2024/04/26 更新

写真a

ヤマモト ケンイチ
山本 健一
YAMAMOTO Ken-ichi
所属
医歯薬学域 助教
職名
助教
外部リンク

学位

  • 博士(医学) ( 2013年3月   岡山大学 )

  • 修士(医学) ( 2009年3月   岡山大学 )

  • 理学士(生物) ( 2007年3月   岡山理科大学 )

研究キーワード

  • 細胞生物学

  • 分子生物学

  • Cell biology

  • Molecular biology

研究分野

  • ライフサイエンス / 分子生物学

学歴

  • 岡山大学    

    - 2013年

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  • 岡山大学    

    - 2013年

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    国名: 日本国

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  • 岡山理科大学   Faculty of Science   Department of Applied Science

    - 2007年

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    国名: 日本国

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経歴

  • - 岡山大学医歯薬学総合研究科 助教

    2015年 - 現在

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  • 佐賀大学医学部分子生命科学講座分子医化学分野 博士研究員

    2013年 - 2015年

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所属学協会

委員歴

  • 岡山大学大学院医歯薬学総合研究科   医歯科学専攻(修士課程)学務委員会 学生募集・就職支援推進部会  

    2017年4月 - 2023年3月   

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論文

  • Lysyl oxidase-like 4 promotes the invasiveness of triple-negative breast cancer cells by orchestrating the invasive machinery formed by annexin A2 and S100A11 on the cell surface

    Tetta Takahashi, Nahoko Tomonobu, Rie Kinoshita, Ken-ichi Yamamoto, Hitoshi Murata, Ni Luh Gede Yoni Komalasari, Youyi Chen, Fan Jiang, Yuma Gohara, Toshiki Ochi, I Made Winarsa Ruma, I Wayan Sumardika, Jin Zhou, Tomoko Honjo, Yoshihiko Sakaguchi, Akira Yamauchi, Futoshi Kuribayashi, Eisaku Kondo, Yusuke Inoue, Junichiro Futami, Shinichi Toyooka, Yoshito Zamami, Masakiyo Sakaguchi

    Frontiers in Oncology   14   2024年3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

    Our earlier research revealed that the secreted lysyl oxidase-like 4 (LOXL4) that is highly elevated in triple-negative breast cancer (TNBC) acts as a catalyst to lock annexin A2 on the cell membrane surface, which accelerates invasive outgrowth of the cancer through the binding of integrin-β1 on the cell surface. However, whether this machinery is subject to the LOXL4-mediated intrusive regulation remains uncertain.

    Methods

    Cell invasion was assessed using a transwell-based assay, protein–protein interactions by an immunoprecipitation–Western blotting technique and immunocytochemistry, and plasmin activity in the cell membrane by gelatin zymography.

    Results

    We revealed that cell surface annexin A2 acts as a receptor of plasminogen via interaction with S100A10, a key cell surface annexin A2-binding factor, and S100A11. We found that the cell surface annexin A2/S100A11 complex leads to mature active plasmin from bound plasminogen, which actively stimulates gelatin digestion, followed by increased invasion.

    Conclusion

    We have refined our understanding of the role of LOXL4 in TNBC cell invasion: namely, LOXL4 mediates the upregulation of annexin A2 at the cell surface, the upregulated annexin 2 binds S100A11 and S100A10, and the resulting annexin A2/S100A11 complex acts as a receptor of plasminogen, readily converting it into active-form plasmin and thereby enhancing invasion.

    DOI: 10.3389/fonc.2024.1371342

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

    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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    記述言語:英語   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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  • Exosomal Wnt7a from a low metastatic subclone promotes lung metastasis of a highly metastatic subclone in the murine 4t1 breast cancer. 査読 国際誌

    Chunning Li, Teizo Yoshimura, Miao Tian, Yuze Wang, Takamasa Kondo, Ken-Ichi Yamamoto, Masayoshi Fujisawa, Toshiaki Ohara, Masakiyo Sakaguchi, Akihiro Matsukawa

    Breast cancer research : BCR   24 ( 1 )   60 - 60   2022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)  

    BACKGROUND: Patients with triple-negative breast cancer (TNBC) often have poorer prognosis than those with other subtypes because of its aggressive behaviors. Cancer cells are heterogeneous, and only a few highly metastatic subclones metastasize. Although the majority of subclones may not metastasize, they could contribute by releasing factors that increase the capacity of highly metastatic cells and/or provide a favorable tumor microenvironment (TME). Here, we analyzed the interclonal communication in TNBC which leads to efficient cancer progression, particularly lung metastasis, using the polyclonal murine 4T1 BC model. METHODS: We isolated two 4T1 subclones, LM.4T1 and HM.4T1 cells with a low and a high metastatic potential, respectively, and examined the effects of LM.4T1 cells on the behaviors of HM.4T1 cells using the cell scratch assay, sphere-forming assay, sphere invasion assay, RT-qPCR, and western blotting in vitro. We also examined the contribution of LM.4T1 cells to the lung metastasis of HM.4T1 cells and TME in vivo. To identify a critical factor which may be responsible for the effects by LM.4T1 cells, we analyzed the data obtained from the GEO database. RESULTS: Co-injection of LM.4T1 cells significantly augmented lung metastases by HM.4T1 cells. LM.4T1-derived exosomes promoted the migration and invasion of HM.4T1 cells in vitro, and blocking the secretion of exosome abrogated their effects on HM.4T1 cells. Analyses of data obtained from the GEO database suggested that Wnt7a might be a critical factor responsible for the enhancing effects. In fact, a higher level of Wnt7a was detected in LM.4T1 cells, especially in exosomes, than in HM.4T1 cells, and deletion of Wnt7a in LM.4T1 cells significantly decreased the lung metastasis of HM.4T1 cells. Further, treatment with Wnt7a increased the spheroid formation by HM.4T1 cells via activation of the PI3K/Akt/mTOR signaling pathway. Finally, infiltration of αSMA-positive fibroblasts and angiogenesis was more prominent in tumors of LM.4T1 cells and deletion of Wnt7a in LM.4T1 cells markedly reduced angiogenesis. CONCLUSIONS: We demonstrated, for the first time, that a low metastatic subclone can enhance lung metastasis of highly metastatic subclone via exosomal Wnt7a and propose Wnt7a as a molecular target to treat TNBC patients.

    DOI: 10.1186/s13058-022-01557-5

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

    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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    記述言語:英語   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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  • Presence of Microplastics in Four Types of Shellfish Purchased at Fish Markets in Okayama City, Japan. 査読

    Kenichi Yamamoto, Toshiyuki Oshiki, Hiroko Kagawa, Masayoshi Namba, Masakiyo Sakaguchi

    Acta medica Okayama   75 ( 3 )   381 - 384   2021年6月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The worldwide microplastic pollution in our environment is a matter of great concern. Harmful effects of plastics have been reported in various types of organisms including murine animals. We examined the presence of microplastics in four types of shellfish purchased from fish markets in Okayama, Japan and served to the public: short-neck clam (Ruditapes philippinarum, asari in Japanese), hard-shell clam (Meretrix lusoria, hamaguri), brackishwater clam (Cyrenidae, shijimi), and oyster (Crassostrea gigas, kaki). Our analyses demonstrated that approx. 3 pieces of microplastics were present per single shellfish, based on the division of the total number of pieces of microplastic obtained from all 4 types of shellfish by the total number of shellfish examined. Since health problems in humans due to microplastics have not yet been confirmed, further examinations of the effects of ingested microplastics are needed.

