triple tandem promoters, hTERT, SV40, and CMV, located downstream of the cDNA plus a polyadenylation signal) had the most potent capability, showing far higher efficiency than that of potent conventional vector systems. The results indicate that the new expression system is useful for production of recombinant proteins in mammalian cells and for application as a gene therapeutic measure.

    DOI: 10.1007/s12033-014-9738-0

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  • Dramatic Increase in Expression of a Transgene by Insertion of Promoters Downstream of the Cargo Gene

    Masakiyo Sakaguchi, Masami Watanabe, Rie Kinoshita, Haruki Kaku, Hideo Ueki, Junichiro Futami, Hitoshi Murata, Yusuke Inoue, Shun-Ai Li, Peng Huang, Endy Widya Putranto, I. Made Winarsa Ruma, Yasutomo Nasu, Hiromi Kumon, Nam-ho Huh

    MOLECULAR BIOTECHNOLOGY   56 ( 7 )   621 - 630   2014年7月

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    記述言語:英語   出版者・発行元:HUMANA PRESS INC  

    For expression of genes in mammalian cells, various vectors have been developed using promoters including CMV, EF-1 alpha, and CAG promoters and have been widely used. However, such expression vectors sometimes fail to attain sufficient expression levels depending on the nature of cargo genes and/or on host cell types. In the present study, we aimed to develop a potent promoter system that enables high expression levels of cargo genes ubiquitously in many different cell types. We found that insertion of an additional promoter downstream of a cargo gene greatly enhanced the expression levels. Among the constructs we tested, C-TSC cassette (C: CMV-RU5' located upstream; TSC: another promoter unit composed of triple tandem promoters, hTERT, SV40, and CMV, located downstream of the cDNA plus a polyadenylation signal) had the most potent capability, showing far higher efficiency than that of potent conventional vector systems. The results indicate that the new expression system is useful for production of recombinant proteins in mammalian cells and for application as a gene therapeutic measure.

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  • A novel gene expression system strongly enhances the anticancer effects of a REIC/Dkk-3-encoding adenoviral vector

    Masami Watanabe, Masakiyo Sakaguchi, Rie Kinoshita, Haruki Kaku, Yuichi Ariyoshi, Hideo Ueki, Ryuta Tanimoto, Shin Ebara, Kazuhiko Ochiai, Junichiro Futami, Shun-Ai Li, Peng Huang, Yasutomo Nasu, Nam-Ho Huh, Hiromi Kumon

    ONCOLOGY REPORTS   31 ( 3 )   1089 - 1095   2014年3月

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    記述言語:英語   出版者・発行元:SPANDIDOS PUBL LTD  

    Gene expression systems with various promoters, including the cytomegalovirus (CMV) promoter, have been developed to increase the gene expression in a variety of normal and cancer cells. In particular, in the clinical trials of cancer gene therapy, a more efficient and robust gene expression system is required to achieve sufficient therapeutic outcomes. By inserting the triple translational enhancer sequences of human telomerase reverse transcriptase (hTERT), Simian virus 40 (SV40) and CMV downstream of the sequence of the BGH polyA, we were able to develop a novel gene expression system that significantly enhances the expression of the genes of interest. We termed this novel gene expression cassette the super gene expression (SGE) system, and herein verify the utility of the SGE cassette for a replication-deficient adenoviral vector. We newly developed an adenoviral vector expressing the tumor suppressor, reduced expression in immortalized cells (REIC)/Dickkopf-3 (Dkk-3), based on the CMV promoter-driven SGE system (Ad-SGE-REIC) and compared the therapeutic utility of Ad-SGE-REIC with that of the conventional adenoviral vectors (Ad-CMV-REIC or Ad-CAG-REIC). The results demonstrated that the CMV promoter-SGE system allows for more potent gene expression, and that the Ad-SGE-REIC is superior to conventional adenoviral systems in terms of the REIC protein expression and therapeutic effects. Since the SGE cassette can be applied for the expression of various therapeutic genes using various vector systems, we believe that this novel system will become an innovative tool in the field of gene expression and gene therapy.

    DOI: 10.3892/or.2013.2958

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  • A novel gene expression system strongly enhances the anticancer effects of a REIC/Dkk-3-encoding adenoviral vector

    Masami Watanabe, Masakiyo Sakaguchi, Rie Kinoshita, Haruki Kaku, Yuichi Ariyoshi, Hideo Ueki, Ryuta Tanimoto, Shin Ebara, Kazuhiko Ochiai, Junichiro Futami, Shun-Ai Li, Peng Huang, Yasutomo Nasu, Nam-Ho Huh, Hiromi Kumon

    ONCOLOGY REPORTS   31 ( 3 )   1089 - 1095   2014年3月

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    記述言語:英語   出版者・発行元:SPANDIDOS PUBL LTD  

