Analysis of hepatic carcinogenesis by interrelationship between RNA-binding oncogene and miRNAs

• Project/Area Number: 24659362
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Kyoto University
• Principal Investigator: HIGASHITSUJI Hiroaki 京都大学, 医学(系)研究科(研究院), 助教 (60281094)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: RNA結合蛋白 / 肝癌 / mRNA processing / mRNA splicing / CLIP / spliceosome / BRCA1 / homologous recombination / miRNA / CIRP / 肝臓がん / がん遺伝子 / 相互作用 / 肝細胞癌 / RNA結合タンパク / 癌遺伝子

Outline of Final Research Achievements

CIRP is one of RNA binding proteins, and induced by stress responces, which include moderate cold stress, ultraviolet, and hypoxia. CIRP functions as oncogene, because CIRP induces mouse primary cell immortalization and transformation. To identify CIRP protein-bound mRNA transcripts in whole transcriptome of human hepatoblastoma cell line HepG2, we apply crosslinking and immunoprecipitation(CLIP). CIRP binds mRNA transcripts of Mre11, Rad50, Rad52, NBS, and ATM, that are involved in DNA repair by BRCA1-associated homologous recombination after DNA damage. However, CIRP does not complex with transcripts of Ku80, XRCC4-like, and DNA-PK, that are involved in DNA repair by non-homologous end joining (NHEJ). Spliceosome contains CIRP. CIRP binds phospho-BRCA1 in the nucleus. phospho-BRCA1-CIRP complex undergoes efficient mRNA processing and splicing, and enhances expression of mature transcripts, facilitating resistance against DNA damage.

Research Products

• [Journal Article] Stress response protein cirp links inflammation and tumorigenesis in colitis-associated cancer. (2014)
  • Author(s): Sakurai T, Kashida H, Watanabe T, Hagiwara S, Mizushima T, Iijima H, Nishida N, Higashitsuji H, Fujita J, Kudo M.
  • Journal Title: Cancer Res. Volume: 74 Pages: 6119-28
  • Peer Reviewed / Open Access
• [Journal Article] Hypothermia protects against fulminant hepatitis in mice by reducing reactive oxygen species production. (2013)
  • Author(s): Sakurai T, Kudo M, Watanabe T, Itoh K, Higashitsuji H, Arizumi T, Inoue T, Hagiwara S, Ueshima K, Nishida N, Fukumoto M, Fujita J.
  • Journal Title: Dig Dis Volume: 31 Issue: 5-6 Pages: 440-6
  • DOI: 10.1159/000355242
  • Peer Reviewed
• [Journal Article] Overexpression of gankyrin in mouse hepatocytes induces hemangioma by suppressing factor inhibiting hypoxia-inducible factor-1 (FIH-1) and activating hypoxia-inducible factor-1. (2013)
  • Author(s): Liu Y, Higashitsuji H, Higashitsuji H, Itoh K, Sakurai T, Koike K, Hirota K, Fukumoto M, Fujita J.
  • Journal Title: Biochem Biophys Res Commun. Volume: 432(1) Pages: 22-27
  • Peer Reviewed
• [Journal Article] Identification of a novel enhancer that binds Sp1 and contributes to induction of cold-inducible RNA-binding protein (cirp) expression in mammalian cells. (2012)
  • Author(s): Sumitomo Y, Higashitsuji H, Higashitsuji H, Liu Y, Fujita T, Sakurai T, et al
  • Journal Title: BMC Biotechnol Volume: 12 Issue: 1 Pages: 72-72
  • DOI: 10.1186/1472-6750-12-72
  • Peer Reviewed
• [Journal Article] Cold-inducible RNA-binding protein (Cirp) interacts with Dyrk1b/Mirk and promotes proliferation of immature male germ cells in mice (2012)
  • Author(s): Masuda T, et al.
  • Journal Title: Proc Natl Acad Sci USA Volume: 109 Issue: 27 Pages: 10885-108901
  • DOI: 10.1073/pnas.1121524109
  • Peer Reviewed
• [Presentation] ほ乳類低温ショックタンパク質CIRPはBRCA1による相同組み替えによるDNA修復を促進する (2014)
  • Author(s): 東辻宏明
  • Organizer: 第６９回日本消化器外科学会総会
  • Place of Presentation: 郡山市立文化センター
  • Year and Date: 2014-07-16 – 2014-07-18
• [Presentation] ほ乳類低温ショックタンパク質Cirpは皮膚創傷治癒を促進する (2013)
  • Author(s): 藤田潤、東辻久子、東辻宏明
  • Organizer: 第８回臨床ストレス応答学会
  • Place of Presentation: 松本市、信州大学医学部付属病院、大会議室
• [Presentation] Overexpression of gankyrin in mouse hepatocytes induces hemangioma. (2013)
  • Author(s): 東辻宏明、東辻久子、藤田潤
  • Organizer: 第２１回JDDW２０１３
  • Place of Presentation: 東京都品川区
• [Presentation] 癌抑制遺伝子BRCA1の不活性型代謝系酵素による核内での機能調節 (2012)
  • Author(s): 東辻宏明
  • Organizer: 日本肝臓学会
  • Place of Presentation: 金沢市
• [Presentation] Proto-oncogene CIRP that is induced by moderate cold temperature (32 degrees centigrade) enhances cell mobility of cancer cells (2012)
  • Author(s): 東辻宏明
  • Organizer: 日本癌学会
  • Place of Presentation: 札幌市