    DOI: 10.18926/AMO/62234

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  • 異なる亜集団の腫瘍細胞から放出されたエクソソームWnt7aによリ4T1細胞の転移は促進される(4T1 cells promote tumor metastasis by exosomal Wnt7a released from distinct subpopulations)

    李 春寧, 大原 利章, 藤澤 真義, 阪口 政清, 山本 健一, 田 ミャオ, 王 宇沢, 吉村 禎造, 松川 昭博

    日本病理学会会誌   110 ( 1 )   231 - 231   2021年3月

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    記述言語:英語   出版者・発行元:(一社)日本病理学会  

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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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  • Cytotoxic Effects of Alcohol Extracts from a Plastic Wrap (Polyvinylidene Chloride) on Human Cultured Liver Cells and Mouse Primary Cultured Liver Cells. 査読

    Ken-Ichi Yamamoto, Hiroko Kagawa, Sakae Arimoto, Xian Wen Tan, Kento Yasui, Toshiyuki Oshiki, Masakiyo Sakaguchi

    Acta medica Okayama   74 ( 4 )   327 - 334   2020年8月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    An increasing accumulation of microplastics and further degraded nanoplastics in our environment is suspected to have harmful effects on humans and animals. To clarify this problem, we tested the cytotoxicity of two types of plastic wrap on human cultured liver cells and mouse primary cultured liver cells. Alcohol extracts from plastic wrap, i.e., polyvinylidene chloride (PVDC), showed cytotoxic effects on the cells. Alcohol extracts of polyethylene (PE) wrap were not toxic. The commercially available PVDC wrap consists of vinylidene chloride, epoxidized soybean oil, epoxidized linseed oil as a stiffener and stabilizer; we sought to identify which component(s) are toxic. The epoxidized soybean oil and epoxidized linseed oil exerted strong cytotoxicity, but the plastic raw material itself, vinylidene chloride, did not. Our findings indicate that plastic wraps should be used with caution in order to prevent health risks.

    DOI: 10.18926/AMO/60371

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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

    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)   出版者・発行元:Elsevier BV  

    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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  • 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.

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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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  • 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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    担当区分:筆頭著者   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.

    DOI: 10.3727/096504018X15433161908259

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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  

    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

    山本 健一

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

    Biochem Biophysics Rep   18   100619 - 100619   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.bbrep.2019.100619

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

    Murata H, Khine CC, Nishikawa A, Yamamoto KI, Kinoshita R, Sakaguchi M

    J Biol Chem   293 ( 49 )   18933 - 18943   2018年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1074/jbc.RA118.004578

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

    Ruma IMW, Kinoshita R, Tomonobu N, Inoue Y, Kondo E, Yamauchi A, Sato H, Sumardika IW, Chen Y, Yamamoto KI, Murata H, Toyooka S, Nishibori M, Sakaguchi M

    Cancers   10 ( 7 )   2018年7月

  • 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

    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

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

    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   掲載種別:研究論文(学術雑誌)   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 査読

    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   掲載種別:研究論文(学術雑誌)   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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  • Distant Bystander Effect of REIC/DKK3 Gene Therapy Through Immune System Stimulation in Thoracic Malignancies. 査読

    Suzawa K, Shien K, Peng H, Sakaguchi M, Watanabe M, Hashida S, Maki Y, Yamamoto H, Tomida S, Soh J, Asano H, Tsukuda K, Nasu Y, Kumon H, Miyoshi S, Toyooka S

    Anticancer Res   37 ( 1 )   301 - 307   2017年

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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. 査読

    Clinical & Experimental Mwtastasis   33 ( 6 )   609 - 627   2016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)  

    DOI: 10.1007/s10585-016-9801-2

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  • 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

  • Active Secretion of Dimerized S100A11 Induced by the Peroxisome in Mesothelioma Cells 査読

    Satomi Saho, Hiroki Satoh, Eisaku Kondo, Yusuke Inoue, Akira Yamauchi, Hitoshi Murata, Rie Kinoshita, Ken ichi Yamamoto, Junichiro Futami, dy Widya Putranto, I. Made, Winarsa Ruma, I. Wayan, Sumardika,Chen Youyi, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh, Shuta T

    Cancer Microenvironment   1 - 13   2016年

  • Periostin contributes to epidermal hyperplasia in psoriasis common to atopic dermatitis 査読

    Kazuhiko Arima, Shoichiro Ohta, Atsushi Takagi, Hiroshi Shiraishi, Miho Masuoka, Kanako Ontsuka, Hajime Suto, Shoichi Suzuki, Ken-ichi Yamamoto, Masahiro Ogawa, Olga Simmons, Yukie Yamaguchi, Shuji Toda, Michiko Aihara, Simon J. Conway, Shigaku Ikeda, Kenji Izuhara

    ALLERGOLOGY INTERNATIONAL   64 ( 1 )   41 - 48   2015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)   出版者・発行元:JAPANESE SOCIETY ALLERGOLOGY  

    Background: Epidermal hyperplasia is a histological hallmark observed in both atopic dermatitis (AD) and psoriasis, although the clinical features and the underlying immunological disorders of these diseases are different. We previously showed that periostin, a matricellular protein, plays a critical role in epidermal hyperplasia in AD, using a mouse model and a 3-dimensional organotypic coculture system. In this study, we explore the hypothesis that periostin is involved in epidermal hyperplasia in psoriasis.
    Methods: To examine expression of periostin in psoriasis patients, we performed immunohistochemical analysis on skin biopsies from six such patients. To investigate periostin's role in the pathogenesis of psoriasis, we evaluated periostin-deficient mice in a psoriasis mouse model induced by topical treatment with imiquimod (IMQ).
    Results: Periostin was substantially expressed in the dermis of all investigated psoriasis patients. Epidermal hyperplasia induced by IMQ treatment was impaired in periostin-deficient mice, along with decreased skin swelling. However, upon treatment with IMQ periostin deficiency did not alter infiltration of inflammatory cells such as neutrophils; production of IL-17, -22, or -23; or induction/expansion of IL-17- and IL-22-producing group 3 innate lymphoid cells.
    Conclusions: Periostin plays an important role during epidermal hyperplasia in IMQ-induced skin inflammation, independently of the IL-23-IL-17/IL-22 axis. Periostin appears to be a mediator for epidermal hyperplasia that is common to AD and psoriasis. Copyright (C) 2014, Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.alit.2014.06.001

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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 査読

    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   掲載種別:研究論文(学術雑誌)   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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  • Extract of Cordyceps militaris inhibits angiogenesis and suppresses tumor growth of human malignant melanoma cells 査読

