exSSSRs-Fc fusion decoys prevent S100A8/A9-mediated cancer metastasis.

• Project/Area Number: 15K14382
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Okayama University
• Principal Investigator: Sakaguchi Masakiyo 岡山大学, 医歯薬学総合研究科, 准教授 (70379840)
• Co-Investigator(Kenkyū-buntansha): 豊岡 伸一 岡山大学, 医歯薬学総合研究科, 教授 (30397880) ; 村田 等 岡山大学, 医歯薬学総合研究科, 講師 (90579096)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 炎症 / がん / 転移 / S100A8/A9 / S100A8/A9受容体 / 浸潤

Outline of Final Research Achievements

It has been compiled growing mass of evidence that S100A8/A9 as a soil signal has significant role in cancer organ specific metastasis through the binding with diverse receptors such as TLR4　and RAGE, as soil sensors. In addition to them, we further succeeded to identify another important receptors, EMMPRIN, NPTNb; and MCAM. Hence, these novel molecules might become promising therapeutic targets. In this study, we prepared the extracellular regions of these molecules fused to the IgG-Fc for aiming longer half-life extension and evaluated the anti-metastatic effects of purified proteins on metastatic melanoma cells. The purified proteins suppressed markedly the S100A8/A9-mediated up-regulation of cancer cell metastasis via capturing the exogenous S100A8/A9. We therefore suggest that the developed biologics comes into a valuable appliance to regulate a “seed and soil” tumor metastasis.

Research Products

• [Journal Article] Promising therapeutic efficacy of a novel REIC/Dkk-3 expressing adenoviral vector for hepatocellular carcinoma. (2017)
  • Author(s): Sawahara H, Shiraha H, Uchida D, Kato H, Kato R, Oyama A, Nagahara T, Iwamuro M, Horiguchi S, Tsutsumi K, Mandai M, Mimura T, Wada N, Takeuchi Y, Kuwaki K, Onishi H, Nakamura S, Watanabe M, Sakaguchi M, et al.
  • Journal Title: J Gastroenterol Hepatol. Volume: - Issue: 10 Pages: 1769-1777
  • DOI: 10.1111/jgh.13757
  • Peer Reviewed / Open Access
• [Journal Article] Distant Bystander Effect of REIC/DKK3 Gene Therapy Through Immune System Stimulation in Thoracic Malignancies. (2017)
  • Author(s): 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.
  • Journal Title: Anticancer Res Volume: 37 Issue: 1 Pages: 301-307
  • DOI: 10.21873/anticanres.11321
  • Peer Reviewed
• [Journal Article] Expression of tumor suppressor REIC/Dkk-3 by a newly improved adenovirus vector with insertion of an hTERT promoter at the 3’-side of the transgene (2017)
  • Author(s): Putranto EW, Kinoshita R, Watanabe M, Sadahira T, Murata H, Yamamoto KI, Futami J, Kataoka K, Inoue Y, Ruma IM, Sumardika IW, Youyi C, Kubo M, Sakaguchi Y, Saito K, Nasu Y, Kumon H, Huh NH, Sakaguchi M.
  • Journal Title: Oncol Lett. Volume: in press
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Robust cancer-specific gene expression by a novel cassette with hTERT and CMV promoter elements (2017)
  • Author(s): Sakaguchi M, Sadahira T, Ueki H, Kinoshita R, Murata H, Yamamoto KI, Futami J, Nasu Y, Ochiai K, Kumon H, Huh NH, Watanabe M.
  • Journal Title: Oncol Rep Volume: in press
  • Peer Reviewed
• [Journal Article] Interaction of cytokeratin 19 head domain and HER2 in the cytoplasm leads to activation of HER2-Erk pathway. (2016)
  • Author(s): Ohtsuka T, Sakaguchi M, Yamamoto H, Tomida S, Takata K, Shien K, Hashida S, Miyata-Takata T, Watanabe M, Suzawa K, Soh J, Youyi C, Sato H, Namba K, Torigoe H, Tsukuda K, Yoshino T, Miyoshi S, Toyooka S.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 39557-39557
  • DOI: 10.1038/srep39557
  • Peer Reviewed / Open Access
• [Journal Article] Interaction of cytokeratin 19 head domain and HER2 in the cytoplasm leads to activation of HER2-Erk pathway. (2016)
  • Author(s): Ohtsuka T, Sakaguchi M, Yamamoto H, Tomida S, Takata K, Shien K, Hashida S, Miyata-Takata T, Watanabe M, Suzawa K, Soh J, Youyi C, Sato H, Namba K, Torigoe H, Tsukuda K, Yoshino T, Miyoshi S, Toyooka S.
