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Regulation of colon cancer suppression and malignant progression by TGF-beta signaling

Research Project

Project/Area Number 19K22558
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 50:Oncology and related fields
Research InstitutionKanazawa University

Principal Investigator

Oshima Masanobu  金沢大学, がん進展制御研究所, 教授 (40324610)

Project Period (FY) 2019-06-28 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2019: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
KeywordsTGF-β / アクチビン / 大腸版 / オルガノイド / 大腸がん / TGF-beta / がん抑制 / 悪性化進展
Outline of Research at the Start

TGF-betaは消化管上皮細胞の分化誘導により、大腸がんのがん抑制遺伝子として機能する。一方で、上皮間葉転換(EMT)により悪性化を誘導する因子でもある。本研究では、このようなTGF-betaによる大腸がん悪性化抑制または促進作用を制御するスイッチ機構としてp53遺伝子変異に着目する。すなわち、異なる型のp53変異の存在により、大腸がん細胞がTGF-betaに対してどう反応するのか、マウスおよびヒト腸管腫瘍組織由来オルガノイドを用いて、マトリゲル中での構造変化解析と、マウスにおける肝転移巣の解析により明らかにする。

Outline of Final Research Achievements

TGF-β signaling suppresses proliferation of intestinal epithelial cells, while it induces epithelial-mesenchymal transition (EMT) of colon cancer cells. Thus, TGF-β plays either of tumor suppressor or tumor promoter role. However, the underlying mechanism has not been elucidated. In this study, we have examined the role of activin, one of TGF-β family cytokines, using mouse intestinal tumor-derived organoids that carried driver mutations in various combinations. Notably, activin treatment suppressed organoid formation of benign tumor cells, while malignant cells with Kras activation mutation showed resistance to activin-induced cell death. Moreover, metastatic cells with p53 mutation showed EMT-like morphological changes and invasion to collagen gel upon activin stimulation. These results suggest that accumulation of driver mutations in Kras and p53 is a possible switching for responses to TGF-β.

Academic Significance and Societal Importance of the Research Achievements

TGF-βはがん細胞のEMT誘導により転移形成に関与すると考えられることから、その阻害薬ががん悪性化に対する治療薬として期待されている。一方で、TGF-βには上皮細胞の分化誘導機能による、がん抑制性の作用が知られており、TGF-βシグナルの亢進ががん予防に作用すると考えらえる。このように相反するTGF-βシグナルの機能について、本研究ではアクチビンに着目した研究を推進し、がん細胞に導入されたドライバー遺伝子変異に依存した制御の可能性を明らかにした。この結果は、がん発生と悪性化の分子機構の解明に貢献し、TGF-β阻害薬等による将来の治療戦略の確立にも重要な知見となる。

Report

(3 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • Research Products

    (19 results)

All 2021 2020 2019 2018 Other

All Int'l Joint Research (1 results) Journal Article (7 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 7 results,  Open Access: 7 results) Presentation (9 results) (of which Int'l Joint Research: 2 results,  Invited: 6 results) Remarks (2 results)

  • [Int'l Joint Research] ソウル国立大学(韓国)

    • Related Report
      2020 Annual Research Report
  • [Journal Article] Malignant subclone drives metastasis of genetically and phenotypically heterogenous cell clusters through fibrotic niche generation2021

    • Author(s)
      Kok Sau Yee、Oshima Hiroko、Takahashi Kei、Nakayama Mizuho、Murakami Kazuhiro、Ueda Hiroki R.、Miyazono Kohei、Oshima Masanobu
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 863-863

    • DOI

      10.1038/s41467-021-21160-0

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Loss of wild-type p53 promotes mutant p53-driven metastasis through acquisition of survival and tumor-initiating properties2020

    • Author(s)
      Nakayama M, Hong CP, Oshima H, Sakai E, Kim SJ, and Oshima M.
    • Journal Title

      Nature Communications

      Volume: 11 Issue: 1 Pages: 2333-2333

    • DOI

      10.1038/s41467-020-16245-1

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] NF-kB activation promotes gastric tumorigenesis through the expansion of SOX2-positive epithelial cells.2019

    • Author(s)
      Echizen K, Horiuchi K, Aoki Y, Yamada Y, Minamoto T, Oshima H, and Oshima M.
    • Journal Title

