Development of the innovative treatment based on the search of microRNA blocking growth signals in urothelial carcinoma

• Project/Area Number: 16K11015
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Kagoshima University
• Principal Investigator: YOSHINO Hirofumi 鹿児島大学, 医歯学域附属病院, 助教 (90642611)
• Co-Investigator(Kenkyū-buntansha): 関 直彦 千葉大学, 大学院医学研究院, 准教授 (50345013)
• Research Collaborator: Matsushita Ryousuke ; Miyamoto Kazutaka ; Yonemori Masaya ; Enokida Hideki
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: マイクロRNA / 尿路上皮癌 / miRNA-199 / miRNA-223 / 治療標的型マイクロRNA / 癌 / 核酸 / シグナル伝達

Outline of Final Research Achievements

We elucidated that expression levels of miRNA-199a-3p/-5p, miRNA-199b-3p/-5p, and miRNA-223 were significantly down regulated in bladder cancer tissues, and that transduction of these miRNA suppressed cell proliferation, migration, and invasion. We also elucidated that miRNA-199 and miRNA-223 individually controlled ITGA3 and WDR62 directly. We finally succeeded to publish these data in journals.
In addition, we succeeded in the establishment of cancer cells which resistant to gemcitabine or cisplatin, and made profiles of miRNA with performed next-generation sequencing analyses. We found that miRNA-486-5p was down regulated in cisplatin-resistant cancer cells according to the profiles, and that miRNA-486-5p transduction suppressed cell proliferation in these cells.

Academic Significance and Societal Importance of the Research Achievements

1「治療標的探索型miRNA」を起点として、尿路上皮癌の再発や治療抵抗性に関わる機能性RNA分子ネットワークの探索を行い、いくつかの治療標的型miRNAを同定し論文化することができた。これらの成果により、miRNAを用いた尿路上皮癌の治療の可能性が示唆された。

