Impairment of microRNA function and carcinogenetic risk by aging

• Project/Area Number: 16H05149
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: The University of Tokyo
• Principal Investigator: OTSUKA MOTOYUKI 東京大学, 医学部附属病院, 講師 (90518945)
• Co-Investigator(Kenkyū-buntansha): 立石 敬介 東京大学, 医学部附属病院, 講師 (20396948) ; 前田 愼 横浜市立大学, 医学研究科, 教授 (40415956)
• 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: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2016: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 加齢 / microRNA / 細胞老化 / SASP / 癌化 / 核酸 / 老化 / non-coding RNA / 発癌 / 内科

Outline of Final Research Achievements

To uncover the mechanisms why aging cells are prone to carcinogenesis, we focused on microRNA function during aging. Normal human derived fibroblasts produced inflammatory cytokines by aging. Especially, Interferon responsive genes were upregulated through nuclear localization of the increased levels of STATs. These phenomena happen in the non-parenchymal cells in the human liver. Thus, aging induce chronic inflammation, which imaparis the microRNA function, leading to the increased risk of carcinogenesis. Because we found that ROCK inhibitor enhances microRNA function, this compound may suppress the risk of carcinogenesis due to aging.

Academic Significance and Societal Importance of the Research Achievements

加齢に伴う発癌の危険性の増加は、高齢化社会に向けて解決しなければならない課題である。本研究ではその分子機構を解析した。細胞老化に伴って炎症性サイトカインの発現が増え慢性炎症を惹起するが、それがmicroRNAの機能を減弱させ、その結果 易発癌性になることを見出した。microRNA機能を増強する化合物として見出したROCK阻害剤は、高齢に伴う発癌リスクを減らす可能性がある。

Research Products

• [Journal Article] Inhibition of HBV Transcription From cccDNA With Nitazoxanide by Targeting the HBx?DDB1 Interaction (2019)
  • Author(s): Sekiba Kazuma、Otsuka Motoyuki、Ohno Motoko、Yamagami Mari、Kishikawa Takahiro、Suzuki Tatsunori、Ishibashi Rei、Seimiya Takahiro、Tanaka Eri、Koike Kazuhiko
  • Journal Title: Cellular and Molecular Gastroenterology and Hepatology Volume: 7 Issue: 2 Pages: 297-312
  • DOI: 10.1016/j.jcmgh.2018.10.010
  • Peer Reviewed / Open Access
• [Journal Article] Pevonedistat, a Neuronal Precursor Cell-Expressed Developmentally Down-Regulated Protein 8-Activating Enzyme Inhibitor, Is a Potent Inhibitor of Hepatitis B Virus (2019)
  • Author(s): Sekiba Kazuma、Otsuka Motoyuki、Ohno Motoko、Yamagami Mari、Kishikawa Takahiro、Seimiya Takahiro、Suzuki Tatsunori、Tanaka Eri、Ishibashi Rei、Funato Kazuyoshi、Koike Kazuhiko
  • Journal Title: Hepatology Volume: in press Issue: 5 Pages: 1903-1915
  • DOI: 10.1002/hep.30491
  • Peer Reviewed / Open Access
• [Journal Article] ISGF3 with reduced phosphorylation is associated with constitutive expression of interferon-induced genes in aging cells (2018)
  • Author(s): Yamagami Mari、Otsuka Motoyuki、Kishikawa Takahiro、Sekiba Kazuma、Seimiya Takahiro、Tanaka Eri、Suzuki Tatsunori、Ishibashi Rei、Ohno Motoko、Koike Kazuhiko
  • Journal Title: npj Aging and Mechanisms of Disease Volume: 4 Issue: 1 Pages: 11-11
  • DOI: 10.1038/s41514-018-0030-6
  • Peer Reviewed / Open Access
• [Journal Article] Repression of miRNA function mediates inflammation-associated colon tumorigenesis. (2017)
  • Author(s): Yoshikawa T., J. F. Wu, M. Otsuka, T. Kishikawa, N. Suzuki, A. Takata, M. Ohno, R. Ishibashi, M. Yamagami, R. Nakagawa, N. Kato, M. Miyazawa, J. Han, and K. Koike
  • Journal Title: Gastroenterology Volume: 152 Issue: 3 Pages: 631-643
  • DOI: 10.1053/j.gastro.2016.10.043
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Transcriptional activation of the MICA gene with an engineered CRISPR-Cas9 system (2017)
  • Author(s): Sekiba K, Yamagami M, Otsuka M, Suzuki T, Kishikawa T, Ishibashi R, Ohno M, Sato M, Koike K
  • Journal Title: Biochem Biophys Res Commun Volume: - Issue: 2 Pages: 521-525
  • DOI: 10.1016/j.bbrc.2017.03.076
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] RASAL1 is a potent regulator of hepatic stellate cell activity and liver fibrosis (2017)
  • Author(s): Takata Akemi、Otsuka Motoyuki、Kishikawa Takahiro、Yamagami Mari、Ishibashi Rei、Sekiba Kazuma、Suzuki Tatsunori、Ohno Motoko、Yamashita Yui、Abe Takaya、Masuzaki Ryota、Ikenoue Tsuneo、Koike Kazuhiko
  • Journal Title: Oncotarget Volume: 8 Issue: 39 Pages: 64840-64852
  • DOI: 10.18632/oncotarget.17609
  • Peer Reviewed / Open Access
• [Remarks] 研究者ホームページ
  • URL: https://sites.google.com/site/225kenncrna/
• [Remarks] 研究室ホームページ
  • URL: https://sites.google.com/site/225kenncrna/