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 33319-33319
  • DOI: 10.1038/srep33319
  • Peer Reviewed / Open Access
• [Journal Article] Novel REIC/Dkk-3-encoding adenoviral vector as a promising therapeutic agent for pancreatic cancer. (2016)
  • Author(s): Sawahara H, Shiraha H, Uchida D, Kato H, Nagahara T, Iwamuro M, Kataoka J, Horiguchi S, Watanabe M, Sakaguchi M, Takaki A, Nouso K, Nasu Y, Kumon H, Okada H
  • Journal Title: Cancer Gene Ther Volume: 23 Issue: 8 Pages: 278-283
  • DOI: 10.1038/cgt.2016.31
  • Peer Reviewed
• [Journal Article] Identification of an S100A8 receptor neuroplastin-β and its heterodimer formation with EMMPRIN. (2016)
  • Author(s): Sakaguchi M, Yamamoto M, Miyai M, Maeda T, Hiruma J, Murata H, Kinoshita R, Ruma IM, Putranto EW, Inoue Y, Morizane S, Huh NH, Tsuboi R, Hibino T.
  • Journal Title: J Invest Dermatol. Volume: 136 Issue: 11 Pages: 2240-2250
  • DOI: 10.1016/j.jid.2016.06.617
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Active Secretion of Dimerized S100A11 Induced by the Peroxisome in Mesothelioma Cells. (2016)
  • Author(s): Saho S, Satoh H, Kondo E, Inoue Y, Yamauchi A, Murata H, Kinoshita R, Yamamoto KI, Futami J, Putranto EW, Ruma IM, Sumardika IW, Youyi C, Suzawa K, Yamamoto H, Soh J, Tomida S, Sakaguchi Y, Saito K, Iioka H, Huh NH, Toyooka S, Sakaguchi M.
  • Journal Title: Cancer Microenviron. Volume: 9 Issue: 2-3 Pages: 93-105
  • DOI: 10.1007/s12307-016-0185-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Histidine-rich glycoprotein prevents septic lethality through regulation of immunothrombosis and inflammation. (2016)
  • Author(s): Wake H, Mori S, Liu K, Morioka Y, Teshigawara K, Sakaguchi M, Kuroda K, Gao Y, Takahashi H, Ohtsuka A, Yoshino T, Morimatsu H, Nishibori M.
  • Journal Title: EBioMedicine Volume: 9 Pages: 180-194
  • DOI: 10.1016/j.ebiom.2016.06.003
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 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. (2016)
  • Author(s): Ruma IM, Putranto EW, Kondo E, Murata H, Watanabe M, Huang P, Kinoshita R, Futami J, Inoue Y, Yamauchi A, Sumardika IW, Youyi C, Yamamoto K, Nasu Y, Nishibori M, Hibino T, Sakaguchi M.
  • Journal Title: Clin Exp Metastasis Volume: 33 Issue: 6 Pages: 609-627
  • DOI: 10.1007/s10585-016-9801-2
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] NRF2 regulates PINK1 expression under oxidative stress conditions (2015)
  • Author(s): Murata H, Takamatsu H, Liu S, Kataoka K, Huh NH, Sakaguchi M.
  • Journal Title: PLoS One Volume: 10 Issue: 11 Pages: e0142438-e0142438
  • DOI: 10.1371/journal.pone.0142438
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The cysteine-rich core domain of REIC/Dkk-3 is critical for its effect on monocyte differentiation and tumor regression. (2015)
  • Author(s): Kinoshita R, Watanabe M, Huang P, Li SA, Sakaguchi M, Kumon H, Futami J.