    I. Made Winarsa Ruma, Endy Widya Putranto, Eisaku Kondo, Risayo Watanabe, Ken Saito, Yusuke Inoue, Ken-Ichi Yamamoto, Susumu Nakata, Masaji Kaihata, Hitoshi Murata, Masakiyo Sakaguchi

    INTERNATIONAL JOURNAL OF ONCOLOGY   45 ( 1 )   209 - 218   2014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)   出版者・発行元:SPANDIDOS PUBL LTD  

    Angiogenesis is essential for tumor development and metastasis. Among several angiogenic factors, vascular endothelial growth factor receptor (VEGF) is important for tumor-derived angiogenesis and commonly overexpressed in solid tumors. Thus, many antitumor strategies targeting VEGF have been developed to inhibit cancer angiogenesis, offering insights into the successful treatment of solid cancers. However, there are a number of issues such as harmful effects on normal vascularity in clinical trials. Taking this into consideration, we employed Cordyceps militaris as an antitumor approach due to its biological safety in vivo. The herbal medicinal mushroom Cordyceps militaris has been reported to show potential anticancer properties including anti-angiogenic capacity; however, its concrete properties have yet to be fully demonstrated. In this study, we aimed to elucidate the biological role of Cordyceps militaris extract in tumor cells, especially in regulating angiogenesis and tumor growth of a human malignant melanoma cell line. We demonstrated that Cordyceps militaris extract remarkably suppressed tumor growth via induction of apoptotic cell death in culture that links to the abrogation of VEGF production in melanoma cells. This was followed by mitigation of Akt1 and GSK-3 beta activation, while p38 alpha phosphorylation levels were increased. Extract treatment in mouse model xenografted with human melanoma cells resulted in a dramatic antitumor effect with downregulation of VEGF expression. The results suggest that suppression of tumor growth by Cordyceps militaris extract is, at least, mediated by its anti-angiogenicity and apoptosis induction capacities. Cordyceps militaris extract may be a potent antitumor herbal drug for solid tumors.

    DOI: 10.3892/ijo.2014.2397

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  • Periostin in Allergic Inflammation 査読

    Kenji Izuhara, Kazuhiko Arima, Shoichiro Ohta, Shoichi Suzuki, Masako Inamitsu, Ken-ichi Yamamoto

    ALLERGOLOGY INTERNATIONAL   63 ( 2 )   143 - 151   2014年6月

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    記述言語:英語   出版者・発行元:JAPANESE SOCIETY ALLERGOLOGY  

    Periostin, an extracellular matrix protein belonging to the fasciclin family, has been shown to play a critical role in the process of remodeling during tissue/organ development or repair. Periostin functions as a matricellular protein in cell activation by binding to their receptors on cell surface, thereby exerting its biological activities. After we found that periostin is a downstream molecule of interleukin (IL)-4 and IL-13, signature cytokines of type 2 immune responses, we showed that periostin is a component of subepithelial fibrosis in bronchial asthma, the first formal proof that periostin is involved in allergic inflammation. Subsequently, a great deal of evidence has accumulated demonstrating the significance of periostin in allergic inflammation. It is of note that in skin tissues, periostin is critical for amplification and persistence of allergic inflammation by communicating between fibroblasts and keratinocytes. Furthermore, periostin has been applied to development of novel diagnostics or therapeutic agents for allergic diseases. Serum periostin can reflect local production of periostin in inflamed lesions induced by Th2-type immune responses and also can predict the efficacy of Th2 antagonists against bronchial asthma. Blocking the interaction between periostin and its receptor, alpha(v) integrin, or down-regulating the periostin expression shows improvement of periostin-induced inflammation in mouse models or in in vitro systems. It is hoped that diagnostics or therapeutic agents targeting periostin will be of practical use in the near future.

    DOI: 10.2332/allergolint.13-RAI-0663

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  • Periostin controls keratinocyte proliferation and differentiation by interacting with the paracrine IL-1α/IL-6 loop 査読

    Journal of Investigative Dermatology   134 ( 5 )   1295 - 1304   2014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)  

    DOI: 10.1038/jid.2013.500

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  • Asthma 査読

    Kenji Izuhara, Shoichi Suzuki, Kazuhiko Arima, Shoichiro Ohta, Masako Inamitsu, Ken-Ichi Yamamoto

    Metabolism of Human Diseases: Organ Physiology and Pathophysiology   215 - 219   2014年1月

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    記述言語:英語   掲載種別:論文集(書籍)内論文   出版者・発行元:Springer-Verlag Wien  

    Asthma is one of the most common chronic diseases, with an estimated 300 million people affected worldwide [ 1 ]. The incidence of asthma continues to increase, especially among children. Asthmais defi ned by its clinical, physiological, and pathological characteristics [ 1 ]. Its predominant clinical feature is recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. The main physiological feature is episodic obstructed breathing characterized by constricted expiratory airways, leading to asthma’s clinical features.The dominant pathological feature is chronic infl ammation of the airways associated with airway hyperresponsiveness, which obstructs or limits airfl ow when airways are exposed to various risk factors.Chronic inflammation is characterized as infi ltration of infl ammatory cells (e.g., mast cells, eosinophils, and T cells
    see chapter “ Overview ” under the part “Immune system”) and is sometimes associated with airway structural changes called “remodeling”such as mucus hyperproduction by epithelial cells, subepithelial fi brosis by fi broblasts, hypertrophy and/or hyperplasia of airway smooth muscle cells, and proliferation of blood vessels.

    DOI: 10.1007/978-3-7091-0715-7_32

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  • [Application of basic research to development of diagnostics and therapeutic agents against inflammatory diseases]. 査読

    Kenji Izuhara, Shoichiro Ohta, Kazuhiko Arima, Shoichi Suzuki, Masako Inamitsu, Ken-ichi Yamamoto

    Rinsho byori. The Japanese journal of clinical pathology   61 ( 10 )   900 - 8   2013年10月

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    記述言語:日本語  

    Biomarkers are generally important for the treatment of patients from the points of diagnosis of disease, assessment of cure, assessment of prognosis such as metastasis or recurrence, prevention of disease, and prediction of drug efficacy. Currently it is well accepted that allergic diseases such as bronchial asthma and atopic dermatitis are not single diseases, but syndromes encompassing different diseases entities. Therefore, it is important to cluster allergic disease patients to assess prognosis or the choice of therapeutic drugs, and useful biomarkers are required for these purposes. Periostin, an extracellular matrix protein, has recently emerged as a biomarker useful for clustering asthma patients. We further found that periostin plays an important role in allergic inflammation and based on this finding we are now developing therapeutic agents targeting periostin against allergic diseases. Since periostin is involved in the pathogenesis of various inflammatory diseases in addition to allergic diseases, such diagnostics and therapeutic agents can be applied to many inflammatory diseases. In this article, we describe the history of periostin research and our application of basic research to the development of diagnostics and therapeutic agents against inflammatory diseases.