    Gene expression systems with various promoters, including the cytomegalovirus (CMV) promoter, have been developed to increase the gene expression in a variety of normal and cancer cells. In particular, in the clinical trials of cancer gene therapy, a more efficient and robust gene expression system is required to achieve sufficient therapeutic outcomes. By inserting the triple translational enhancer sequences of human telomerase reverse transcriptase (hTERT), Simian virus 40 (SV40) and CMV downstream of the sequence of the BGH polyA, we were able to develop a novel gene expression system that significantly enhances the expression of the genes of interest. We termed this novel gene expression cassette the super gene expression (SGE) system, and herein verify the utility of the SGE cassette for a replication-deficient adenoviral vector. We newly developed an adenoviral vector expressing the tumor suppressor, reduced expression in immortalized cells (REIC)/Dickkopf-3 (Dkk-3), based on the CMV promoter-driven SGE system (Ad-SGE-REIC) and compared the therapeutic utility of Ad-SGE-REIC with that of the conventional adenoviral vectors (Ad-CMV-REIC or Ad-CAG-REIC). The results demonstrated that the CMV promoter-SGE system allows for more potent gene expression, and that the Ad-SGE-REIC is superior to conventional adenoviral systems in terms of the REIC protein expression and therapeutic effects. Since the SGE cassette can be applied for the expression of various therapeutic genes using various vector systems, we believe that this novel system will become an innovative tool in the field of gene expression and gene therapy.

    DOI: 10.3892/or.2013.2958

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  • 3P-020 高純度・水溶性ヒト全長Cancer/Testis抗原リソースの整備(タンパク質工学,一般講演)

    藤田 佳那, 木戸 桃子, 新土居 奈緒美, 勝瀬 奈津美, 愛宕 祐基, 木下 理恵, 野々村 英典, 本莊 知子, 二見 淳一郎

    日本生物工学会大会講演要旨集   66   199 - 199   2014年

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    記述言語:日本語   出版者・発行元:日本生物工学会  

    CiNii Article

    CiNii Books

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    その他リンク: http://search.jamas.or.jp/link/ui/2016046025

  • 3P-014 タンパク質カチオン化技術を用いた高感度抗体検出技術の開発(タンパク質工学,一般講演)

    木戸 桃子, 藤田 佳那, 勝瀬 奈津美, 新土居 奈緒美, 愛宕 祐基, 木下 理恵, 野々村 英典, 本莊 知子, 二見 淳一郎

    日本生物工学会大会講演要旨集   66   198 - 198   2014年

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    記述言語:日本語   出版者・発行元:日本生物工学会  

    CiNii Article

    CiNii Books

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    その他リンク: http://search.jamas.or.jp/link/ui/2016046020

  • BIO-NANOCAPSULE-LIPOSOME CONJUGATES FOR IN VIVO PINPOINT DRUG AND GENE DELIVERY

    Takeshi Kasuya, Joohee Jung, Rie Kinoshita, Yasumasa Goh, Takashi Matsuzaki, Masumi Iijima, Nobuo Yoshimoto, Katsuyuki Tanizawa, Shun&apos;ichi Kuroda

    METHODS IN ENZYMOLOGY; LIPOSOMES, PT F   464   147 - 166   2009年

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    記述言語:英語   出版者・発行元:ELSEVIER ACADEMIC PRESS INC  

    A bio-nanocapsule (BNC) is an similar to 50-nm hepatitis B virus (HBV) subviral particle comprising HBV envelope L proteins and a lipid bilayer, and is synthesized in recombinant Saccharomyces cerevisiae. When BNCs are administered intravenously in a mouse xenograft model, they can accumulate specifically in human liver-derived tissues and enter cells efficiently by the HBV-derived human liver-specific infection machinery, localized at the outer-membrane pre-5 region of the L protein. BNC specificity for the human liver can be altered to other tissues by substituting the pre-S region using targeting molecules (e.g., antibodies, lectins, cytokines). BNCs can spontaneously form complexes with liposomes (LPs) by the membrane fusogenic activity of the pre-S region. LPs containing various therapeutic materials (e.g., chemicals, proteins, DNA, RNA) can therefore be covered with BNCs to form an similar to 150-nm BNC-LP conjugate. BNC-LP conjugates injected intravenously can deliver incorporated materials to target tissues specifically and efficiently by utilizing the HBV-derived infection machinery. The stability of BNC-LP conjugates in the blood circulation is similar to that of PEGylated LPs. In this chapter, we describe the preparation and in vivo application of BNC-LP conjugates, and the potential of BNC-LP conjugates as in vivo pinpoint drug delivery systems.

    DOI: 10.1016/S0076-6879(09)64008-8

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  • BIO-NANOCAPSULE-LIPOSOME CONJUGATES FOR IN VIVO PINPOINT DRUG AND GENE DELIVERY

    Takeshi Kasuya, Joohee Jung, Rie Kinoshita, Yasumasa Goh, Takashi Matsuzaki, Masumi Iijima, Nobuo Yoshimoto, Katsuyuki Tanizawa, Shun&apos;ichi Kuroda

