Faculty Profiles - SAKAGUCHI Masakiyo

MISC - SAKAGUCHI Masakiyo

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S100A11は筋浸潤性膀胱癌細胞と線維芽細胞のクロストークに関与し腫瘍進行に寄与する(S100A11 contributes to tumor progression with cross talking between muscle invasive bladder cancer cells and fibroblasts)

光井洋介, 定平卓也, 渡部昌実, 丸山雄樹, 荒木元朗, 渡邉豊彦, 阪口政清, 那須保友

西日本泌尿器科 81 ( 増刊 ) 138 - 138 2019.10

Comparing effects of small molecular weight compounds on proliferation and chemotaxis of pancreatic cancer cells

Masahiro Yamamura, Akira Yamauchi, Naoki Katase, Masakiyo Sakaguchi, Yosuke Katata, Hiroaki Tanioka, Makoto Okawaki, Takeshi Nagasaka, Yoshiyuki Yamaguchi

CANCER RESEARCH 79 ( 13 ) 2019.7

Melanoma cell adhesion molecule (MCAM) induces dissemination of melanoma upon S100A8/A9 binding

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

日本癌学会学術総会抄録集(Web) 78th 2019

S100タンパク質に着眼したがん転移機構の解明とその制御.

SAKAGUCHI Masakiyo

岡山医学会雑誌 130 135 - 139 2018.10

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 2018.7

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 2018.7

Exogenous DKK-3/REIC inhibits Wnt/beta-catenin signaling and cell proliferation in human kidney cancer KPK1

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

ONCOLOGY LETTERS 14 ( 5 ) 5638 - 5642 2017.11

Language：English Publisher：SPANDIDOS PUBL LTD

The third member of the Dickkopf family (DKK-3), also known as reduced expression in immortalized cells (REIC), is a tumor suppressor present in a variety of tumor cells. Regarding the regulation of the Wnt/beta-catenin signaling pathway, exogenous DKK-1 and DKK-2 are reported to inhibit Wnt signaling by binding the associated effectors. However, whether exogenous DKK-3 inhibits Wnt signaling remains unclear. A recombinant protein of human full-length DKK-3 was used to investigate the exogenous effects of the protein in vitro in KPK1 human renal cell carcinoma cells. It was demonstrated that the expression of phosphorylated (p-)beta-catenin (inactive form as the transcriptional factor) was increased in KPK1 cells treated with the exogenous DKK-3 protein. The levels of non-p-beta-catenin (activated form of beta- catenin) were consistently decreased. It was revealed that the expression of transcription factor (TCF) 1 and c-Myc, the downstream transcription factors of the Wnt/beta-catenin signaling pathway, was inhibited following treatment with DKK-3. A cancer cell viability assay confirmed the anti-proliferative effects of exogenous DKK-3 protein, which was consistent with a suppressed Wnt/beta-catenin signaling cascade. In addition, as low-density lipoprotein receptor-related protein 6 (LRP6) is a receptor of DKK-1 and DKK-2 and their interaction on the cell surface inhibits Wnt/beta-catenin signaling, it was examined whether the exogenous DKK-3 protein affects LRP6-mediated Wnt/beta-catenin signaling. The LRP6 gene was silenced and the effects of DKK-3 on the time course of the upregulation of p-beta-catenin expression were subsequently analyzed. Notably, LRP6 depletion elevated the base level of p-beta-catenin; however, there was no significant effect on its upregulation course or expression pattern. These findings indicate that exogenous DKK-3 upregulates p-beta-catenin and inhibits Wnt/beta-catenin signaling in an LRP6-independent manner. Therefore, exogenous DKK-3 protein may inhibit the proliferation of KPK1 cells via inactivating Wnt/beta-catenin signaling.

DOI： 10.3892/ol.2017.6833

Web of Science

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Promising therapeutic efficacy of a novel reduced expression in immortalized cells/dickkopf-3 expressing adenoviral vector for hepatocellular carcinoma

Hiroaki Sawahara, Hidenori Shiraha, Daisuke Uchida, Hironari Kato, Ryo Kato, Atsushi Oyama, Teruya Nagahara, Masaya Iwamuro, Shigeru Horiguchi, Koichiro Tsutsumi, Mari Mandai, Tetsushige Mimura, Nozomu Wada, Yasuto Takeuchi, Kenji Kuwaki, Hideki Onishi, Shinichiro Nakamura, Masami Watanabe, Masakiyo Sakaguchi, Akinobu Takaki, Kazuhiro Nouso, Takahito Yagi, Yasutomo Nasu, Hiromi Kumon, Hiroyuki Okada