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  • Inhibition of RAGE signaling through the intracellular delivery of inhibitor peptides by PEI cationization 査読

    Endy Widya Putranto, Hitoshi Murata, Ken-Ichi Yamamoto, Ken Kataoka, Hidenori Yamada, Jun-Ichiro Futami, Masakiyo Sakaguchi, Nam-Ho Huh

    INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE   32 ( 4 )   938 - 944   2013年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPANDIDOS PUBL LTD  

    The receptor for advanced glycation end products (RAGE) is a multi-ligand cell surface receptor and a member of the immunoglobulin superfamily. RAGE is involved in a wide range of inflammatory, degenerative and hyper-proliferative disorders which span over different organs by engaging diverse ligands, including advanced glycation end products, S100 family proteins, high-mobility group protein B1 (HMGB1) and amyloid beta. We previously demonstrated that the cytoplasmic domain of RAGE is phosphorylated upon the binding of ligands, enabling the recruitment of two distinct pairs of adaptor proteins, Toll-interleukin 1 receptor domain-containing adaptor protein (TIRAP) and myeloid differentiation protein 88 (MyD88). This engagement allows the activation of downstream effector molecules, and thereby mediates a wide variety of cellular processes, such as inflammatory responses, apoptotic cell death, migration and cell growth. Therefore, inhibition of the binding of TIRAP to RAGE may abrogate intracellular signaling from ligand-activated RAGE. In the present study, we developed inhibitor peptides for RAGE signaling (RAGE-I) by mimicking the phosphorylatable cytosolic domain of RAGE. RAGE-I was efficiently delivered into the cells by polyethylenimine (PEI) cationization. We demonstrated that RAGE-I specifically bound to TIRAP and abrogated the activation of Cdc42 induced by ligand-activated RAGE. Furthermore, we were able to reduce neuronal cell death induced by an excess amount of S100B and to inhibit the migration and invasion of glioma cells in vitro. Our results indicate that RAGE-I provides a powerful tool for therapeutics to block RAGE-mediated multiple signaling.

    DOI: 10.3892/ijmm.2013.1467

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  • DOCK7 is a critical regulator of the RAGE-Cdc42 signaling axis that induces formation of dendritic pseudopodia in human cancer cells 査読

    Ken-Ichi Yamamoto, Hitoshi Murata, Endy Widya Putranto, Ken Kataoka, Akira Motoyama, Toshihiko Hibino, Yusuke Inoue, Masakiyo Sakaguchi, Nam-Ho Huh

    ONCOLOGY REPORTS   29 ( 3 )   1073 - 1079   2013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)   出版者・発行元:SPANDIDOS PUBL LTD  

    Cellular migration is a fundamental process linked to cancer metastasis. Growing evidence indicates that the receptor for advanced glycation end products (RAGE) plays a pivotal role in this process. With regard to downstream signal transducers of RAGE, diaphanous-1 and activated small guanine nucleotide triphosphatases, Rac1 and Cdc42, have been identified. To obtain precise insight into the direct downstream signaling mechanism of RAGE, we screened for proteins interacting with the cytoplasmic domain of RAGE employing an immunoprecipitation-liquid chromatography coupled with an electrospray tandem mass spectrometry system. In the present study, we found that the cytoplasmic domain of RAGE interacted with an atypical DOCK180-related guanine nucleotide exchange factor, dedicator of cytokinesis protein 7 (DOCK7). DOCK7 bound to the RAGE cytoplasmic domain and transduced a signal to Cdc42, resulting in the formation of abundant highly branched filopodia-like protrusions, dendritic pseudopodia. Blocking of the function of DOCK7 greatly abrogated the formation of dendritic pseudopodia and suppressed cellular migration. These results indicate that DOCK7 functions as an essential and downstream regulator of RAGE-mediated cellular migration through the formation of dendritic pseudopodia.

    DOI: 10.3892/or.2012.2191

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  • S100A7 promotes the migration and invasion of osteosarcoma cells via the receptor for advanced glycation end products 査読

    Ken Kataoka, Tomoyuki Ono, Hitoshi Murata, Mika Morishita, Ken-Ichi Yamamoto, Masakiyo Sakaguchi, Nam-Ho Huh

    ONCOLOGY LETTERS   3 ( 5 )   1149 - 1153   2012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)   出版者・発行元:SPANDIDOS PUBL LTD  

    Osteosarcoma is the most common malignant tumor of bone in childhood and adolescence. Despite intensive research for new therapies, the outcome in patients with metastasis remains extremely poor. S100 proteins are involved in the proliferation, cell cycle progression and metastasis of numerous malignant tumors, including osteosarcoma. In the present study, we identified S100A7 as a candidate to promote the migration of osteosarcoma cells. S100A7 promoted the migration and invasion of osteosarcoma cells as assayed in vitro. An in vitro pull-down assay revealed the binding of the recombinant S100A7 protein with its putative receptor, the receptor for advanced glycation end products (RAGE). The downregulation of RAGE by a specific siRNA markedly suppressed the migration and invasion of osteosarcoma cells. Furthermore, the matrix metalloproteinase activity of osteosarcoma cells was enhanced by S100A7 and suppressed by the downregulation of RAGE. These results indicate that S100A7 promotes the migration and invasion of osteosarcoma cells through RAGE. The S100A7-RAGE axis may thus be a new target for preventing the invasion and/or metastasis of osteosarcoma.

    DOI: 10.3892/ol.2012.612

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  • TIRAP, an Adaptor Protein for TLR2/4, Transduces a Signal from RAGE Phosphorylated upon Ligand Binding 査読

    Masakiyo Sakaguchi, Hitoshi Murata, Ken-ichi Yamamoto, Tomoyuki Ono, Yoshihiko Sakaguchi, Akira Motoyama, Toshihiko Hibino, Ken Kataoka, Nam-ho Huh

    PLOS ONE   6 ( 8 )   e23132-e23132   2011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)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    The receptor for advanced glycation end products (RAGE) is thought to be involved in the pathogenesis of a broad range of inflammatory, degenerative and hyperproliferative diseases. It binds to diverse ligands and activates multiple intracellular signaling pathways. Despite these pivotal functions, molecular events just downstream of ligand-activated RAGE have been surprisingly unknown. Here we show that the cytoplasmic domain of RAGE is phosphorylated at Ser391 by PKCf upon binding of ligands. TIRAP and MyD88, which are known to be adaptor proteins for Toll-like receptor-2 and -4 (TLR2/4), bound to the phosphorylated RAGE and transduced a signal to downstream molecules. Blocking of the function of TIRAP and MyD88 largely abrogated intracellular signaling from ligand-activated RAGE. Our findings indicate that functional interaction between RAGE and TLRs coordinately regulates inflammation, immune response and other cellular functions.

