Exploring molecular network of functional nucleic acid and developing therapeutic innovations in drug-resistant renal cell carcinoma

• Project/Area Number: 16H05464
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Urology
• Research Institution: Kagoshima University
• Principal Investigator: NAKAGAWA Masayuki 鹿児島大学, 医歯学域医学系, 教授 (90164144)
• Co-Investigator(Kenkyū-buntansha): 榎田 英樹 鹿児島大学, 医歯学域医学系, 准教授 (80347103) ; 関 直彦 千葉大学, 大学院医学研究院, 准教授 (50345013)
• Research Collaborator: Yoshino Hirofumi ; Matsushita Ryousuke ; Miyamoto Kazutaka ; Yonemori Masaya
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2017: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2016: ¥8,710,000 (Direct Cost: ¥6,700,000、Indirect Cost: ¥2,010,000)
• Keywords: マイクロRNA / 腎癌 / スニチニブ耐性 / microRNA / 腎細胞癌 / 薬剤耐性

Outline of Final Research Achievements

Based on microRNA expression profile of drug-resistant renal cell carcinoma (RCC), miR-210-3p was downregulated and had tumor suppressive function via targeting TWIST1. miR-1271a was upregulated and had oncogenic function via targeting tumor suppressive BMPR1B. On the other hand, based on the gene expression profile in RCC with drug-resistant to HIF2αinhibitors, serine synthesis pathway was activated through PHGDH gene up-regulation. We found out PHGDH inhibitors as was useful for overcoming drug-resistance to HIF2αinhibitors. In terms of sunitinib-resistant RCC, miR-99a-3p was downregulated and had tumor suppressive function via targeting RRM2 gene having DNA polymerization and repair. These studies explored novel molecular network of drug-resistant renal cell carcinoma and will probably lead to seem to develop therapeutic innovations.

Academic Significance and Societal Importance of the Research Achievements

本研究で使用した分子標的薬治療後の剖検検体を用いたマイクロRNAプロファイルは、世界的に殆ど報告が無く、研究を進める上で大きなアドバンテージとなった。miR-210-3-p, miR-1271a, miR-99a-3pの解析を基点として、治療標的となる重要な分子の同定に成功した。またHIF2α阻害薬の耐性獲得腎癌においてはPHGDH遺伝子の発現亢進によるセリン合成経路の活性化を発見しPHGDHの阻害薬が耐性克服に有効であることを突き止めた。現在、有効な治療法が乏しい治療抵抗性腎癌に対する新たな治療戦略を見出した事は、臨床的に非常に重要な情報をもたらしたと考える。

Research Products

• [Journal Article] Potential tumor-suppressive role of microRNA-99-3p in sunitinib-resistant renal cell carcinoma cells through the regulation of RRM2 (2019)
  • Author(s): Osako Y, Yoshino H, Sakaguchi T, Sugita S, Yonemori M, Nakagawa M, Enokida H.
  • Journal Title: International Journal of Oncology Volume: 54 Pages: 1759-1770
  • DOI: 10.3892/ijo.2019.4736
  • Peer Reviewed / Open Access
• [Journal Article] Downregulation of microRNA-1274a induces cell apoptosis through regulation of (2018)
  • Author(s): Yoshino H, Yonezawa T, Yonemori M, Miyamoto K, Sakaguchi T, Sugita S, Osako Y, Tatarano S, Nakagawa M, Enokida H.
  • Journal Title: Oncol Rep Volume: 39 Pages: 173-181
  • DOI: 10.3892/or.2017.6098
  • Peer Reviewed
• [Journal Article] microRNA-210-3p depletion by CRISPR/Cas9 promoted tumorigenesis through revival of TWIST1 in renal cell carcinoma. (2017)
  • Author(s): Yoshino H, Yonemori M, Miyamoto K, Tatarano S, Kofuji S, Nohata N, Nakagawa M, Enokida H.
  • Journal Title: Oncotarget Volume: 8 Issue: 13 Pages: 20881-20894
  • DOI: 10.18632/oncotarget.14930
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] スニチニブ耐性腎細胞癌におけるmiR-99-3pの機能解析 (2018)
  • Author(s): 大迫洋一，吉野裕史，坂口大，杉田智，榎田英樹，中川昌之
  • Organizer: 日本泌尿器科学会総会
• [Presentation] Suppression of oncogenic microRNA-1274a induces cell apoptosis through BMPR1B acceleration in renal cell carcinoma (2018)
  • Author(s): Enokida H
  • Organizer: 2018 AUA annual meeting
  • Int'l Joint Research