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Identification of aberrant pathways by integrated analysis in stepwise hepatocarcinogenesis

Research Project

Project/Area Number 24249068
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Digestive surgery
Research InstitutionNihon University

Principal Investigator

TAKAYAMA Tadatoshi  日本大学, 医学部, 教授 (30280944)

Co-Investigator(Kenkyū-buntansha) MIDORIKAWA Yutaka  日本大学, 医学部, 助教 (10292905)
TSUTSUMI Shuichi  東京大学, 先端科学技術研究センター, 特任准教授 (30345152)
TUSJI Shingo  東京大学, 先端科学技術研究センター, 特任助教 (80431823)
Project Period (FY) 2012-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥45,240,000 (Direct Cost: ¥34,800,000、Indirect Cost: ¥10,440,000)
Fiscal Year 2014: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
Fiscal Year 2013: ¥15,470,000 (Direct Cost: ¥11,900,000、Indirect Cost: ¥3,570,000)
Fiscal Year 2012: ¥22,490,000 (Direct Cost: ¥17,300,000、Indirect Cost: ¥5,190,000)
Keywords肝癌多段階発癌 / 次世代シークエンス / p53 / WNT / TERT / 統合解析 / 早期肝癌 / 次世代シークエンサー / WNT経路 / p53経路 / β-カテニンン / SWI/SNF / PI3K?mTOR / 肝細胞癌 / 包括的メチル化解析 / 発癌メカニズム
Outline of Final Research Achievements

Early hepatocellular carcinoma (HCC) is histologically diagnosed as the existence of intratumoral portal tracts and develops into classical HCC. To identify sequential genomic changes in stepwise hepatocarcinogenesis, we analyzed 47 early and 105 classical HCCs using next generation sequencer. Mutations in p53/RB and WNT pathways were recurrently observed both in early and classical HCCs. Exome and RNA sequences frequently showed mutation of promoter region and increased expression of TERT. On the other hand, inactivation in SWI/SNF complexes were observed more often in classical HCC (23.8%) than early HCC (8.5%, P=0.027), and mTOR/PI3K pathway was aberrantly activated in classical HCC (8.5% vs 29.5%, P=0.003) by integrated analysis. Taken together, inactivating mutations of p53/RB and WNT signaling pathways and TERT up-regulation are the first events in hepatocarcinogenesis and aberrations of SWI/SNF complexes and mTOR/PI3K pathway may play pivotal roles in the progression of HCC.

Report

(4 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Annual Research Report
  • 2012 Annual Research Report

Research Products

(29 results)

All 2015 2014 2013 2012

All Journal Article (16 results) (of which Peer Reviewed: 16 results,  Acknowledgement Compliant: 4 results,  Open Access: 2 results) Presentation (7 results) Book (6 results)

  • [Journal Article] Decreased blood loss reduces postoperative complications in resection for hepatocellular carcinoma.2015

    • Author(s)
      Aramaki O, Takayama T, Higaki T, Nakayama H, Ohkubo T, Midorikawa Y, Moriguchi M, Matsuyama Y.
    • Journal Title

      Journal of Hepatobiliary Pancreatic Science

      Volume: in press

    • DOI

      10.1002/jhbp.101

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Surgical outcomes in patients with hepatocellular carcinoma associated with metabolic syndrome.2015

    • Author(s)
      Yoshida N, Takayama T, Midorikawa Y, Higaki T, Nakayama H, Moriguchi M, Tsuji S.
    • Journal Title

      World J Surg.