    DOI: 10.1371/journal.pone.0023132

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  • Internalization of REIC/Dkk-3 protein by induced pluripotent stem cell-derived embryoid bodies and extra-embryonic tissues 査読

    Ken Kataoka, Masakiyo Sakaguchi, Kun Peng Li, Chika Taketa, Ken-Ichi Yamamoto, Gang Du, Hiroaki Funahashi, Hitoshi Murata, Nam-Ho Huh

    INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE   26 ( 6 )   853 - 859   2010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)   出版者・発行元:SPANDIDOS PUBL LTD  

    REIC/Dkk-3 was first identified as a down-regulated gene in a number of human immortalized cells and human tumor-derived cell lines. Overexpression of the REIC/Dkk-3 gene using an adenovirus vector (Ad-REIC) has showed a potent selective therapeutic effect on various human cancers through induction of ER stress. Furthermore, we recently showed that Ad-REIC has an indirect host-mediated anti-tumor activity by induction of IL-7. However, the physiological function of REIC/Dkk-3 is still unclear. As a first step to study the possible receptor(s) for secreted REIC/Dkk-3, we analyzed the internalization of Cy3-labeled recombinant REIC/Dkk-3 protein. Among the cell lines screened, mouse induced pluripotent stem (iPS) cells showed a unique pattern of internalization. The internalization was observed in peripheral cells of spherical colonies formed spontaneously, but not in undifferentiated iPS cells. When we analyzed embryoid bodies (EBs) derived from iPS cells, REIC/Dkk-3 protein was internalized specifically by differentiated cells located at the periphery of EBs. Interestingly, Dkk-1 was internalized by undifferentiated cells at the center of the EBs. When developmental tissue was analyzed, internalization of REIC/Dkk-3 protein was strictly limited to extra-embryonic tissue, such as the trophectoderm layer of 4.5 days post-coitus (dpc) blastocysts and the chorionic membrane at 16.5 dpc. The mechanism of the internalization was confirmed to be endocytosis. These findings will contribute to knowledge on the interaction of REIC/Dkk-3 with a possible receptor(s).

    DOI: 10.3892/ijmm_00000534

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  • Transcriptional regulation of a brown adipocyte-specific gene, UCP1, by KLF11 and KLF15 査読

    Ken-ichi Yamamoto, Masakiyo Sakaguchi, Reinhold J. Medina, Aya Niida, Yoshihiko Sakaguchi, Masahiro Miyazaki, Ken Kataoka, Nam-ho Huh

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   400 ( 1 )   175 - 180   2010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)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Several growth factors and transcription factors have been reported to play important roles in brown adipocyte differentiation and modulation of thermogenic gene expression, especially the expression of UCP1. In this study, we focused on KLF11 and KLF15, which were expressed highly in brown adipose tissue. Our data demonstrated that KLF11 and KLF15 interacted directly with the UCP1 promoter using GC-box and GT-boxes, respectively. Co-transfection of KLF11 and KLF15 in the mesenchymal stem cell line muBM3.1 during brown adipocyte differentiation enhanced the expression level of UCP1. KLF11, but not KLF15, was essential for UCP1 expression during brown adipocyte differentiation of muBM3.1. (C) 2010 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.bbrc.2010.08.039

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  • A Novel Three-Dimensional Culture System for Isolation and Clonal Propagation of Neural Stem Cells Using a Thermo-Reversible Gelation Polymer 査読

    Xin-Zhi Yang, Ken Kataoka, Reinhold Medina, Ken-Ichi Yamamoto, Swe Swe Than, Masahiro Miyazaki, Nam-Ho Huh

    TISSUE ENGINEERING PART C-METHODS   15 ( 4 )   615 - 623   2009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)   出版者・発行元:MARY ANN LIEBERT INC  

    In the present study, we examined the possible utility of a three-dimensional culture system using a thermo-reversible gelation polymer to isolate and expand neural stem cells (NSCs). The polymer is a synthetic biologically inert polymer and gelates at temperatures higher than the gel-sol transition point (similar to 20 degrees C). When fetal mouse brain cells were inoculated into the gel, spherical colonies were formed (similar to 1% in primary culture and similar to 9% in passage cultures). The spheroid-forming cells were positive for expression of the NSC markers nestin and Musashi. Under conditions facilitating spontaneous neural differentiation, the spheroid-forming cells expressed genes characteristic to astrocytes, oligodendrocytes, and neurons. The cells could be successively propagated at least to 80 poly-D-lysines over a period of 20 weeks in the gel culture with a growth rate higher than that observed in suspension culture. The spheroids formed by fetal mouse brain cells in the gel were shown to be of clonal origin. These results indicate that the spheroid culture system is a convenient and powerful tool for isolation and clonal expansion of NSCs in vitro.

    DOI: 10.1089/ten.tec.2008.0516

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▼全件表示

MISC

  • ヒトiPS細胞由来神経細胞と動物モデルを用いた軸索変性誘導分子SARM1の阻害剤開発

    村田等, 安藤隆幸, 安井優, 越智俊樹, 友信奈保子, 山本健一, 木下理恵, 阪口政清

    組織培養研究(Web)   41 ( 2 )   2023年

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  • 軸索変性誘導分子SARM1の阻害剤開発

    村田等, 安藤隆幸, 大磯和真, 友信奈保子, 山本健一, 木下理恵, 阪口政清

    日本神経化学会大会抄録集(Web)   65th   2022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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  • 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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  • 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   掲載種別:書評論文,書評,文献紹介等   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.

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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

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

  • 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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  • 基礎研究の炎症疾患診断薬・治療薬開発への応用

    出原賢治, 太田昭一郎, 有馬和彦, 鈴木章一, 稲光正子, 山本健一

    臨床病理   61 ( 10 )   900 - 908   2013年10月

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    記述言語:日本語   出版者・発行元:日本臨床検査医学会  

    J-GLOBAL

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  • 気管支喘息の研究 アップデート I.気管支喘息の分子病態

    出原賢治, 鈴木章一, 有馬和彦, 稲光正子, 山本健一, 増岡美穂, 太田昭一郎

    アレルギー・免疫   20 ( 7 )   958 - 964   2013年6月

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    記述言語:日本語  

    J-GLOBAL

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  • S100A8およびS100A9タンパク質の新規受容体の探索とそのがん進展における役割(Identification of novel receptors for pro-inflammatory S100A8/A9 proteins and their potential roles in tumor progression)

    阪口 政清, 日比野 利彦, 村田 等, 井上 裕介, 山本 健一, 片岡 健, 許 南浩

    日本癌学会総会記事   71回   59 - 59   2012年8月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • 多機能受容体RAGEの下流信号伝達機構の解明(TIRAP is a critical transducer of RAGE-mediated inflammatory signaling)

    阪口 政清, 村田 等, 山本 健一, 阪口 義彦, 本山 晃, 日比野 利彦, 片岡 健, 許 南浩

    日本癌学会総会記事   70回   225 - 225   2011年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • S100A7による骨肉腫細胞の遊走・浸潤の多機能受容体RAGEを介した制御機構(Promotion of migration and invasion of osteosarcoma cells by S100A7 through RAGE)

    片岡 健, 阪口 政清, 小野 智之, 森下 美加, 山本 健一, 村田 等, 許 南浩

    日本癌学会総会記事   70回   79 - 79   2011年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • S100タンパク質受容体の結合解析