    METHODS IN ENZYMOLOGY; LIPOSOMES, PT F   464   147 - 166   2009年

     詳細を見る

    記述言語:英語   出版者・発行元:ELSEVIER ACADEMIC PRESS INC  

    A bio-nanocapsule (BNC) is an similar to 50-nm hepatitis B virus (HBV) subviral particle comprising HBV envelope L proteins and a lipid bilayer, and is synthesized in recombinant Saccharomyces cerevisiae. When BNCs are administered intravenously in a mouse xenograft model, they can accumulate specifically in human liver-derived tissues and enter cells efficiently by the HBV-derived human liver-specific infection machinery, localized at the outer-membrane pre-5 region of the L protein. BNC specificity for the human liver can be altered to other tissues by substituting the pre-S region using targeting molecules (e.g., antibodies, lectins, cytokines). BNCs can spontaneously form complexes with liposomes (LPs) by the membrane fusogenic activity of the pre-S region. LPs containing various therapeutic materials (e.g., chemicals, proteins, DNA, RNA) can therefore be covered with BNCs to form an similar to 150-nm BNC-LP conjugate. BNC-LP conjugates injected intravenously can deliver incorporated materials to target tissues specifically and efficiently by utilizing the HBV-derived infection machinery. The stability of BNC-LP conjugates in the blood circulation is similar to that of PEGylated LPs. In this chapter, we describe the preparation and in vivo application of BNC-LP conjugates, and the potential of BNC-LP conjugates as in vivo pinpoint drug delivery systems.

    DOI: 10.1016/S0076-6879(09)64008-8

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  • Detection of oligomerization and conformational changes in the Na(+)/H(+) antiporter from Helicobacter pylori by fluorescence resonance energy transfer

    A Karasawa, Y Tsuboi, H Inoue, R Kinoshita, N Nakamura, H Kanazawa

    JOURNAL OF BIOLOGICAL CHEMISTRY   280 ( 51 )   41900 - 41911   2005年12月

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    記述言語:英語   出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    Oligomerization and conformational changes in the Na(+)/H(+) antiporter from Helicobacter pylori (HPNhaA) were studied by means of fluorescence resonance energy transfer (FRET) analysis. Na(+)/H(+) antiporter-deficient Escherichia coli cells expressing C-terminal fusions of HPNhaA to green fluorescent protein (GFP) variants exhibited wild-type levels of antiporter activity in their everted membrane vesicles. Vesicles containing both HPNhaA-CFP and HPNhaA-YFP or HPNhaA-Venus exhibited FRET from CFP (donor) to YFP or Venus (acceptor), suggesting that HPNhaA forms an oligomer. Co-precipitation of HPNhaA tagged by Venus and FLAG sequences confirmed oligomerization. FRET decreased extensively after treatment of the vesicles with proteinase K, which released GFP variants from the fusion proteins. FRET was not observed by merely mixing vesicles expressing the donor or acceptor fusion alone. Fluorescence of Venus is less sensitive to anions and stronger than that of anion-sensitive YFP. Using HPNhaA-Venus as the acceptor, Li(+) was found to cause a significant decrease in FRET regardless of the presence or absence of Delta pH across the membranes, whereas Na(+) caused a much weaker effect. This Li(+) effect was minimal in vesicles prepared from cells expressing HPNhaA containing an Asp(141) to Asn mutation, which results in defective Li(+)/H(+) antiporter activity, possibly Li(+) binding. These results demonstrate that monomer interactions within the HPNhaA oligomer are weakened possibly by Li(+) binding. Dynamic interactions between HPNhaA monomers were detectable in membranes by FRET analysis, thus providing a new approach to study dynamic conformational changes in NhaA during antiport activity.

    DOI: 10.1074/jbc.M510795200

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  • Detection of oligomerization and conformational changes in the Na(+)/H(+) antiporter from Helicobacter pylori by fluorescence resonance energy transfer

    A Karasawa, Y Tsuboi, H Inoue, R Kinoshita, N Nakamura, H Kanazawa

    JOURNAL OF BIOLOGICAL CHEMISTRY   280 ( 51 )   41900 - 41911   2005年12月

     詳細を見る

    記述言語:英語   出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    Oligomerization and conformational changes in the Na(+)/H(+) antiporter from Helicobacter pylori (HPNhaA) were studied by means of fluorescence resonance energy transfer (FRET) analysis. Na(+)/H(+) antiporter-deficient Escherichia coli cells expressing C-terminal fusions of HPNhaA to green fluorescent protein (GFP) variants exhibited wild-type levels of antiporter activity in their everted membrane vesicles. Vesicles containing both HPNhaA-CFP and HPNhaA-YFP or HPNhaA-Venus exhibited FRET from CFP (donor) to YFP or Venus (acceptor), suggesting that HPNhaA forms an oligomer. Co-precipitation of HPNhaA tagged by Venus and FLAG sequences confirmed oligomerization. FRET decreased extensively after treatment of the vesicles with proteinase K, which released GFP variants from the fusion proteins. FRET was not observed by merely mixing vesicles expressing the donor or acceptor fusion alone. Fluorescence of Venus is less sensitive to anions and stronger than that of anion-sensitive YFP. Using HPNhaA-Venus as the acceptor, Li(+) was found to cause a significant decrease in FRET regardless of the presence or absence of Delta pH across the membranes, whereas Na(+) caused a much weaker effect. This Li(+) effect was minimal in vesicles prepared from cells expressing HPNhaA containing an Asp(141) to Asn mutation, which results in defective Li(+)/H(+) antiporter activity, possibly Li(+) binding. These results demonstrate that monomer interactions within the HPNhaA oligomer are weakened possibly by Li(+) binding. Dynamic interactions between HPNhaA monomers were detectable in membranes by FRET analysis, thus providing a new approach to study dynamic conformational changes in NhaA during antiport activity.

