Metabolomic analyses in microRNA-reduced HCC

• Project/Area Number: 25460979
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: The University of Tokyo
• Principal Investigator: KOndo Yuji 東京大学, 医学部附属病院, 助教 (00572231)
• Co-Investigator(Kenkyū-buntansha): 大塚 基之 東京大学, 医学部附属病院, 助教 (90518945) ; 吉田 晴彦 東京大学, 医学部附属病院, 登録研究員 (60240305)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 肝臓学 / microRNA / 肝癌 / 癌幹細胞 / メタボローム

Outline of Final Research Achievements

Reduced expression of microRNA122 (miR122) is frequently observed in hepatocellular carcinoma (HCC) with aggressive phenotype. However, the molecular mechanisms underlying these observations are not well understood. Using comprehensive metabolomic analyses, we found that the intracellular levels of arginine were increased in miR122-silenced transgenic mouse liver tissues, through upregulation of cationic amino acid transporter member 1 (CAT1), a transporter of arginine. Arginine is the substrate for nitric oxide synthetase, and intracellular NO levels were indeed increased in miR122-silenced HCC cells, with increased expression levels of cancer-stem-cell markers and resistance to anti-cancer drug treatments. Conversely, maintenance of the miR122-silenced HCC cells in arginine-depleted culture media or the overexpression of miR122 reversed all of these features.These results suggest that arginine depletion may be a novel therapeutic approach to managing this disease.

Research Products

• [Int'l Joint Research] Icahn School of Medicine at Mount Sinai(米国)
• [Journal Article] Comparison of improved prognosis between hepatitis B- and hepatitis C-related hepatocellular carcinoma. (2015)
  • Author(s): Minami T, Tateishi R, Shiina S, Nakagomi R, Kondo M, Fujiwara N, Mikami S, Sato M, Uchino K, Enooku K, Nakagawa H, Asaoka Y, Kondo Y, Yoshida H, Koike K.
  • Journal Title: Hepatol Res. Volume: epub Issue: 10
  • DOI: 10.1111/hepr.12468
  • Peer Reviewed
• [Journal Article] Sarcopenia, Intramuscular Fat Deposition, and Visceral Adiposity Independently Predict the Outcomes of Hepatocellular Carcinoma (2015)
  • Author(s): Fujiwara N, Nakagawa H, Kudo Y, Tateishi R, Taguri M, Watadani T, Nakagomi R, Kondo M, Nakatsuka T, Minami T, Sato M, Uchino K, Enooku K, Kondo Y, Asaoka Y, Tanaka Y, Ohtomo K, Shiina S, Koike K
  • Journal Title: J Hepatol Volume: 62 Issue: 1 Pages: 131-140
  • DOI: 10.1016/j.jhep.2015.02.031
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Decreased miR122 in hepatocellular carcinoma leads to chemoresistance with increased arginine. (2015)
  • Author(s): Kishikawa T, Otsuka M, Tan PS, Ohno M, Sun X, Yoshikawa T, Shibata C, Takata A, Kojima K, Takehana K, Ohishi M, Ota S, Noyama T, Kondo Y, Sato M, Soga T, Hoshida Y, Koike K.
  • Journal Title: Oncotarget. Volume: 6 Pages: 8339-52
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Diagnostic and therapeutic application of noncoding RNAs for hepatocellular carcinoma. (2015)
  • Author(s): Shibata C, Otsuka M, Kishikawa T, Ohno M, Yoshikawa T, Takata A, Koike K.
  • Journal Title: World J Hepatol. Volume: 27 Issue: 1 Pages: 1-6
  • DOI: 10.4254/wjh.v7.i1.1
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The flavonoid apigenin inhibits hepatitis C virus replication by decreasing mature microRNA122 levels. (2014)
  • Author(s): Shibata C, Ohno M, Otsuka M, Kishikawa T, Goto K, Muroyama R, Kato N, Yoshikawa T, Takata A, Koike K.
  • Journal Title: Virology Volume: 462-463 Pages: 42-48
  • DOI: 10.1016/j.virol.2014.05.024
  • Peer Reviewed
• [Journal Article] Regulation of the expression of the liver cancer susceptibility gene MICA by microRNAs. (2013)
  • Author(s): Kishikawa T, Otsuka M, Yoshikawa T, Ohno M, Takata A, Shibata C, Kondo Y, Akanuma M, Yoshida H, Koike K.
  • Journal Title: Sci Rep. Volume: 3 Issue: 1 Pages: 2739-2739
  • DOI: 10.1038/srep02739
  • Peer Reviewed
• [Journal Article] Spontaneous clearance of serum hepatitis C virus RNA during the clinical course of hepatocellular carcinoma in patients with chronic hepatitis C. (2013)
  • Author(s): Minami T, Tateishi R, Shiina S, Fujiwara N, Mikami S, Sato M, Uchino K, Enooku K, Asaoka Y, Kondo Y, Yoshida H, Koike K.
  • Journal Title: Hepatol Res. Volume: : Issue: 10
  • DOI: 10.1111/hepr.12203
  • Peer Reviewed
• [Journal Article] CT with hepatic arterioportography as a pretreatment examination for hepatocellular carcinoma patients : a randomized controlled trial (2013)
  • Author(s): Ohki T, Tateishi R, Akahane M, Mikami S, Sato M, Uchino K, Arano T, Enooku K, Kondo Y, Yamashiki N, Goto T, Shiina S, Yoshida H, Matsuyama Y, Omata M, Ohtomo K, Koike K
  • Journal Title: Am JGastroenterol Volume: 108(8) Issue: 8 Pages: 1305-13
  • DOI: 10.1038/ajg.2013.109
  • Peer Reviewed
• [Remarks] グループホームページ
  • URL: https://sites.google.com/site/225kenncrna/
• [Remarks] 東京大学 肝がん治療グループのホームページ
  • URL: http://park.itc.u-tokyo.ac.jp/livercancer/