    森下美加, 村田等, 山本健一, 片岡健, 阪口政清, HUH Nam‐Ho

    日本分子生物学会年会プログラム・要旨集(Web)   34th   4P-0293 (WEB ONLY)   2011年

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    記述言語:日本語  

    J-GLOBAL

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  • 正常皮膚におけるREIC/Dkk‐3の発現制御因子の検索

    前原奈都美, 片岡健, DU Gang, 村田等, 山本健一, 阪口政清, HUH Nam‐Ho

    日本分子生物学会年会プログラム・要旨集(Web)   34th   1P-0254 (WEB ONLY)   2011年

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    記述言語:日本語  

    J-GLOBAL

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  • KLF11とKLF15によるUCP1の発現制御

    山本 健一, 阪口 政清, 片岡 健, 許 南浩

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   83回・33回   2P - 0822   2010年12月

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    記述言語:日本語   出版者・発行元:(公社)日本生化学会  

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  • マウス骨髄間葉系幹細胞の褐色脂肪分化をKLF11およびKLF15は促進する

    片岡健, 山本健一, 阪口政清, HUH Nam‐ho

    硬組織再生生物学会学術大会・総会プログラム・抄録集   19th   40   2010年7月

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    記述言語:日本語  

    J-GLOBAL

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  • 褐色脂肪細胞分化におけるKLF11とKLF15の役割

    山本健一, 阪口政清, MEDINA Reinhold, 新居田彩, 宮崎正博, 片岡健, HUH Nam‐Ho

    組織培養研究   29 ( 1 )   82   2010年3月

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    記述言語:日本語  

    J-GLOBAL

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  • 分化したマウスES細胞およびiPS細胞のCy3標識REIC/Dkk‐3タンパク質の取り込み

    片岡健, 阪口政清, 李坤鵬, 武田千佳, 山本健一, 許南浩

    再生医療   8   223   2009年2月

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    記述言語:日本語  

    J-GLOBAL

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  • Eagle’s Minimum Essential Medium (MEM)培地の細胞コロニー形成能は製造した会社のMEMによって異なる.

    Takemura Yoshihito, Yamamoto Ken-ichi, Asada Nobuhiko, Namba Masayoshi

    Tissue Culture Research Communications   26 ( 1 )   143 - 147   2007年

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  • 水道水でつくったEagle’s minimum essential mediumの培養細胞への傷害作用は同じ水道水でつくったDulbecoo’s modified Eagle’s medium培地で消失する.

    Yamamoto Ken-ichi, Takemura Yoshihito, Asada Nobuhiko, Namba Masayoshi

    Tissue Culture Research Communications   25 ( 1 )   147 - 150   2006年

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▼全件表示

講演・口頭発表等

  • 核内 PD-L1 は MCRIP1 を抑制することでトリプルネガティブ乳がん細胞の浸潤能を促進する

    合原 勇馬, 友信 奈保子, 木下 理恵, 山本 建一, 村田 等, 阪口 政清

    第82回日本癌学会学術総会  2023年9月22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:日本語   会議種別:ポスター発表  

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  • Lysyl oxidase-like 4 exerts an atypical role in breast cancer progression that targets the cell-surface annexin A2

    第82回日本癌学会学術総会  2023年9月22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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  • 糞便微生物移植治療から見出した腸内の放線菌の 生理活性評価

    阪口義彦, 武晃, 後藤和義, 原正也, 友信奈保子, 山本健一, 菊池雄太, 坂本光央, 加藤はる, 大宮直木, 阪口政清, 永浜政博

    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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  • STAT1/3 シグナル経路によるNAD+代謝酵素制御を介した神経軸索変性と細胞死の抑制

    安井優, 村田等, 大磯和真, 越智俊樹, 友信奈保子, 山本健一, 木下理恵, 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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  • 細胞表面アネキシンA2/S100A11 結合に着目した 乳がん進行の機序解明

    髙橋徹多, 友信奈保子, Ni LuhGedeYoniKomalasari, 合原勇馬, 山本健一, 木下理恵, 村田等, 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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  • ヒトメラノーマ細胞の増殖と血管新生における冬虫夏草の抗腫瘍作用評価

    長﨑直也, 堀井聡, I Wayan Sumardika, I Made Winarsa Ruma, 友信奈保子, 木下理恵, 山本健一, 村田等, 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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  • ヒトiPS 細胞由来神経細胞と動物モデルを用いた 軸索変性誘導分子SARM1 の阻害剤開発

    村田等, 安藤隆幸, 安井優, 越智俊樹, 友信奈保子, 山本健一, 木下理恵, 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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  • 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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  • 亜鉛結合により活性化されるZEB1 転写因子の 乳がん進展における意義の解明

    山本健一, 平林大輔, 丸山顕嘉, 友信奈保子, 木下理恵, Ni Luh Gade, Yoni Komalasari, 村田等, 合原勇馬, 江帆, 山内明, 栗林太, 豊岡伸一, 井上裕介, 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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  • REIC タンパク質によるPD-L1 制御を介した抗腫瘍機序の解明

    合原勇馬, 友信奈保子, 木下理恵, 村田等, 山本健一, 難波正義, 許南浩, 公文裕己, 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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  • TLR4 accelerates bladder cancer progression upon interaction with S100A8/A9

    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:英語   会議種別:口頭発表(一般)  

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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

    第55回日本結合組織学会学術大会  2023年6月24日 

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    開催年月日: 2023年6月24日 - 2023年6月25日

    記述言語:日本語   会議種別:ポスター発表  

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  • REIC/Dkk-3の受容体への結合はトリプルネガティブ乳がんのPD-L1の発現を抑制する

    吉澤 智香子, 合原 勇馬, 友信 奈保子, 木下 理恵, 二見 淳一郎 , 村田 等, 山本 健一, 阪口 政清 

    第45回日本分子生物学会年会  2022年12月1日 

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    開催年月日: 2022年11月30日 - 2022年12月2日

    会議種別:ポスター発表  

    開催地:千葉県千葉市  

  • A critical role of S100A8/A9-NPTNbeta axis in the lung cancer dissemination

    2022年10月1日 

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    開催年月日: 2022年9月29日 - 2022年10月1日

    会議種別:ポスター発表  

  • REIC タンパク質による免疫チェックポイント制御機構の解明

    合原 勇馬、友信 奈保子、木下 理恵、山本 健一、阪口 政清

    第81回日本癌学会学術総会  2022年9月30日 

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    開催年月日: 2022年9月29日 - 2022年10月1日

    会議種別:ポスター発表  

    開催地:神奈川県横浜市  

  • HRG によるメラノーマの S100A8/A9 を介した脳指向性転移抑制効果の検討

    友信 奈保子、Yoni Komalasari、合原 勇馬、木下 理恵、山本 健一、山内 明、近藤 英作、豊岡 伸一、阪口 政清

    第81回日本癌学会学術総会  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

    会議種別:ポスター発表  

    開催地:神奈川県横浜市  

  • 培養肝細胞を用いたプラスチックラップによる細胞傷害性の解析

    山本 健一, Xian Wen Tan, 有元 佐賀恵, 押木 俊之, 難波 正義, 阪口 政清

    日本組織培養学会 第93回大会  2022年9月3日 

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    開催年月日: 2022年9月2日 - 2022年9月3日