    DOI: 10.1074/jbc.M510795200

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▼全件表示

講演・口頭発表等

  • 膵がん進展における S100A8/A9 の役割解明と治療方法の開発

    木下 理恵, 友信 奈保子, 山内 明, 二見 淳一郎, 豊岡 伸一, 阪口 政清

    第81回日本癌学会学術総会  2023年9月21日 

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    開催年月日: 2023年9月21日 - 2023年9月23日

    記述言語:英語   会議種別:ポスター発表  

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  • 膵がん進展におけるS100A8/A9 の機能解析と抗体による治療への応用

    宮本航大, 木下理恵, 小林和子, 友信奈保子, 山本健一, 村田等, 許南浩, 豊岡伸一, 阪口政清

    日本組織培養学会第95回大会  2023年9月1日 

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    開催年月日: 2023年8月31日 - 2023年9月1日

    記述言語:日本語   会議種別:ポスター発表  

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  • S100A8/A9 とその新制御分子のバランスで成立するがん転移の機序解明

    友信奈保子, 木下理恵, 合原勇馬, Ni Luh Gede, Yoni Komalasari, Fan Jiang, 村田等, 山本健一, 山内明, 近藤英作, 豊岡伸一, 西堀正洋, 阪口政清

    日本組織培養学会第95回大会  2023年9月1日 

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    開催年月日: 2023年8月31日 - 2023年9月1日

    記述言語:日本語   会議種別:口頭発表(一般)  

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  • 腫瘍微小環境を悪性化するS100A8/A9を標的としたがん治療薬の開発

    日本癌学会学術総会 第81回大会  2022年9月29日 

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    開催年月日: 2022年9月29日 - 2022年10月1日

    記述言語:英語   会議種別:ポスター発表  

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  • 炎症性疾患に対する抗S100A8/A9抗体療法におけるマクロファージの役割

    木下理恵, 小林和子, 荒木恒太, 佐藤博紀, 友信奈保子, 村田等, 山本健一, 許 南浩, 豊岡伸一, 阪口政清

    日本組織培養学会 第94回大会  2022年7月7日 

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    開催年月日: 2022年7月7日 - 2022年7月8日

    記述言語:英語   会議種別:ポスター発表  

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  • Development of exSSSRs(extracellular S100 soil sensor receptors)-Fc fusion proteins and S100A8/A9 antibody for suppression of cancer metastasis

    Rie Kinoshita, Hiroki Sato, Akira Yamauchi, Yuta Takahashi, Yusuke Inoue, I Wayan Sumardika, Youyi Chen ,Nahoko Tomonobu, Kota Araki, Kazuhiko Shien, Shuta Tomida, Hidejiro Torigoe, Kei Namba, Eisuke Kurihara, Yusuke Ogoshi, Hitoshi Murata, Ken-ichi Yamamoto, Junichiro Futami, Endy Widya PutrantoI, I Made Winarsa Ruma, Hiromasa Yamamoto, Junichi Soh, Toshihiko Hibino, Masahiro Nishibori, Eisaku Kondo, Shinichi Toyooka and Masakiyo Sakaguchi

    第9回International DAMPs and Alarmins Symposium 

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    開催年月日: 2019年11月6日 - 2019年11月8日

    記述言語:英語   会議種別:ポスター発表  

    開催地:岡山市 岡山大学Junko Fukutake Hall  

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  • 転移がんに有効なS100A8/A9阻害薬の開発

    木下 理恵、友信 奈保子、山内 明、枝園 和彦、冨田 秀太、村田 等、二見 淳一郎、近藤 英作、豊岡 伸一、阪口 政清

    第78回日本癌学会学術総会 

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    開催年月日: 2019年9月26日 - 2019年9月28日

    記述言語:日本語   会議種別:ポスター発表  

    開催地:京都 国立京都国際会館  

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  • メラノーマ原発巣における転移機構に関わるMCAM-S100A8/A9シグナル経路の分子学的解析

    友信 奈保子、木下 理恵、近藤 英作、山内 明、二見 淳一郎、豊岡 伸一、阪口 政清

    第78回日本癌学会学術総会 

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    開催年月日: 2019年9月26日 - 2019年9月28日

    記述言語:日本語   会議種別:ポスター発表  

    開催地:京都 国立京都国際会館  

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  • 膵臓がんにおける腫瘍周囲微小環境機構の解析

    山本 健一, 光井 洋介, 高松 仁志, 友信 奈保子, 二見 淳一郎, 木下 理恵, 村田 等, 阪口 政清

    2019年度若手支援技術講習会 

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    開催年月日: 2019年9月5日 - 2019年9月7日

    記述言語:日本語   会議種別:ポスター発表  

    開催地:長野 蓼科グランドホテル滝の湯  

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  • JNKによるリン酸化を介したSARM1のNAD+分解活性とミトコンドリア機能制御

