Oncogenetic process by the complexed system due to heterochromatin-derived RNA

• Project/Area Number: 16KT0109
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Multi-year Fund
• Section: 特設分野
• Research Field: Complex Systems Disease Theory
• 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): 前田 愼 横浜市立大学, 医学研究科, 教授 (40415956) ; 伊地知 秀明 東京大学, 医学部附属病院, 講師 (70463841)
• Project Period (FY): 2016-07-19 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000); Fiscal Year 2018: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2017: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2016: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 複雑系 / ヘテロクロマチン / RNA / 反復配列RNA / 膵癌 / 癌化 / 反復配列 / 核酸 / 癌 / トランスレーショナルリサーチ

Outline of Final Research Achievements

By focusing the expression of repetitive RNA from heterochromatin region from the early stage of pancreatic cancer, its biological function was examined. Repetitive RNA expression resulted in the accumulation of DNA damages and chromosomal instability through binding with YBX-1 protein. By detecting the repetitive RNA from the patinets’ sera, this may be a novel biomarker for the detection of early pancreatic cancer. In addition, we newly identified a novel circular RNA expressing specifically in pancreatic cancer and its expression in the tissues were examined. Through the analyses of complexed system involving DNA, RNA, and protein, clinically useful biomarkers can be developed.

Academic Significance and Societal Importance of the Research Achievements

膵癌は予後の悪いがんの筆頭ともいえるが、それは 発癌メカニズムが不明である点と、早期発見がしにくい点が 理由として挙げられる。膵癌早期から、通常では発現していない一定の配列の繰り返しを持つ特殊なRNAが発現してくることが分かっている。本研究によって、この反復配列RNAの発現が複雑な系を介して細胞の遺伝子異常を惹起し、癌化に絡んでいることが判明した。今後 反復配列RNAの血中での検出による膵癌早期発見への応用や、このRNAを標的とした新規治療法の開発がのぞまれる。

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] Satellite RNA Increases DNA Damage and Accelerates Tumor Formation in Mouse Models of Pancreatic Cancer (2018)
  • Author(s): Kishikawa Takahiro、Otsuka Motoyuki、Suzuki Tatsunori、Seimiya Takahiro、Sekiba Kazuma、Ishibashi Rei、Tanaka Eri、Ohno Motoko、Yamagami Mari、Koike Kazuhiko
  • Journal Title: Molecular Cancer Research Volume: 16 Issue: 8 Pages: 1255-1262
  • DOI: 10.1158/1541-7786.mcr-18-0139
  • Peer Reviewed / Open Access
• [Journal Article] DHX9 regulates production of hepatitis B virus-derived circular RNA and viral protein levels (2018)
  • Author(s): Sekiba Kazuma、Otsuka Motoyuki、Ohno Motoko、Kishikawa Takahiro、Yamagami Mari、Suzuki Tatsunori、Ishibashi Rei、Seimiya Takahiro、Tanaka Eri、Koike Kazuhiko
  • Journal Title: Oncotarget Volume: 9 Issue: 30 Pages: 20953-20964
  • DOI: 10.18632/oncotarget.25104
  • 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] 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
• [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] 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] Satellite RNAs promote pancreatic oncogenic process via the dysfunction of YBX1. (2016)
  • Author(s): Kishikawa T, Otsuka M, Yoshikawa T, Ohno M, Ijichi H, and Koike K
  • Journal Title: Nature Communications Volume: 7 Issue: 1 Pages: 13006-13006
  • DOI: 10.1038/ncomms13006
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Quantitation of circulating satellite RNAs in pancreatic cancer patients. (2016)
  • Author(s): 4.Kishikawa T, #Otsuka M, Yoshikawa T, Ohno M, Yamamoto K, Yamamoto N, Kotani A, Koike K.
  • Journal Title: JCI Insight Volume: 1
  • Peer Reviewed / Open Access / Acknowledgement Compliant