Development of nuclear acid medicine by using tumor suppressive microRNA conjugated with high molecular nano-micelle

• Project/Area Number: 16K15691
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Urology
• Research Institution: Kagoshima University
• Principal Investigator: TATARANO Shuichi 鹿児島大学, 医歯学域医学系, 助教 (30624655)
• 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: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: ナノミセル / マイクロRNA / 核酸医薬 / 腎癌 / 膀胱癌 / 腎細胞癌 / microRNA

Outline of Final Research Achievements

Based on microRNA expression profile of drug-resistant renal cell carcinoma, 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.
Followed by, we established nano-micelle type drug delivery system (DDS) by conjugating unit polyion complexes (u-PIC) and chimera microRNA in which 10 base nucleotides from its 3 prime region were exchanged to DNA. When the DDSs with 40 nM of miRNAs were administrated to the cultured cancer cells, the concentration of each microRNA was elevated to 100 times or more than pre-administrations. Also, from 20 to 50% knockdown effect of each target genes and apoptosis induction were observed.

Academic Significance and Societal Importance of the Research Achievements

unit polyion complexes (u-PIC)は生体内で安定するキメラ型2重鎖miRNAを内包することが可能であり、ナノミセル型ドラッグデリバリーシステム（DDS）の開発に成功した。各miRNAは培養癌細胞に効率よく取り込まれて抗腫瘍効果を発揮することが確認できた。次の段階のin-vivo投与実験を経て将来の核酸医薬創薬に向けて有意義な情報を得ることが出来た。

Research Products

• [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: 印刷中
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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: British Journal of Cancer Volume: 116 Issue: 8 Pages: 1077-1087
  • DOI: 10.1038/bjc.2017.43
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 膀胱癌に対するナノミセル型薬物搬送システムを介した癌抑制型マイクロRNAによる新規核酸治療の開発 (2019)
  • Author(s): 榎田英樹
  • Organizer: 第107回 日本泌尿器科学会総会
• [Presentation] Suppression of oncogenic microRNA-1274a induces cell apoptosis through (2018)
  • Author(s): Enokida H
  • Organizer: 2018アメリカ泌尿器科学会総会
  • Int'l Joint Research