    会議種別:ポスター発表  

    開催地:広島  

  • "7he role of macrophages in anti-S100A8/A9 therapy for inflammatory diseases 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、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8日 

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    開催年月日: 2022年7月7日 - 2022年7月8日

    会議種別:ポスター発表  

    開催地:大阪府  

  • REIC protein suppresses tumor progression through PD-L1 regulation in cancer cells

    Yuma Gohara, Nahoko Tomonobu, Rie Kinoshita, Hitoshi Murata, Ken-ichi Yamamoto, Masayoshi Namba, Nam-ho Huh, Hiromi Kumon, Masakiyo Sakaguchi

    日本組織培養学会第94回大会  2022年7月8日 

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    開催年月日: 2022年7月7日 - 2022年7月8日

    会議種別:口頭発表(一般)  

    開催地:大阪府  

  • Lysyl oxidase-like 4 is prominent in breast cancer progression through its en]ymatic activities

    2022年7月8日 

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    開催年月日: 2022年7月7日 - 2022年7月8日

    会議種別:口頭発表(一般)  

  • 軸索変性誘導分子 SARM1の阻害剤開発

    村田 等、安藤 隆幸、大磯 和真、友信 奈保子、山本 健一、木下 理恵、阪口 政清

    NEURO2022  2022年6月30日 

     詳細を見る

    開催年月日: 2022年6月30日 - 2022年7月3日

    会議種別:ポスター発表  

    開催地:沖縄県  

  • 疾患特異的iPS細胞と動物モデルを用いたパーキンソン病における軸索変性誘導分子 SARM1のリン酸化制御解析

    村田 等, 越智 俊樹, 友信 奈保子, 山本 健一, 木下 理恵, 阪口 政清

    日本組織培養学会第93会大会  2021年9月3日 

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    開催年月日: 2021年9月2日 - 2022年9月3日

    会議種別:口頭発表(一般)  

    開催地:広島県広島市  

  • S100A8/A9を標的とした炎症性疾患に対する治療法の開発

    木下 理恵 , 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93会大会  2021年9月3日 

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    開催年月日: 2021年9月2日 - 2021年9月3日

    会議種別:口頭発表(一般)  

    開催地:広島県広島市  

  • 培養肝細胞を用いたプラスチックラップによる細胞傷害性の解析

    山本 健一 , Xian Wen Tan , 有元 佐賀恵 , 押木 俊之 , 難波 正義 , 阪口 政清

    日本組織培養学会第93会大会  2021年9月3日 

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    開催年月日: 2021年9月2日 - 2021年9月3日

    会議種別:ポスター発表  

  • キシリトールの細胞内グルタチオン調節によるがん選択的細胞死誘導機序の解明

    友信 奈保子,木下 理恵,山本 健一,村田 等,阪口 政清

    日本組織培養学会第93会大会  2021年9月2日 

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    開催年月日: 2021年9月2日 - 2021年9月3日

    会議種別:口頭発表(一般)  

    開催地:広島県広島市  

  • ロテノン誘発パーキンソニズムの病態形成におけるSARM1リン酸化制御の意義

    村田 等、越智 俊樹、山本 健一、木下 理恵、阪口 政清

    第43回日本分子生物学会年会 

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    開催年月日: 2020年12月2日 - 2020年12月4日

    会議種別:ポスター発表  

    開催地:横浜  

  • 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

    第22回日本がん免疫学会総会  2018年 

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    会議種別:口頭発表(一般)  

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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

    第41回日本分子生物学会年会  2018年 

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    記述言語:英語   会議種別:ポスター発表  

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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

    第41回日本分子生物学会年会  2018年 

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  • SARM1 induces neuronal cell death by inhibition of mitochondrial respiration

    2017年 

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  • Identification of novel receptors for pro-inflammatory S100A8/A9 protein and its role(s) in cancer metastasis

    2017年 

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  • Therapeutic Strategies for suppression of cancer metastasis on the basis of finding novel S100A8/A9 receptors

    2017年 

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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

    第39回日本分子生物学会年会  2017年 

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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

    日本組織培養学会第90回大会  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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  • Extract of Cordyceps militaries inhibits angiogenesis and suppresses tumor growth of human malignant melanoma cells

    第89回日本組織培養学会  2016年 

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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

    第39回日本分子生物学会年会  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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  • A critical role of S100A8/A9-NPTN axis in the lung cancer dissemination

    Ken-ichi Yamamoto, Nhoko Tomonobu, Rie Kinoshita, Junichiro Futami, Akira Yamauchi, Shinichi Toyooka, Eisaku Kondo, Masakiyo Sakaguchi

    第81回 日本癌学会学術総会 

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    会議種別:ポスター発表  

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  • 培養肝細胞を用いたプラスチックラップによる細胞傷害性の解析

    山本 健一, Xian Wen Tan, 有元 佐賀恵, 押木 俊之, 難波 正義, 阪口 政清

    日本組織培養学会 第93回大会 

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    会議種別:ポスター発表  

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  • ロテノン誘発パーキンソニズムの病態形成におけるSARM1リン酸化制御の意義

    村田 等、越智 俊樹、山本 健一、木下 理恵、阪口 政清

    第43回日本分子生物学会年会 

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    会議種別:ポスター発表  

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産業財産権

  • 遺伝子発現用カセット及びその産生物

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    出願人:岡山大学

    出願番号:特願2016-059297  出願日:2016年3月23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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  • 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:岡山大学

    出願番号:特願2018-507366 

    公表番号:WO2017-164230 

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共同研究・競争的資金等の研究

  • 難治性潰瘍での変性コラーゲンの局在証明、再上皮化遅延の病態解明とその治療法開発

    研究課題/領域番号:23K09079  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(C)

    久保 美代子, 山本 健一, 米澤 朋子, 大橋 俊孝

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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)  基盤研究(C)

    山本 健一, 木下 理恵, 阪口 政清

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    担当区分:研究代表者 

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

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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

    研究課題/領域番号:20K09847  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)

    久保 美代子, 牧野 英一, 山本 健一, 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 )

