Functional analysis of Runx3 in fibroblasts within breast cancer

• Project/Area Number: 19K16754
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Juntendo University
• Principal Investigator: okubo shoki 順天堂大学, 医学部, 助手 (20827878)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: RUNX3 / 乳癌 / 癌微小環境 / CAFs / 乳癌CAFs / TGF-b / Wnt-b-catenin / 癌促進的作用 / TGF-bシグナル / RUNX / Wntシグナル

Outline of Research at the Start

癌促進性癌微小環境の形成が癌悪性化の進展に重要であるが、その分子機構は十分に理解されていない。申請者らの先行研究より、乳癌由来CAFsにおいてreceptor-regulated Smad (R-Smad)結合蛋白であるRunt-related transcription factor 3 (Runx3)およびWnt-β-cateninシグナルが亢進していることが明らかになった。Runx3がTGF-βおよびWnt-β-cateninシグナルのクロストークに寄与し、CAFsの癌促進能を媒介している可能性を調査しさらにCAFsにおけるRunx3発現を標的とした新規癌治療の開発の基礎の構築を目指す。

Outline of Final Research Achievements

CAFs, which are abundant in the cancer microenvironment, act on nearby breast cancer cells to promote malignant transformation of cancer, but their molecular mechanism is not fully understood. In this study, RUNX3-shRNA was introduced into human breast cancer-derived CAFs in order to analyze the role of Runx3 in the cancer-promoting ability of CAFs. It was suggested that the decreased expression of RUNX3 in CAFs significantly suppressed the proliferation of human breast cancer cells co-transplanted in immunodeficient mice. In the future, we plan to investigate whether the decrease in the cancer-promoting ability of CAFs due to the suppression of RUNX3 expression is due to the decrease in TGF-b-Smad2 / 3 and Wnt-b-catenin signals.

Academic Significance and Societal Importance of the Research Achievements

CAFsがどの様に癌促進能を維持しているのかは不明な点が多い。本研究はCAFsでTGF-bオートクラインシグナルを媒介する遺伝子群を明らかにし、RUNX3がどのようにTGF-bやWnt-b-cateninシグナルの活性化に寄与するかを明らかにして、将来のCAFsを標的にした新規癌治療法の開発に役立てることを目的としている

Research Products

• [Journal Article] Carnitine insufficiency is associated with fatigue during lenvatinib treatment in patients with hepatocellular carcinoma. (2020)
  • Author(s): Okubo H, Ando H, Ishizuka K, Kitagawa R, Okubo S, Saito H, Kokubu S, Miyazaki A, Ikejima K, Shiina S, Nagahara A.
  • Journal Title: PLoS One Volume: 15 Issue: 3 Pages: e0229772-e0229772
  • DOI: 10.1371/journal.pone.0229772
  • Peer Reviewed
• [Journal Article] Linked Color Imaging and the Kyoto Classification of Gastritis: Evaluation of Visibility and Inter-Rater Reliability. (2019)
  • Author(s): Takeda T, Asaoka D, Nojiri S, Nishiyama M, Ikeda A, Yatagai N, Ishizuka K, Hiromoto T, Okubo S, Suzuki M, Nakajima A, Nakatsu Y, Komori H, Akazawa Y, Nakagawa Y, Izumi K, Matsumoto K, Ueyama H, Sasaki H, Shimada Y, Matsumoto K, Osada T, Hojo M, Kato M, Nagahara A.
  • Journal Title: Digestion. Volume: 12 Issue: 5 Pages: 1-10
  • DOI: 10.1159/000501534
  • Peer Reviewed
• [Journal Article] Improved Visibility of Barrett's Esophagus with Linked Color Imaging: Inter- and Intra-Rater Reliability and Quantitative Analysis. (2019)
  • Author(s): Takeda T, Nagahara A, Ishizuka K, Okubo S, Haga K, Suzuki M, Nakajima A, Komori H, Akazawa Y, Izumi K, Matsumoto K, Ueyama H, Shimada Y, Matsumoto K, Asaoka D, Shibuya T, Sakamoto N, Osada T, Hojo M, Nojiri S, Watanabe S.
  • Journal Title: Digestion. Volume: 97 Issue: 2 Pages: 183-194
  • DOI: 10.1159/000485459
  • Peer Reviewed
• [Journal Article] Hemorrhagic polyps formed like fundic gland polyps during long-term proton pump inhibitor administration. (2019)
  • Author(s): Takeda T, Asaoka D, Tajima Y, Matsumoto K, Takeda N, Hiromoto T, Okubo S, Saito H, Aoyama T, Shibuya T, Sakamoto N, Hojo M, Osada T, Nagahara A, Yao T, Watanabe S.
  • Journal Title: Clin J Gastroenterol. Volume: 10 Issue: 5 Pages: 478-484
  • DOI: 10.1007/s12328-017-0756-x
  • Peer Reviewed