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 32 ( 10 ) 1769 - 1777 2017.10

Language：English Publisher：WILEY

Background and Aim: Reduced expression in immortalized cells (REIC)/dickkopf-3 (Dkk-3) is a tumor suppressor gene that is downregulated in various cancers. In our previous study of prostate cancer, the REIC/Dkk-3-expressing adenoviral vector (Ad-REIC) was found to induce cancer-selective apoptosis. This study recently developed a novel super gene expression (SGE) system and used this system to re-construct an Ad-REIC vector, termed the Ad-SGE-REIC, to achieve more effective therapeutic outcomes. In this study, the therapeutic effects of Ad-SGE-REIC on hepatocellular carcinoma (HCC) was assessed.
Methods: Human HCC cell lines (HLE, Huh7, HepG2, HLF, SK-Hep1, and PLC), human HCC tissues, and mouse HCC cell line (Hepa1-6) were used in this study. REIC/Dkk-3 expression was assessed by immunoblotting and immunohistochemistry. The relative cell viability and the apoptotic effect were examined in vitro, and the anti-tumor effects of Ad-SGE-REIC treatment were analyzed in the mouse xenograft model. This study additionally assessed anti-tumor immunological effects on the immunocompetent mice.
Results: REIC/Dkk-3 expression was decreased in HCC cell lines and HCC tissues. Ad-SGE-REIC reduced cell viability and induced apoptosis in HCC cell lines (HLE and Huh7), inhibited tumor growth in the mouse xenograft model, and demonstrated in vivo anti-cancer immunostimulatory effects on the HCC cell line (Hepa1-6).
Conclusions: Ad-SGE-REIC treatment not only enhanced cell killing effects in vitro but also elicited significant therapeutic effects, with tumor growth suppression, in vivo. REIC/Dkk-3 gene therapy using Ad-SGE-REIC potentially represents an innovative new therapeutic tool for HCC.

DOI： 10.1111/jgh.13757

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Identification of a novel component leading to anti-tumor activity besides the major ingredient cordycepin in Cordyceps militaris extract

Takeharu Wada, I. Wayan Sumardika, Shingo Saito, I. Made Winarsa Ruma, Eisaku Kondo, Masami Shibukawa, Masakiyo Sakaguchi

JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES 1061 209 - 219 2017.9

Language：English Publisher：ELSEVIER SCIENCE BV

In accordance with our previous study that was carried out to identify novel anti-tumor ingredients, chromatographic separation in combination with an anti-tumor activity assay was used for analysis of Cordyceps militaris extract in this study. Various modes of chromatography including reversed-phase, cation-exchange and anion exchange were used to separate components of Cordyceps militaris, which showed various chemical properties. Anti-tumor activity of each fraction was assessed by a Hoechst staining-based apoptosis assay using malignant melanoma MeWo cells. By these repeated approaches through chromatographic segregation and cell biological assay, we finally succeeded in identifying the target substance from a certain fraction that included neutral hydrophilic components using a pre-column and post-column chlorine adduct ionization LC APCI MS method. The target substance was a mono-carbohydrate, xylitol, that induced apoptotic cell death in MeWo cells but not in normal human OUMS-24 fibroblasts. This is the first study showing that Cordyceps militaris extract contains a large amount of xylitol. Thus, our results will contribute greatly to uncovering the mysterious multifunctional herbal drug Cordyceps militaris as an anti-tumor agent.

DOI： 10.1016/j.jchromb.2017.07.022

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An HNF4-microRNA-194/192 signaling axis maintains hepatic cell function

Aoi Morimoto, Mana Kannari, Yuichi Tsuchida, Shota Sasaki, Chinatsu Saito, Tsuyoshi Matsuta, Tsukasa Maeda, Megumi Akiyama, Takahiro Nakamura, Masakiyo Sakaguchi, Nobukazu Nameki, Frank J. Gonzalez, Yusuke Inoue