  • Journal Title: Oncology Reports Volume: In press Issue: 6 Pages: 2908-2914
  • DOI: 10.3892/or.2015.3885
  • Peer Reviewed
• [Journal Article] TAE226, a Bis-Anilino Pyrimidine Compound, Inhibits the EGFR-Mutant Kinase Including T790M Mutant to Show Anti-Tumor Effect on EGFR-Mutant Non-Small Cell Lung Cancer Cells (2015)
  • Author(s): Otani H, Yamamoto H, Takaoka M, Sakaguchi M, Soh J, Jida M, Ueno T, Kubo T, Asano H, Tsukuda K, Kiura K, Hatakeyama S, Kawahara E, Naomoto Y, Miyoshi S, Toyooka S
  • Journal Title: PLoS One Volume: 10 Issue: 6 Pages: e0129838-e0129838
  • DOI: 10.1371/journal.pone.0129838
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hepatocyte Nuclear Factor 4α Controls Iron Metabolism and Regulates Transferrin Receptor 2 in Mouse Liver (2015)
  • Author(s): Matsuo S, Ogawa M, Muckenthaler MU, Mizui Y, Sasaki S, Fujimura T, Takizawa M, Ariga N, Ozaki H, Sakaguchi M, Gonzalez FJ, Inoue Y
  • Journal Title: J Biol Chem Volume: 290 Issue: 52 Pages: 30855-30865
  • DOI: 10.1074/jbc.m115.694414
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 神経細胞死・軸索変性に関与するSARM1のリン酸化制御 (2016)
  • Author(s): 村田 等、西川 茜、山本 健一、木下 理恵、阪口 政清
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市)
  • Year and Date: 2016-11-30
• [Presentation] HNF4αによるmiRNAを介した遺伝子発現制御機構の解析 (2016)
  • Author(s): 秋山 萌, 守本 葵, 神成 真名, 土田雄一, 松田 強志, 齊藤 千夏, 佐々木翔太, 前田 つかさ, 阪口 政清, Frank J.Gonzalez, 井上 裕介
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市)
  • Year and Date: 2016-11-30
• [Presentation] 核内受容体HNF4γの機能解析 (2016)
  • Author(s): 佐々木 翔太, 浦部 瑞穗, 前田 つかさ, 入江 亮太, 鈴木 淳子, 阪口 政清, Frank J. Gonzalez, 井上 裕介
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市)
  • Year and Date: 2016-11-30
• [Presentation] Interaction between Pancreatic cancer cells and MSC for cancer progression (2016)
  • Author(s): Eisaku Kondo, Ken Saito, Hidekazu Iioka, Masakiyo Sakaguchi
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市)
  • Year and Date: 2016-10-06
• [Presentation] The cell polarity regulator Crumbs3 promotes adenocarcinoma metastasis through the regulation of glycolipid dynamics (2016)
  • Author(s): Hidekazu Iioka, Ken Saito, Masakiyo Sakaguchi, Eiichi Morii, Eisaku Kondo
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市)
  • Year and Date: 2016-10-06
• [Presentation] Development of a novel biologics for suppression of S100A8/A9-induced cancer metastasis (2016)
  • Author(s): Rie Kinoshita, Hitoshi Murata, Yusuke Inoue, Eisaku Kondo, Nam-Ho Huh, Masakiyo Sakaguchi
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市)
  • Year and Date: 2016-10-06
• [Presentation] Regulation of Cellular Stress Response By Mitochondrial Kinase Pink1 (2016)
  • Author(s): Hitoshi Murata, Hitoshi Takamatsu, Ken Kataoka, Nam-ho HUH, Masakiyo Sakaguchi
  • Organizer: 日本組織培養学会第89回大会
  • Place of Presentation: 千里ライフサイエンスセンター(大阪府豊中市)
  • Year and Date: 2016-05-25
• [Presentation] Extract of Cordyceps militaries inhibits angiogenesis and suppresses tumor growth of human malignant melanoma cells (2016)
  • Author(s): イ マデ ウィナルサ ルマ, エンディ ウィダヤ プトラント, 近藤 英作, 井上 裕介, 山本 健一, 村田 等, 阪口 政清
  • Organizer: 日本組織培養学会第89回大会
  • Place of Presentation: 千里ライフサイエンスセンター(大阪府豊中市)
  • Year and Date: 2016-05-25
• [Presentation] Beta3 integrin cDNA-transduced human keratinocytes grow far better on fibrin gels as compared to normal human keratinocytes (2016)
  • Author(s): 久保 美代子, 阪口 政清
  • Organizer: 日本組織培養学会第89回大会
  • Place of Presentation: 千里ライフサイエンスセンター(大阪府豊中市)
  • Year and Date: 2016-05-25
• [Presentation] Potential role of tumor suppressor gene REIC/Dkk-3 as an inflammatory mediator in skin tissue (2015)