    1. 難治性潰瘍モデルを用いてαvβ3発現HKのin vivoでの機能を検索した。
    難治性潰瘍モデルとしてフィブリン(FB)を潰瘍底にコートする方法を行った(慢性創傷ではフィブロネクチン(FN)分布が減少し、FB沈着が増加するので)。方法1:ヌードマウス背部皮膚に直径8 mmの全層皮膚欠損創を2か所作製し、FBゲル(FN除去FG: 3 mg/ml、トロンビン: 12 U/ml混合)をコートした。その上部にαvβ3発現ヒト表皮角化細胞(αvβ3発現HK)あるいは正常ヒト表皮角化細胞(NHK、コントロール)のcell suspension(2 x 100,000個)をFBゲル(FN除去FG: 0.3 mg/ml、トロンビン: 1.2 U/ml混合)内に混合して移植した。創傷被覆材でカバーした後、経時的(4、7、14日) に肉眼的観察と組織学的検査(HE染色標本)とを行った。その結果、7日目でαvβ3発現HKはNHKに比べて再上皮化(生着+周辺表皮からの上皮化)が有意に増加した。14日目で両者とも再上皮化が完了し、有意差はなかった(n= 6)。方法2:シリコンチャンバー(Hat型とCap型、直径11 mm)を全層皮膚欠損創(上記と同様に作製)に装着する方法を行った。この方法は潰瘍周辺からの表皮遊走(マウス由来)をブロックする事ができるので移植細胞のみの生着と上皮化を観察できる。FBゲルのコートならびに細胞移植の方法は方法1と同様に行った。その結果、7日目、14日目でαvβ3発現HKはNHKに比べて生着および上皮化が有意に増加した(n= 5)。以上より、αvβ3発現HK移植はin vivoで再上皮化を促進する事が明らかになった。
    <BR>
    2. αvβ3発現HK使用の安全性を調べた。
    αvβ3発現HK(2 x 100,000個、レトロウイルスベクター法で作製)をFBゲル(FN除去FG: 0.3 mg/ml、トロンビン: 1.2 U/ml)内に混合し、ヌードマウスの背部に皮下注射した。8週目の組織学的検査(HE染色標本)で腫瘍形成のない事を確認した。

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  • 新規S100A8/A9阻害分子の発見に基づいたがん脳指向転移の機構解明とその制御

    研究課題/領域番号:20H03516  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(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, 村田 等

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    配分額:17420000円 ( 直接経費:13400000円 、 間接経費:4020000円 )

    本年度の研究では、(1)HRGとS100A8/A9が遠隔の腫瘍に応答して脳内環境のどの細胞からそれぞれ産生放出されているかを理解すること、(2)HRGの低下と脳転移に関連性があるかを検証すること、さらに、計画終了後の展開を念頭に時間が許せば、(3)HRGによるS100A8/A9阻害作用がなぜ脳選択的に起こるのか、その糸口を見出すことである。成果は以下の通りである。
    <BR>
    (1)S100A8/A9はミクログリア細胞が産生していることが判明したが、HRGは免疫染色用の良い抗体がなく患者由来組織切片において検出することができていない。
    (2)血漿を用いたELISA検討からHRGは脳転移がん患者さんで顕著に低下することが判明した。
    (3)脳転移の起こりやすくしたB16-BL6クローン(HRGへの反応が鈍い細胞)についてRNAseq解析を行った。その結果、親株と比較して数多くの遺伝子発現変動が起こっており、その中でも脳転移の引き金になる、あるいはHRG耐性の理由となる可能性のある遺伝子変動をとらえることができた。

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  • S100A11-RAGEシグナルを標的とした膵臓がん微小環境の解析とその治療

    研究課題/領域番号:19K16714  2019年04月 - 2022年03月

    日本学術振興会  科学研究費助成事業 若手研究  若手研究

    山本 健一

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    担当区分:研究代表者 

    配分額:3120000円 ( 直接経費:2400000円 、 間接経費:720000円 )

    本研究では、がん細胞とその周囲にある線維芽細胞とのクロストークを主としたがん微小環境の解析を目的。この解析は独自に発見したS100A11- RAGEを基軸として進め、がん感化型線維芽細胞から分泌されるがん悪性化因子を同定し、膵臓がん周囲の微小環境下で起きる現象を解き明かすことを目的とする。また、このがん悪性化機構に対し、独自で作製した抗RAGE抗体を用いて腫瘍周囲の線維化の抑制と抗腫瘍効果、抗がん剤治療との併用の検証を目的としている。 2019年度までに膵臓がん細胞が分泌するS100A11は線維芽細胞の持つRAGE受容体を介して線維芽細胞の細胞内でMyDD88-mTOR-p70S6Kの活性化による細胞増殖が促進すること、またS100A11による刺激を受けた線維芽細胞が分泌するPGE2が膵臓がん細胞の遊走能や浸潤能を亢進させることを見出し、報告している。RAGE受容体はS100A11の他のS100タンパク質もリガンドとして機能することが報告されている。膵臓がん細胞はこれまでにS100A6、S100A8、S100A9などの発現亢進が報告されている。そこで、S100A11-RAGEの作用が膵臓がん周囲線維芽細胞の増殖にどれだけ重要かを観察するため、あらかじめS100A11で免疫したマウスと通常のマウスに膵臓がん細胞と繊維が細胞を混ぜて移植し、その腫瘍形成の比較を行った。その結果、あらかじめ免疫を行ったマウスでの腫瘍の成長が抑制され、腫瘍周囲の繊維化も減少していた。

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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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  • アレルギー疾患の慢性化機序の解明とそれに対する治療戦略の確立

    研究課題/領域番号:25293224  2013年04月 - 2016年03月

    日本学術振興会  科学研究費助成事業  基盤研究(B)

    出原 賢治, 有馬 和彦, 鈴木 章一, 太田 昭一郎, 小川 雅弘, 布村 聡, 山本 健一, 稲光 正子, 南里 康弘, 増岡 美穂

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    配分額:18330000円 ( 直接経費:14100000円 、 間接経費:4230000円 )

    2型免疫反応はアレルギー性炎症の主体であるが,2型サイトカインであるIL-4やIL-13によるアレルギー炎症の形成機序の詳細は不明のままである。我々はIL-4やIL-13の誘導遺伝子であるペリオスチンに着目して,その機能解析や疾患との関連性について解析を進めた。本研究では,線維芽細胞から産生されたペリオスチンと皮膚表皮細胞より産生されたIL-1が協調して線維芽細胞でのIL-6産生を誘導することを明らかにした。さらに,アレルギー性結膜炎患者の涙液において高濃度のペリオスチンを検出し,その濃度が重症度と相関することから,アレルギー性結膜炎の診療における涙液ペリオスチン測定の有用性を明らかにした。

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担当授業科目

  • アンチエイジング特論 (2023年度) 特別  - その他

  • アンチエイジング特論(医学) (2023年度) 特別  - その他

  • 医歯科学概論 (2023年度) 集中  - その他

  • 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

  • 腫瘍学 (2023年度) 特別  - その他

  • アンチエイジング特論(医学) (2022年度) 特別  - その他

  • 医学セミナー(チュートリアル) (2022年度) 第1学期

  • 医学生物学 (2022年度) 特別

  • 医歯科学概論 (2022年度) 集中  - その他

  • 生化学 (2022年度) 集中

  • 生命の不思議1 (2022年度) 第3学期

  • 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

  • 腫瘍学 (2022年度) 特別

  • 医歯科学概論 (2021年度) 集中  - 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

 

メディア報道

  • 連続シンポジウム「SDGs地域課題を探る」 新聞・雑誌

    山陽新聞  2022年6月4日

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    執筆者:本人以外 

  • 貝類からプラ検出 海への流出防止へ総力を 新聞・雑誌

    山陽新聞  社説  2022年5月29日

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    執筆者:本人以外 

  • 市販貝類からプラ糸くず 新聞・雑誌

    山陽新聞  2022年5月12日

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    執筆者:本人以外