      Oncogene

      Volume: accepted Issue: 22 Pages: 4250-4263

    • DOI

      10.1038/s41388-019-0702-0

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] CRISPR-Cas9 mediated gene knockout in intestinal tumor organoids provides functional validation for colorectal cancer driver genes.2019

    • Author(s)
      Takeda H, Kataoka S, Nakayama M, Ali MAE, Oshima H, Yamamoto D, Park JW, Takegami Y, An T, Jenkins NA, Copeland NG, and Oshima M.
    • Journal Title

      Proc Natl Acad Sci USA

      Volume: 116 Issue: 31 Pages: 15635-15644

    • DOI

      10.1073/pnas.1904714116

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] p53 mutation in colon cancer.2019

    • Author(s)
      Nakayama M and Oshima M.
    • Journal Title

      J Mol Cell Biol,

      Volume: Epub. ahead of print Issue: 4 Pages: 1-10

    • DOI

      10.1093/jmcb/mjy075

    • NAID

      120006605142

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Interleukin 1 Up-regulates MicroRNA 135b to Promote Inflammation-Associated Gastric Carcinogenesis in Mice.2018

    • Author(s)
      Han TS, Voon DC, Oshima H, Nakayama M, Echizen K, Sakai E, Yong ZWE, Murakami K, Yu L, Minamoto T, Ock CY, Jenkins BJ, Kim SJ, Yang HK, Oshima M
    • Journal Title

      Interleukin 1 Up-regulates MicroRNA 135b to Promote Inflammation-Associated Gastric Carcinogenesis in Mice

      Volume: 156 Issue: 4 Pages: 1140-1155

    • DOI

      10.1053/j.gastro.2018.11.059

    • NAID

      120006621945

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Stat3 is indispensable for damage-induced crypt regeneration but not for Wnt-driven intestinal tumorigenesis.2018

    • Author(s)
      Oshima H, Kok SY, Nakayama M, Murakami K, Voon DC, Kimura T, Oshima M
    • Journal Title

      FASEB J.

      Volume: 33 Issue: 2 Pages: 1873-1886

    • DOI

      10.1096/fj.201801176r

    • NAID

      120006621946

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 炎症とがん転移2020

    • Author(s)
      大島正伸
    • Organizer
      第41回日本炎症・再生医学会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 大腸がんの悪性化進展における炎症性バイオマーカー2020

    • Author(s)
      大島正伸、中山瑞穂、Dong Wang、大島浩子、渡辺信嗣
    • Organizer
      第40回日本分子腫瘍マーカー研究会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] How genetic alterations promote malignant progression of colon cancer?2020

    • Author(s)
      Oshima M.
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Gain-of-function mutation of p53 for malignant progression of cancer2020

    • Author(s)
      Oshima M.
    • Organizer
      第43回日本分子生物学会年会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] p53-loss of heterozygosity with p53 gain-of-function mutation leads to cancer dormancy of intestinal tumors.2019

    • Author(s)
      Nakayama M, Sakai E, Oshima H, Tan P, Oshima M.
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Research-status Report
  • [Presentation] Mechanism for intestinal tumor metastasis by polyclonal origins.2019

    • Author(s)
      Sau Yee Kok, Oshima H, Sakai E, Nakayama M, Oshima M.
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Research-status Report
  • [Presentation] Regulation of Foxo3a localization in gastric cancer cells.2019

    • Author(s)
      Oshima H, Maeda Y, Tsuji T, Oshima M.
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Research-status Report
  • [Presentation] Biological mechanism of polyclonal metastasis of colorectal cancer.2019

    • Author(s)
      Oshima M.
    • Organizer
      50th Commemorative International Symposium of the Princess Takamatsu Cancer Research Fund
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Multistep tumorigenesis and polyclonal metastasis of colon cancer.2019

    • Author(s)
      Oshima M.
    • Organizer
      24th Annual Meeting of the Korean Society of Cancer Prevention (KSCP)
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Remarks] 金沢大学がん進展制御研究所 腫瘍遺伝学研究分野

    • URL

      http://genetics.w3.kanazawa-u.ac.jp

    • Related Report
      2020 Annual Research Report
  • [Remarks] 金沢大学がん進展制御研究所主要遺伝学研究分野 HP

    • URL

      http://genetics.w3.kanazawa-u.ac.jp

    • Related Report
      2019 Research-status Report

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Published: 2019-07-04   Modified: 2022-01-27  

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