    村田等, 山本健一, 木下理恵, 阪口政清

    第42回日本神経科学大会、第62回日本神経化学会大会 

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    開催年月日: 2019年7月25日 - 2019年7月28日

    記述言語:日本語   会議種別:ポスター発表  

    開催地:新潟市 朱鷺メッセ  

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  • 分泌性S100A11-受容体RAGEシグナルを介した膵臓がん周辺微小環境における間質線維芽細胞の増殖誘導の解明

    山本 健一、高松 仁志、友信 奈保子、光井 洋介、二見 淳一郎、木下 理恵、村田 等、阪口 政清

    第41回日本分子生物学会年会  2018年 

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    開催年月日: 2018年11月28日 - 2018年11月30日

    記述言語:日本語   会議種別:ポスター発表  

    開催地:パシフィコ横浜  

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  • JNKによるリン酸化はSARM1のNAD分解活性を制御し、ミトコンドリア呼吸阻害を誘導する

    村田 等、山本健一、木下理恵、阪口政清

    第41回日本分子生物学会年会  2018年 

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    開催年月日: 2018年11月28日 - 2018年11月30日

    記述言語:日本語   会議種別:ポスター発表  

    開催地:パシフィコ横浜  

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  • がん転移抑制剤として効果を有するS100A8/A9中和抗体の開発

    木下理恵、山内明、枝園和彦、富田秀太、村田等、豊岡伸一、近藤英作、阪口政清

    第77回日本癌学会学術総会  2018年 

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    開催年月日: 2018年9月27日 - 2018年9月29日

    記述言語:日本語   会議種別:ポスター発表  

    開催地:大阪国際会議場・リーガロイヤルホテル大阪  

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  • 膵がん進展に導く膵がん細胞−間質線維芽細胞クロストークを介在する分泌性S100A11−受容体RAGE連携の役割

    光井 洋介、山本健一、Sumardika I Wayan、木下理恵、村田 等、二見淳一郎、高松仁、山本靖彦、西堀正洋、豊岡伸一、渡部昌実、那須 保友、阪口 政清

    第22回日本がん免疫学会総会  2018年 

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    開催年月日: 2018年8月1日 - 2018年8月3日

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:岡山コンベンションセンター  

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  • 分泌性S100A11-受容体RAGEシグナルに着眼した膵がん間質増大のメカニズムの解明

    山本健一、高松仁志、光井洋介、木下理恵、村田 等、二見淳一郎、山本靖彦、西堀正洋、豊岡伸一、阪口政清

    第22回日本がん免疫学会総会  2018年 

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    開催年月日: 2018年8月1日 - 2018年8月3日

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:岡山コンベンションセンター  

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  • 健常者及びパーキンソン病患者iPS細胞由来の神経細胞を用いたミトコンドリア機能解析

    村田等 山本健一 木下理恵 阪口政清

    第39回日本分子生物学会年会  2017年 

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    開催年月日: 2017年12月6日 - 2017年12月9日

    記述言語:日本語   会議種別:ポスター発表  

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  • S100A8/A9 とその受容体との結合遮断を目指した転移抑制タンパク質製剤の開発

    木下理恵、山内明、枝園和彦、富田秀太、豊岡伸一、近藤英作、阪口政清

    第76回日本癌学会学術総会  2017年 

     詳細を見る

    開催年月日: 2017年9月28日 - 2017年9月30日

    記述言語:日本語   会議種別:ポスター発表  

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  • S100A8/A9を標的としたがん転移制御法の開発

    木下理恵 村田等 山本健一 許南浩 日比野利彦 阪口政清

    日本組織培養学会第90回大会  2017年 

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    開催年月日: 2017年6月30日 - 2017年7月1日

    記述言語:日本語   会議種別:ポスター発表  

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  • ミトコンドリア呼吸鎖複合体への作用を介したSARM1の神経細胞死誘導

    村田等 西川茜 山本健一 木下理恵 阪口政清

    日本組織培養学会第90回大会  2017年 

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    開催年月日: 2017年6月30日 - 2017年7月1日

    記述言語:日本語   会議種別:口頭発表(一般)  

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  • 転移先臓器を感知する受容体

    阪口政清 木下理恵 村田等 山本健一 日比野利彦 許南浩

    日本組織培養学会第90回大会  2017年 

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    開催年月日: 2017年6月30日 - 2017年7月1日

    記述言語:日本語   会議種別:口頭発表(一般)  

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  • 神経細胞死・軸索変性に関与するSARM1のリン酸化制御

    村田等、西川茜、山本健一、木下理恵、阪口政清

    第39回日本分子生物学会年会  2016年 

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    開催年月日: 2016年11月30日 - 2016年12月2日

    記述言語:日本語   会議種別:ポスター発表  

    開催地:横浜  

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  • 癌転移抑制を目指した新規タンパク質製剤の開発

    木下理恵、村田等、井上祐介、近藤英作、許南浩、阪口政清

    第75回日本癌学会学術総会  2016年 

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    開催年月日: 2016年10月6日 - 2016年10月8日

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:横浜  

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  • PINK1 regulation of mitochondrial homeostasis and cell survival.

