Newly identified REIC receptor regulates the immune responses against tumors

• Project/Area Number: 18K15320
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Okayama University
• Principal Investigator: Kinoshita Rie 岡山大学, 医歯薬学総合研究科, 助教 (40518297)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: REIC / 受容体 / 癌

Outline of Final Research Achievements

REIC is a tumor suppressor gene and has been studied as a promising therapeutic gene for cancer gene therapy. Intratumoral injection of adenovirus vector carrying the human REIC (Ad-REIC) elicits cancer cell-specific apoptosis and anti-cancer immune responses. but the role of secretory REIC protein is still poorly understood.
In the present study, we identified some new receptors of the REIC protein by LC-Ms and immunoprecipitation methods. Further analyses showed that the secretory REIC protein induced the phosphorylation of ERK and AKT through the new identified receptors in NK cells and neuronal-like SH-SY5Y cells and suppressed the stress-induced cytotoxicity and the expression of some inflammatory cytokines.
Taken together, our results indicate that the secretory REIC protein is responsible for cellular homeostasis. Because REIC/Dkk-3 is a naturally circulating serum protein, the upregulation REIC/Dkk-3 protein expression could be a promising option for cancer therapy.

Academic Significance and Societal Importance of the Research Achievements

がん抑制遺伝子REICは、多岐にわたるがん種において発現が低下しており、がん遺伝子治療薬として開発が進められている。しかし正常細胞や免疫細胞においての分泌REICタンパク質の詳細な分子機構は未解明であった。本研究は、REICタンパク質の新規受容体を同定し、全身の重要臓器における恒常性維持機構へのREICの関与を分子レベルで解明することに寄与した。現在、REICはタンパク質製剤としても開発を進めており、本研究の成果である抗がん免疫活性化に重要なタンパク質ドメインの特定は、治療薬早期実用化を大きく推進する。