Research Products

• [Journal Article] Tumor-suppressive microRNA-223 targets WDR62 directly in bladder cancer. (2019)
  • Author(s): Sugita S, Yoshino H, Yonemori M, Miyamoto K, Matsushita R, Sakaguchi T, Itesako T, Tatarano S, Nakagawa M, Enokida H.
  • Journal Title: Int J Oncol. Volume: -
  • Peer Reviewed
• [Journal Article] Potential tumor-suppressive role of microRNA-99a-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: Int J Oncol. Volume: -
  • Peer Reviewed
• [Journal Article] HRAS as a potential therapeutic target of salirasib RAS inhibitor in bladder cancer. (2018)
  • Author(s): Sugita S, Enokida H, Yoshino H, Miyamoto K, Yonemori M, Sakaguchi T, Osako Y, Nakagawa M.
  • Journal Title: Int J Oncol. Volume: 53 Pages: 725-736
  • Peer Reviewed
• [Journal Article] Bromodomain protein BRD4 inhibitor JQ1 regulates potential prognostic molecules in advanced renal cell carcinoma. (2018)
  • Author(s): Sakaguchi T, Yoshino H, Sugita S, Miyamoto K, Yonemori M, Osako Y, Meguro-Horike M, Horike SI, Nakagawa M, Enokida H.
  • Journal Title: Oncotarget Volume: 9 Pages: 23003-23017
  • 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 Pages: 20881-20894
  • DOI: 10.18632/oncotarget.14930
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] PHGDH as a Key Enzyme for Serine Biosynthesis in HIF2α-Targeting Therapy for (2017)
  • Author(s): Yoshino H, Nohata N, Miyamoto K, Yonemori M, Sakaguchi T, Sugita S, Itesako T, Kofuji S, Nakagawa M, Dahiya R, Enokida H.
  • Journal Title: Cancer Res Volume: 77 Pages: 6321-6329
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Regulation of ITGA3 by the dual-stranded microRNA-199 family as a potential prognostic marker in bladder cancer. (2017)
  • Author(s): Sakaguchi T, Yoshino H, Yonemori M, Miyamoto K, Sugita S, Matsushita R, Itesako T, Tatarano S, Nakagawa M, Enokida H.
  • Journal Title: Br J Cancer Volume: 116 Pages: 1077-1087
  • DOI: 10.1038/bjc.2017.43
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Tumour-suppressive miRNA-26a-5p and miR-26b-5p inhibit cell aggressiveness by regulating PLOD2 in bladder cancer (2016)
  • Author(s): Miyamoto K, Seki N, Matsushita R, Yonemori M, Yoshino H, Nakagawa M, Enokida H.
  • Journal Title: British Journal of Cancer Volume: 115 Pages: 354-363
  • DOI: 10.1038/bjc.2016.179
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Dual tumor-suppressors miR-139-5p and miR-139-3p targeting matrix metalloprotease 11 in bladder cancer. (2016)
  • Author(s): Yonemori M, Seki N, Yoshino H, Matsushita R, Miyamoto K, Nakagawa M, Enokida H.
  • Journal Title: Cancer Science Volume: 107 Pages: 1233-1242
  • DOI: 10.1111/cas.13002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Targeting PHGDH exerts anti-oncogenic effects in bladder cancer (2019)
  • Author(s): Hirofumi Yoshino
  • Organizer: 欧州泌尿器科学
  • Int'l Joint Research
• [Presentation] The tumor suppressor microRNA-223 targets WDR62 directly in bladder cancer (2018)
  • Author(s): Satoshi Sugita
  • Organizer: 米国泌尿器科学会
  • Int'l Joint Research
• [Presentation] Targeting metabolism re-programming as a therapy for drug-resistant renal cell carcinoma (2018)
  • Author(s): Hirofumi Yoshino, Kazutaka Miyamoto, Masaya Yonemori, Satoru Sugita, Takashi Sakaguchi, Hideki Enokida, Masayuki Nakagawa
  • Organizer: 欧州泌尿器科学会
  • Int'l Joint Research
• [Presentation] 膀胱癌におけるIntegrin α3（ITGA3）制御を介したmicroRNA-199 familyの癌抑制的作用 (2017)
  • Author(s): 坂口 大、吉野裕史、米森雅也、宮元一隆、杉田 智、松下良介、榎田英樹、中川昌之
  • Organizer: 第105回日本泌尿器科学会総会
  • Place of Presentation: かごしま県民交流センター（鹿児島県鹿児島市）
  • Year and Date: 2017-04-21
• [Presentation] CRISPR/Cas9-mediated miR-20-3p depletion promoted tumorigenesis through revival of TWIST in renal cell carcinoma (2017)
  • Author(s): Hirofumi Yoshino, Masaya Yonemori, Kazutaka Miyamoto, Satoshi Kofuji, Nijiro Nohata, Hideki Enokida, Masayuki Nakagawa
  • Organizer: 米国泌尿器科学会
  • Int'l Joint Research
• [Presentation] CRISPR/CAas9によるmicroRNA編集による腎癌の進展メカニズムの解明 (2017)
  • Author(s): 吉野裕史、米森雅也、宮元一隆、榎田英樹、中川昌之
  • Organizer: 日本泌尿器科学会総会
• [Presentation] Tumor suppressive miRNA-26a/b inhibit cell migration and invasion through targeting a prognostic marker, Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) in bladder cancer. (2016)
  • Author(s): Miyamoto K, Seki N, Matsushita R, Yonemori M, Yoshino H, Nakagawa M, Enokida H.
  • Organizer: 第68回西日本泌尿器科学会
  • Place of Presentation: 海峡メッセ下関（山口県下関市）
  • Year and Date: 2016-11-24
• [Presentation] Dual-strands of microRNA-139 (miR-139-5p and miR-139-3p) targeting matrix metalloprotease 11 (MMP11) in bladder cancer (2016)
  • Author(s): Yonemori M, Seki N, Yoshino H, Matsushita R, Miyamoto K, Nakagawa M, Enokida H.
  • 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