    HITOSHI MURATA, Ken-ichi Yamamoto, Rie Kinoshita, Ken Kataoka, Nam-ho Huh and Masakiyo Sakaguchi.

    the 2016 World Congress on In Vitro Biology  2016年 

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    開催年月日: 2016年6月11日 - 2016年6月15日

    記述言語:英語   会議種別:シンポジウム・ワークショップ パネル(指名)  

    開催地:San Diego, USA  

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  • ピロリ菌Na+/H+ antiporterter (NhaA)のイオン輸送における第11膜貫通領域の機能の解析

    木下理恵、坪井裕見、桑原直之、井上弘樹、中村徳弘、金澤浩

    日本生体エネルギー研究会 第30回討論会  2004年  日本生体エネルギー研究会

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    開催年月日: 2004年12月

    会議種別:口頭発表(一般)  

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  • Purification and reconstitution of Helicobacter pylori Na+/H+ antiporter (NhaA)

    木下理恵、坪井裕見、桑原直之、井上弘樹、中村徳弘、金澤浩

    日本生化学会 第76回大会  2003年  日本生化学会

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    開催年月日: 2003年10月

    会議種別:口頭発表(一般)  

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  • ベータセルリン 結合蛋白のクローニングと解析

    木下理恵、堂浦秀記、柳居加奈子、多田宏子、山田秀徳、妹尾昌治

    日本分子生物学会 第24回年会  2001年  日本分子生物学会

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    開催年月日: 2001年12月

    会議種別:口頭発表(一般)  

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  • S100A8/A9 とその受容体との結合遮断を目指した転移抑制タンパク質製剤の開発

    第76回日本癌学会学術総会  2017年 

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  • 転移先臓器を感知する受容体

    日本組織培養学会第90回大会  2017年 

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  • S100A8/A9を標的としたがん転移制御法の開発

    日本組織培養学会第90回大会  2017年 

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  • SARM1 induces neuronal cell death by inhibition of mitochondrial respiration

    2017年 

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  • 癌転移抑制を目指した新規タンパク質製剤の開発

    第75回日本癌学会学術総会  2016年 

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  • PINK1 regulation of mitochondrial homeostasis and cell survival.

    the 2016 World Congress on In Vitro Biology  2016年 

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産業財産権

  • 炎症性肺疾患の予防及び/又は治療剤

    阪口政清, 豊岡伸一, 木下理恵, 荒木恒太

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    出願人:国立大学法人岡山大学

    出願番号:EP 20882559.6  出願日:2022年5月30日

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  • 炎症性肺疾患の予防及び/又は治療剤

    阪口政清, 豊岡伸一, 木下理恵, 荒木恒太

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    出願人:国立大学法人岡山大学

    出願番号:AU 2020376350  出願日:2022年5月9日

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  • 炎症性肺疾患の予防及び/又は治療剤

    阪口政清, 豊岡伸一, 木下理恵, 荒木恒太

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    出願人:国立大学法人岡山大学

    出願番号:CA 3155346  出願日:2022年4月20日

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  • 炎症性肺疾患の予防及び/又は治療剤

    阪口政清, 豊岡伸一, 木下理恵, 荒木恒太

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    出願人:国立大学法人岡山大学

    出願番号:US17/768865  出願日:2022年4月14日

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  • 炎症性肺疾患の予防及び/又は治療剤

    阪口政清, 豊岡伸一, 木下理恵, 荒木恒太

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    出願人:国立大学法人岡山大学

    出願番号:CN 202080071786.X  出願日:2022年4月13日

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  • 炎症性肺疾患の予防及び/又は治療剤

    阪口政清, 豊岡伸一, 木下理恵, 荒木恒太

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    出願人:国立大学法人岡山大学

    出願番号:TW110110562  出願日:2021年3月24日

    出願国:外国  

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  • 抗S100A8/A9抗体とその用途

    阪口政清, 豊岡伸一, 木下理恵, 冨田秀太, 枝園和彦, 佐藤博紀, 二見淳一郎, 近藤英作, 井上裕介, 山内明

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    出願人:国立大学法人岡山大学 国立大学法人新潟大学 国立大学法人群馬大学 学校法人川崎学園

    出願番号:19792052. 3  出願日:2020年11月20日

    公開番号:3791894  公開日:2021年3月17日

    出願国:外国  

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  • 肺炎症性疾患の予防及び/又は治療剤

    阪口政清, 豊岡伸一, 木下理恵, 荒木恒太

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    出願人:国立大学法人岡山大学

    出願番号:PCT/JP2020/39460  出願日:2020年10月30日

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  • 抗S100A8/A9抗体とその用途

    阪口政清, 豊岡伸一, 木下理恵, 冨田秀太, 枝園和彦, 佐藤博紀, 二見淳一郎, 近藤英作, 井上裕介, 山内明

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    出願番号:201980028619.4  出願日:2020年10月27日

    公開番号:CN11204090982 A  公開日:2020年12月4日

    出願国:外国  

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  • 抗S100A8/A9抗体とその用途

    阪口政清, 豊岡伸一, 木下理恵, 冨田秀太, 枝園和彦, 佐藤博紀, 二見淳一郎, 近藤英作, 井上裕介, 山内明

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    出願番号:US17/050384  出願日:2020年10月23日