Research Products

• [Journal Article] Xylitol acts as an anticancer monosaccharide to induce selective cancer death via regulation of the glutathione level (2020)
  • Author(s): Tomonobu Nahoko、Komalasari Ni Luh Gede Yoni、Sumardika I Wayan、Jiang Fan、Chen Youyi、Yamamoto Ken-ichi、Kinoshita Rie、Murata Hitoshi、Inoue Yusuke、Sakaguchi Masakiyo
  • Journal Title: Chemico-Biological Interactions Volume: 324 Pages: 109085-109085
  • DOI: 10.1016/j.cbi.2020.109085
  • NAID: 120006892917
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] S100 Soil Sensor Receptors and Molecular Targeting Therapy Against Them in Cancer Metastasis. (2020)
  • Author(s): Tomonobu N, Kinoshita R, Sakaguchi M.
  • Journal Title: Transl Oncol Volume: 3 Issue: 4 Pages: 100753-100753
  • DOI: 10.1016/j.tranon.2020.100753
  • NAID: 120006869552
  • Peer Reviewed / Open Access
• [Journal Article] exMCAM-Fc, an S100A8/A9-mediated-metastasis blocker, efficiently reduced the number of circulating tumor cells that appeared in the blood flow (2020)
  • Author(s): Tomonobu Nahoko、Kinoshita Rie、Sakaguchi Masakiyo
  • Journal Title: Molecular Biology Reports Volume: 47 Issue: 6 Pages: 4879-4883
  • DOI: 10.1007/s11033-020-05495-3
  • Peer Reviewed / Open Access
• [Journal Article] Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11 Through Activation of Surrounding Fibroblasts (2019)
  • Author(s): Mitsui Yosuke、Tomonobu Nahoko、Watanabe Masami、Kinoshita Rie、Sumardika I Wayan、Youyi Chen、Murata Hitoshi et al.
  • Journal Title: Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics Volume: 27 Issue: 8 Pages: 945-956
  • DOI: 10.3727/096504019x15555408784978
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Critical role of the MCAM-ETV4 axis triggered by extracellular S100A8/A9 in breast cancer aggressiveness. (2019)
  • Author(s): Chen Y, Sumardika IW, Tomonobu N, Kinoshita R, Inoue Y, Iioka H, Mitsui Y, Saito K, Ruma IMW, Sato H, Yamauchi A, Murata H, Yamamoto KI, Tomida S, Shien K, Yamamoto H, Soh J, Futami J, Kubo M, Putranto EW, Murakami T, Liu M, Hibino T, Nishibori M, Kondo E, Toyooka S, Sakaguchi M.
  • Journal Title: Neoplasia. Volume: 21(7) Issue: 7 Pages: 627-640
  • DOI: 10.1016/j.neo.2019.04.006
  • NAID: 120006948963
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Convenient methodology for extraction and subsequent selective propagation of mouse melanocytes in culture from adult mouse skin tissue. (2019)
  • Author(s): Tomonobu N, Kinoshita R, Sumardika IW, Chen Y, Inoue Y, Yamauchi A, Yamamoto KI, Murata H, Sakaguchi M
  • Journal Title: Biochem Biophys Rep. Volume: - Pages: 100619-100619
  • DOI: 10.1016/j.bbrep.2019.100619
  • NAID: 120006948964
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Extracellular S100A11 plays a critical role in spread of the fibroblast population in pancreatic cancers (2019)
  • Author(s): Takamatsu H, Yamamoto K, Tomonobu N, Murata H, Inoue Y, Yamauchi A, Sumardika W, Youyi C, Kinoshita R, Yamamura M, Fujiwara H, Mitsui Y, Araki K, Futami J, Saito K, Iioka H, Ruma MW, Putranto EW, Nishibori M, Kondo E, Yamamoto Y, Toyooka S, Sakaguchi M
  • Journal Title: Oncol Res Volume: - Issue: 6 Pages: 713-727
  • DOI: 10.3727/096504018x15433161908259
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neuroplastin-β mediates S100A8/A9-induced lung cancer disseminative progression. (2019)
  • Author(s): Sumardika IW, Chen Y, Tomonobu N, Kinoshita R, Ruma IMW, Sato H, Kondo E, Inoue Y, Yamauchi A, Murata H, Yamamoto KI, Tomida S, Shien K, Yamamoto H, Soh J, Futami J, Putranto EW, Hibino T, Nishibori M, Toyooka S, Sakaguchi M
  • Journal Title: Mol Carcinog. Volume: - Issue: 6 Pages: 980-995
  • DOI: 10.1002/mc.22987
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Melanoma cell adhesion molecule is the driving force behind the dissemination of melanoma upon S100A8/A9 binding in the original skin lesion. (2019)