JOURNAL OF BIOLOGICAL CHEMISTRY 292 ( 25 ) 10574 - 10585 2017.6

Language：English Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Hepatocyte nuclear factor 4 (HNF4) controls the expression of liver-specific protein-coding genes. However, some microRNAs are also modulated by HNF4, and it is not known whether they are direct targets of HNF4 and whether they influence hepatic function. In this study, we found that HNF4 regulates microRNAs, indicated by marked down-regulation of miR-194 and miR-192 (miR-194/192) in liver-specific Hnf4a-null (Hnf4a(H)) mice. Transactivation of the shared miR-194/192 promoter was dependent on HNF4 expression, indicating that miR-194/192 is a target gene of HNF4. Screening of potential mRNAs targeted by miR-194/192 revealed that expression of genes involved in glucose metabolism (glycogenin 1 (Gyg1)), cell adhesion and migration (activated leukocyte cell adhesion molecule (Alcam)), tumorigenesis and tumor progression (Rap2b and epiregulin (Ereg)), protein SUMOylation (Sumo2), epigenetic regulation (Setd5 and Cullin 4B (Cln4b)), and the epithelial-mesenchymal transition (moesin (Msn)) was up-regulated in Hnf4a(H) mice. Moreover, we also found that miR-194/192 binds the 3-UTR of these mRNAs. siRNA knockdown of HNF4 suppressed miR-194/192 expression in human hepatocellular carcinoma (HCC) cells and resulted in up-regulation of their mRNA targets. Inhibition and overexpression experiments with miR-194/192 revealed that Gyg1, Setd5, Sumo2, Cln4b, and Rap2b are miR-194 targets, whereas Ereg, Alcam, and Msn are miR-192 targets. These findings reveal a novel HNF4 network controlled by miR-194/192 that may play a critical role in maintaining the hepatocyte-differentiated state by inhibiting expression of genes involved in dedifferentiation and tumorigenesis. These insights may contribute to the development of diagnostic markers for early HCC detection, and targeting of the miR-194/192 pathway could be useful for managing HCC.

DOI： 10.1074/jbc.M117.785592

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Advanced approach to prevent cancer metastasis based on S100A8/A9-mediated seed and soil theory

49 ( 7 ) 359 - 362 2017.6

Innovative approach to prevent cancer metastasis based on S100A8/A9-mediated seed and soil theory

49 ( 3 ) 143 - 146 2017.3

Distant Bystander Effect of REIC/DKK3 Gene Therapy Through Immune System Stimulation in Thoracic Malignancies

Ken Suzawa, Kazuhiko Shien, Huang Peng, Masakiyo Sakaguchi, Masami Watanabe, Shinsuke Hashida, Yuho Maki, Hiromasa Yamamoto, Shuta Tomida, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Yasutomo Nasu, Hiromi Kumon, Shinichiro Miyoshi, Shinichi Toyooka

ANTICANCER RESEARCH 37 ( 1 ) 301 - 307 2017.1

Language：English Publisher：INT INST ANTICANCER RESEARCH

Background: Reduced expression in immortalized cell (REIC)/Dickkoph-3 (DKK3) is a tumor-suppressor gene, and its overexpression by adenovirus vector (Ad-REIC) exhibits a remarkable therapeutic effect on various human cancer types through a mechanism triggered by endoplasmic reticulum stress. Materials and Methods: We examined the direct anti-tumor effect of Ad-REIC gene therapy on lung cancer and malignant mesothelioma cell lines in vitro, and the distant bystander effect using immunocompetent mouse allograft models with bilateral flank tumors. Results: Ad-REIC treatment showed antitumor effect in many lung cancer and malignant mesothelioma cell lines in vitro. In an in vivo model, Ad-REIC treatment inhibited the growth not only of directly treated tumors but also of distant untreated tumors. By immunohistochemical analysis, infiltration of T-cells and natural killer (NK) cells and expression of the major histocompatibility complex (MHC) class I molecules were observed in bilateral tumors. Conclusion: Ad-REIC treatment not only had a direct antitumor effect but also an indirect bystander effect through stimulation of the immune system.

DOI： 10.21873/anticanres.11321

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

阪口政清, 木下理恵, 村田等, 山本健一, 許南浩, 日比野利彦

月刊「細胞」6月号 49 ( 7 ) 43 - 46 2017

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

S100-SPECT uncovers cellular and molecular events of pre-metastatic niche formation and following organ-specific cancer metastasis.

Sakaguchi M

Theranostics 7 ( 10 ) 2649 - 2651 2017

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

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

Oncol Res 2017

【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

Critical role of novel receptors to S100A8/A9, EMMPRIN and NPTNβ, on keratinocyte growth and inflammation in atopic dermatitis

49 ( 6 ) 594 - 598 2017

Active Secretion of Dimerized S100A11 Induced by the Peroxisome in Mesothelioma Cells. International journal

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

Cancer microenvironment : official journal of the International Cancer Microenvironment Society 9 ( 2-3 ) 93 - 105 2016.12

Language：English

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

DOI： 10.1007/s12307-016-0185-2

PubMed

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