    公開番号:us2021/0054061  公開日:2021年2月25日

    出願国:外国  

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  • 抗S100A8/A9抗体とその用途

    阪口政清, 豊岡伸一, 冨田秀太, 枝園和彦, 佐藤博紀, 木下理恵, 二見淳一郎, 荒木恒太, 岡﨑幹夫, 近藤英作, 井上裕介, 山内明

     詳細を見る

    出願人:国立大学法人岡山大学 国立大学法人新潟大学 国立大学法人群馬大学 学校法人川崎学園

    出願番号:JP2020-516238  出願日:2020年10月6日

    出願国:国内  

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  • 抗S100A8/A9抗体

    阪口政清, 豊岡伸一, 冨田秀太, 枝園和彦, 佐藤博紀, 木下理恵, 二見淳一郎, 近藤英作, 井上裕介, 山内明

     詳細を見る

    出願人:国立大学法人岡山大学 国立大学法人新潟大学 国立大学法人群馬大学 学校法人川崎学園

    出願番号:特願2018-087576  出願日:2018年4月27日

    出願国:国内  

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  • リン酸化SARM1、抗体、SARM1リン酸化阻害剤、神経変性患者の予防または治療薬、スクリーニング方法、SARM1改変体及び使用

    村田 等, 阪口政清, 木下理恵, 山本健一

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    出願人:国立大学法人岡山大学

    出願番号:特願2018-507366  出願日:2018年4月2日

    公開番号:特開WO2017/164230  公開日:2017年9月27日

    特許番号/登録番号:特許7198489  登録日:2022年12月21日 

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  • 活性構造のREIC/Dkk-3タンパク質を特異的に認識して結合する抗体、及び該抗REIC/Dkk-3抗体を用いた癌治療のモニタリング

    木下理恵 二見淳一郎 公文裕巳

     詳細を見る

    出願人:国立大学法人岡山大学

    出願番号:特願2017-543279  出願日:2016年9月27日

    特許番号/登録番号:特許6975424  登録日:2021年11月10日 

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  • 遺伝子発現用カセット及びその産生物

    阪口 政清, 西堀 正洋, 公文 裕巳, 村田 等, 山本 健一, 木下 理恵

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    出願人:国立大学法人岡山大学

    出願番号:特願2016-059297  出願日:2016年3月23日

    公開番号:特開2017-169486  公開日:2017年9月28日

    特許番号/登録番号:特許6871679  登録日:2021年4月20日 

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共同研究・競争的資金等の研究

  • 原発巣の腫瘍縮小および転移抑制効果を示す膵がん治療薬の開発

    研究課題/領域番号:23K06717  2023年04月 - 2027年03月

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    木下 理恵, 阪口 政清

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    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

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  • S100A8/A9-向転移とHRG-抗転移の細胞間・分子間クロストークの解明

    研究課題/領域番号:23H02748  2023年04月 - 2026年03月

    日本学術振興会  科学研究費助成事業  基盤研究(B)

    阪口 政清, 山本 健一, 近藤 英作, 豊岡 伸一, 木下 理恵, 西堀 正洋, 山内 明, 友信 奈保子, 村田 等

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    配分額:18720000円 ( 直接経費:14400000円 、 間接経費:4320000円 )

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  • 乾癬、アトピー性皮膚炎におけるMCAMの意義探求とその制御製剤による病態制御

    研究課題/領域番号:22K08405  2022年04月 - 2025年03月

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    山本 健一, 木下 理恵, 阪口 政清

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    配分額:4160000円 ( 直接経費:3200000円 、 間接経費:960000円 )

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  • 肺虚血再灌流障害におけるS100A8/A9の役割の解明と新しい治療法の開発

    研究課題/領域番号:20K09164  2020年04月 - 2023年03月

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    岡崎 幹生, 大谷 真二, 山根 正修, 坂上 倫久, 豊岡 伸一, 山本 寛斉, 木下 理恵, 杉本 誠一郎, 阪口 政清

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    重症肺疾患に対して、肺移植手術が唯一残された治療法となることがあるが、一時的な虚血と血液の再灌流により炎症が生じる虚血再灌流障害は依然として肺移植時の大きな問題点である。肺移植後の移植肺の機能不全は虚血再灌流障害によるものがほとんどで、基礎研究による肺虚血再灌流障害の分子メカニズムの解明や革新的治療薬が開発できると、肺移植による治療成績が格段に向上する。最近申請者らは、経時的かつ網羅的遺伝子発現解析から、肺虚血再灌流後に最も早期に過剰発現する遺伝子としてS100A8/A9を見出した。S100A8/A9は、多様な炎症反応の引き金となるためIRIの治療のターゲットとして極めて有望である。本研究では、申請者らが開発したS100A8/A9を標的とした中和抗体を用いて、肺虚血再灌流障害の抑制効果を検証し、臨床応用に向けたProof of Conceptを確立することを目的とする。
    マウス肺虚血再灌流障害モデルでS100A8/A9中和抗体の効果を検証した。抗体を投与した30分後に左肺を60分クランプし(虚血)、再灌流後120分に評価し、Control群と比較・検討した。虚血再灌流障害群(IgG Control群)はSham群と比較して、有意にPaO2が低下していた。それに対して、S100A8/A9中和抗体投与群ではControl群と比較して、優位にPaO2が改善していた。病理組織学的にもS100A8/A9中和抗体群では、Control群と比較して、虚血再灌流障害に伴う炎症細胞浸潤が有意に抑制されていた。またTUNEL染色でも、S100A8/A9中和抗体群では、Control群と比較して有意にアポトーシスが抑制されていた。S100A8/A9中和抗体による肺虚血再灌流障害抑制効果を認めた。