  • Author(s): uki Ayabe, Taiki Tsuruda, Masakiyo Sakaguchi, Ken Kataoka
  • Organizer: ASCB annual meeting
  • Place of Presentation: カリフォルニア州サンディエーゴ
  • Year and Date: 2015-12-12
  • Int'l Joint Research
• [Presentation] S100A8 promoted Th1-related gene expression and S100A9 induced Th2 differentiation via activation of GATA-3 (2015)
  • Author(s): Toshihiko Hibino, Masashi Miyai, Saeko Nakajima, Mami Yamamoto-Tanaka, Tatsuo Maeda, Masakiyo Sakaguchi, Kenji Kabashima、 Ryoji Tsuboi
  • Organizer: 日本研究皮膚科学会 第40回年次学術大会・総会
  • Place of Presentation: 岡山
  • Year and Date: 2015-12-11
• [Presentation] S100A8/A9 induces skin inflammation and keratinocyte proliferation via neuroplasatin-beta/EMMPRIN heterodimer receptor in atopic dermatitis (2015)
  • Author(s): Masashi Miyai, Masakiyo Sakaguchi, Mami Yamamoto-Tanaka, Tatsuo Maeda, Junichiro Hiruma, Ryoji Tsuboi, Toshihiko Hibino
  • Organizer: 日本研究皮膚科学会 第40回年次学術大会・総会
  • Place of Presentation: 岡山
  • Year and Date: 2015-12-11
• [Presentation] 肺動脈性肺高血圧症におけるRAGEシグナルの亢進 (2015)
  • Author(s): 中村一文、更科俊洋、赤木達、伊藤浩、阪口政清、大藤剛宏
  • Organizer: 第4回日本肺循環学会・第3回日本肺高血圧学会 合同学術集会
  • Place of Presentation: 東京
  • Year and Date: 2015-10-03
• [Presentation] NRF2 pathway activation as a target to counteract mitochondrial dysfunction in Parkinson’s disease (2015)
  • Author(s): Hitoshi Murata, Hitoshi Takamatsu, Nam-ho Huh, Masakiyo Sakaguchi
  • Organizer: The 9th ICME International Conference on Complex Medical Engineering (CME 2015)
  • Place of Presentation: 岡山
  • Year and Date: 2015-06-16
  • Int'l Joint Research
• [Presentation] TNF-αによるREIC/Dkk-3の発現制御とケラチノサイトの挙動への影響 (2015)
  • Author(s): 綾部 雄基、鶴田 太輝、阪口 政清、片岡 健
  • Organizer: 日本組織培養学会第88回大会
  • Place of Presentation: 広島
  • Year and Date: 2015-05-16
• [Presentation] TIR/BB-loop mimetic AS-1 Inhibits Proliferation of Pulmonary Artery Smooth Muscle Cells from Patients with Pulmonary Arterial Hypertension (2015)
  • Author(s): Kazufumi Nakamura, Masakiyo Sakaguchi, Toshihiro Sarashina, Satoshi Akagi, Aya Miura, Takahiro Oto, Aiko Ogawa, Hiromi Matsubara, Hiroshi Ito
  • Organizer: 第79回日本循環器学会
  • Place of Presentation: 大阪
  • Year and Date: 2015-04-24
• [Presentation] Identification of a novel binding protein playing a critical role in HER2 activation in lung cancer cells (2015)
  • Author(s): Tomoaki Ohtsuka, Masakiyo Sakaguchi, Katsuyoshi Takata, Shinsuke Hashida, Mototsugu Watanabe, Ken Suzawa, Yuho Maki, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka
  • Organizer: AACR Annual Meeting 2015
  • Place of Presentation: フィラデルフィア州、ペンシルバニア
  • Year and Date: 2015-04-18
  • Int'l Joint Research
• [Book] 月刊「細胞」 (2017)
  • Author(s): 阪口政清、木下理恵、村田 等、山本健一、許 南浩、日比野利彦
  • Total Pages: 52
  • Publisher: ニューサイエンス社
• [Book] 臨床免疫・アレルギー科 (2017)
  • Author(s): 阪口政清, 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
  • Publisher: 科学評論社
• [Patent(Industrial Property Rights)] 遺伝子発現用カセット及びその産生物 (2016)
  • Inventor(s): 阪口政清、西堀正洋、村田 等、山本健一、木下理恵
  • Industrial Property Rights Holder: 国立大学法人 岡山大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-10-03
  • Overseas
• [Patent(Industrial Property Rights)] 好中球活性化に起因する疾患の治療薬、治療方法及び検査方法 (2016)
  • Inventor(s): 西堀正洋、森秀治、和氣秀徳、他、阪口政清
  • Industrial Property Rights Holder: 国立大学法人 岡山大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-01-14
  • Acquisition Date: 2016-11-29
  • Overseas
• [Patent(Industrial Property Rights)] 遺伝子発現用カセット及びその産生物 (2015)
  • Inventor(s): 阪口政清、西堀正洋、公文裕巳、村田 等、山本健一、木下理恵
  • Industrial Property Rights Holder: 阪口政清、西堀正洋、公文裕巳、村田 等、山本健一、木下理恵
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2015-198160
  • Filing Date: 2015-10-06