  • Author(s): Chen Y, Sumardika IW, Tomonobu N, Winarsa Ruma IM, Kinoshita R, Kondo E, Inoue Y, Sato H, Yamauchi A, Murata H, Yamamoto KI, Tomida S, Shien K, Yamamoto H, Soh J, Liu M, Futami J, Sasai K, Katayama H, Kubo M, Putranto EW, Hibino T, Sun B, Nishibori M, Toyooka S, Sakaguchi M
  • Journal Title: Cancer Lett. Volume: - Pages: 178-190
  • DOI: 10.1016/j.canlet.2019.03.023
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] exSSSRs (extracellular S100 soil sensor receptors)-Fc fusion proteins work as prominent decoys to S100A8/A9-induced lung tropic cancer metastasis. (2018)
  • Author(s): Kinoshita R, Sato H, Yamauchi A, Takahashi Y, Inoue Y, Sumardika IW, Chen Y, Tomonobu N, Araki K, Shien K, Tomida S, Torigoe H, Namba K, Kurihara E, Ogoshi Y, Murata H, Yamamoto KI, Futami J, Putranto EW, Ruma IMW, Yamamoto H, Soh J, Hibino T, Nishibori M, Kondo E, Toyooka S, Sakaguchi M
  • Journal Title: Int J Cancer. Volume: - Issue: 12 Pages: 3138-3145
  • DOI: 10.1002/ijc.31945
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Embigin Promotes Prostate Cancer Progression by S100A4-Dependent and-Independent Mechanisms. (2018)
  • Author(s): 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
  • Journal Title: Cancers (Basel) Volume: 10 Issue: 7 Pages: 239-239
  • DOI: 10.3390/cancers10070239
  • Peer Reviewed / Open Access
• [Journal Article] c-Jun N-terminal kinase (JNK)-mediated phosphorylation of SARM1 regulates NAD(+) cleavage activity to inhibit mitochondrial respiration. (2018)
  • Author(s): Murata H, Khine CC, Nishikawa A, Yamamoto KI, Kinoshita R, Sakaguchi M.
  • Journal Title: J Biol Chem. Volume: 293 Issue: 49 Pages: 18933-18943
  • DOI: 10.1074/jbc.ra118.004578
  • Peer Reviewed
• [Journal Article] Newly developed anti-S100A8/A9 monoclonal antibody efficiently prevents lung tropic cancer metastasis. (2018)
  • Author(s): Kinoshita R, Sato H, Yamauchi A, Takahashi Y, Inoue Y, Sumardika IW, Chen Y, Tomonobu N, Araki K, Shien K, Tomida S, Torigoe H, Namba K, Kurihara E, Ogoshi Y, Murata H, Yamamoto KI, Futami J, Putranto EW, Ruma IMW, Yamamoto H, Soh J, Hibino T, Nishibori M, Kondo E, Toyooka S, Sakaguchi M.
  • Journal Title: Int J Cancer. Volume: 印刷中 Issue: 2 Pages: 569-575
  • DOI: 10.1002/ijc.31982
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] ｂ-1,3-galactosyl-O-glycosyl-glycoprotein ｂ-1,6-N-acetylglucosaminyltransferase 3 Increases MCAM Stability, Which Enhances S100A8/A9-Mediated Cancer Motility. (2017)
  • Author(s): Sumardika I Wayan、Youyi Chen、Kondo Eisaku、Inoue Yusuke、Ruma I Made Winarsa、Murata Hitoshi、Kinoshita Rie、Yamamoto Ken-Ichi、Tomida Shuta、Shien Kazuhiko、Satoh Hiroki、Yamauchi Akira、Futami Junichiro、Putranto Endy Widya、Hibino Toshihiko、Toyooka Shinichi、Nishibori Masahiro、Sakaguchi Masakiyo
  • Journal Title: Oncology Reserch Volume: in press Issue: 3 Pages: 431-444
  • DOI: 10.3727/096504017x15031557924123
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Novel therapeutic approach based on S100A8/A9-mediated organ tropic cancer metastasis (2019)
  • Author(s): 木下理恵、友信奈保子、山内明、枝園和彦、富田秀太、豊岡伸一、近藤英作、阪口政清
  • Organizer: 日本癌学会
• [Presentation] Development of exSSSRs(extracellular S100 soil sensor receptors)-Fc fusion proteins and S100A8/A9 antibody for suppression of cancer metastasis (2019)
  • Author(s): Rie Kinoshita, Hiroki Sato, Akira Yamauchi, Yuta Takahashi, Yusuke Inoue, I Wayan Sumardika, Youyi Chen, Nahoko Tomonobu, Kota Araki, Junichiro Futami, Endy Widya Putranto, I.Made Winarsa Ruma, Hiromasa Yamamoto, Junichi Soh, Toshihiko Hibino, Masahiro Nishibori, Eisaku Kondo, Shinichi Toyooka, Masakiyo Sakaguchi
  • Organizer: 第9回International DAMPs and Alarmins Symposium (9th iDEAs)
  • Int'l Joint Research
• [Presentation] Development of a novel S100A8/A9 neutralizing monoclonal antibody for suppression of cancer metastasis (2018)
  • Author(s): 木下理恵、山内明、枝園和彦、富田秀太、豊岡伸一、近藤英作、阪口政清
  • Organizer: 日本癌学会
• [Presentation] 抗がん抗原抗体で腫瘍免疫応答をモニタリングするMUSCAT-Assay (2018)
  • Author(s): 二見淳一郎、本荘知子、吉岡実咲、勝河祐希、Hannaneh Ahmadi、木下理恵、藤枝奈緒、垣見和宏
  • Organizer: 日本がん免疫学会