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  • がんの免疫逃避機構を制御する新規REIC受容体の解析

    研究課題/領域番号:18K15320  2018年04月 - 2020年03月

    日本学術振興会  科学研究費助成事業  若手研究

    木下 理恵

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    がん抑制遺伝子REIC(Reduced expression in immortalized cells)は、細胞内外での機能が報告されているが、分泌REICタンパク質の受容体は同定されておらず、詳細な分子機構は未解明であった。本研究では、REICタンパク質の新規受容体を数種同定し、その免疫細胞および神経細胞上の受容体を介したシグナル伝達機構の解析を進めた。本研究により、REICは抗アポトーシスシグナルを制御しており、細胞の恒常性維持機構に関与していることが示唆された。これらのデータは、実施中の複数種のがんに対するREIC発現アデノウイルスの治験に科学的根拠をもたらすものである。

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  • 新規S100受容体による原発巣転移前がん微小環境構築とがん転移動力獲得の分子機構

    研究課題/領域番号:17H03577  2017年04月 - 2020年03月

    日本学術振興会  科学研究費助成事業  基盤研究(B)

    阪口 政清, 山本 健一, 冨田 秀太, 豊岡 伸一, 木下 理恵, 村田 等, 枝園 和彦

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    配分額:17810000円 ( 直接経費:13700000円 、 間接経費:4110000円 )

    臓器指向性転移を誘導する新規S100A8/A9受容体群の作動原理を解明することを目指した。SSSRsの内、MCAMとNPTNβに関する転移動力供給のシグナル伝達メカニズムが不明であったが、研究からMCAMとNPTNβについて転移動力を引き出す各々の下流信号伝達を解明するに至った。解析の結果、メラノーマと乳がんでは、MCAM→TPL2(MAPKKK)→ETV4(転写因子)が、肺がんでは、NPTNβ→RAS & TRAF2(アダプター因子)→NFIA/NFIB(転写因子)→SPDEF(転写因子)が転移を促す重要信号伝達経路として新規に同定することができた。

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  • がん特異的なREICの構造を判別する薬効評価系の開発及びその構造と機能の評価

    研究課題/領域番号:16K18440  2016年04月 - 2018年03月

    日本学術振興会  科学研究費助成事業  若手研究(B)

    木下 理恵

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    配分額:3900000円 ( 直接経費:3000000円 、 間接経費:900000円 )

    REICは、様々ながん種において発現が低下しており、がん抑制遺伝子として機能する。そしてREICの強い抗がん作用を利用して、アデノウイルスを用いた遺伝子治療製剤(Ad-REIC)が開発され、前立腺がん・悪性中皮腫を対象とした臨床試験が実施中である。本研究では、この治療をモニターする方法を確立するため、血中REIC濃度を定量可能な新規REICモノクローナル抗体を取得し、sandwich ELISA系を検討した。そしてAd-REIC投与後にREICタンパク質の血中濃度が上昇することを示した。REICは、複数種のがんで臨床試験を実施・計画中であり、REIC治療の薬効評価法として実用化を推進中である。

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担当授業科目

  • 細胞生物学実習 (2023年度) 特別  - その他

  • 細胞生物学演習 (2023年度) 特別  - その他

  • 細胞生物学I(演習・実習) (2023年度) 特別  - その他

  • 細胞生物学I(講義・演習) (2023年度) 特別  - その他

  • 細胞生物学II(演習・実習) (2023年度) 特別  - その他

  • 細胞生物学II(講義・演習) (2023年度) 特別  - その他

  • 細胞生物学I(演習・実習) (2022年度) 特別  - その他

  • 細胞生物学I(講義・演習) (2022年度) 特別  - その他

  • 細胞生物学II(演習・実習) (2022年度) 特別  - その他

  • 細胞生物学II(講義・演習) (2022年度) 特別  - その他

  • 細胞生物学I(演習・実習) (2021年度) 特別  - その他

  • 細胞生物学I(講義・演習) (2021年度) 特別  - その他

  • 細胞生物学II(演習・実習) (2021年度) 特別  - その他

  • 細胞生物学II(講義・演習) (2021年度) 特別  - その他

  • 細胞生物学I(演習・実習) (2020年度) 特別  - その他

  • 細胞生物学I(講義・演習) (2020年度) 特別  - その他

  • 細胞生物学II(演習・実習) (2020年度) 特別  - その他

  • 細胞生物学II(講義・演習) (2020年度) 特別  - その他

▼全件表示