      Volume: 39 Pages: 471-477

    • DOI

      10.1007/s00268-014-2828-0

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Transmembrane serine protease TMPRSS2 activates hepatitis C virus infection.2015

    • Author(s)
      Esumi M, Ishibashi M, Yamaguchi H, Nakajima S, Tai Y, Kikuta S, Sugitani M, Takayama T, Tahara M, Takeda M, Wakita T
    • Journal Title

      Hepatology

      Volume: 61(2) Pages: 437-446

    • DOI

      10.1002/hep.27426

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Trans-ancestry mutational landscape of hepatocellular carcinoma genomes.2014

    • Author(s)
      Totoki Y, Tatsuno K, Covington KR, Ueda H, Creighton CJ, Kato M, Tsuji S, Donehower LA, Slagle BL, Nakamura H, Yamamoto S, Shinbrot E, Hama N, Lehmkuhl M, Hosoda F, Arai Y, Walker K, Dahdouli M, Gotoh K, Nagae G, Gingras MC, Muzny DM, …, Takayama T, Fukayama M, Gibbs RA, Wheeler DA, Aburatani H, Shibata T
    • Journal Title

      Nature Genetics

      Volume: 46 Pages: 1267-1273

    • DOI

      10.1038/ng.3126

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Aberrant promoter methylation of PPP1R3C and EFHD1 in plasma of colorectal cancer patients.2014

    • Author(s)
      Takane K, Midorikawa Y, Yagi K, Sakai A, Aburatani H, Takayama T, Kaneda A
    • Journal Title

      Cancer Med

      Volume: 3 Pages: 1235-45

    • DOI

      10.1002/cam4.273

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Subcutaneous drainage to prevent wound infection in liver resection: a randomized controlled trial.2014

    • Author(s)
      Nakayama H, Takayama T, Okubo T, Higaki T, Midorikawa Y, Moriguchi M, Aramaki O, Yamazaki S..
    • Journal Title

      Journal of Hepato-Billiary-Pancreatic Sciences

      Volume: 21

    • DOI

      10.1002/jhbp.93

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Postoperative outcomes of patients with hepatocellular carcinoma negative for all virus-related markers.2013

    • Author(s)
      Yamato I, Takayama T, Midorikawa Y, Higaki T, Nakayama H, Moriguchi M, Nakajima Y, Matsuoka S, Ogawa M, Moriyama M.
    • Journal Title

      Surg Today

      Volume: 43 Pages: 865-870

    • DOI

      10.1007/s00595-012-0308-4

    • NAID

      10031189765

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Good Candidates for a Third Liver Resection of Colorectal Metastasis.2013

    • Author(s)
      Yamazaki S, Takayama T, Okada S, Iwama A, Midorikawa Y, Moriguchi M, Nakayama H, Higaki T, Sugitani M.
    • Journal Title

      World J Surg

      Volume: 37 Pages: 487-453

    • DOI

      10.1007/s00268-012-1887-3

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Pharmacokinetics of docetaxel in gastric cancer patients with malignant ascites.2013

    • Author(s)
      Tamegai H, Kaiga T, Kochi M, Fujii M, Kanamori N, Mihara Y, Funada T, Shimizu H, Jinno D, Takayama T.
    • Journal Title

      Cancer Chemother Pharmacol

      Volume: 71 Pages: 727-731

    • DOI

      10.1007/s00280-012-2066-9

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Marginal survival benefit in the treatment of early hepatocellular carcinoma.2013

    • Author(s)
      Midorikawa Y
    • Journal Title

      J Hepatol

      Volume: 58 Pages: 306-11

    • DOI

      10.1016/j.jhep.2012.09.026

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Criteria for drain removal following liver resection.2012

    • Author(s)
      Yamazaki S
    • Journal Title

      Br J Surg

      Volume: 99 Pages: 1584-90

    • DOI

      10.1002/bjs.8916

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Chimeric acceleration by donor CD4+CD25+T-reg depleted fraction in splenocyte transplantation.2012

    • Author(s)
      Kutsuna N
    • Journal Title

      J Surg Res

      Volume: 172 Pages: 133-8

    • DOI

      10.1016/j.jss.2012.01.003

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] CDX1 directs gastric intestinal metaplasia via induction of stemness-associated reprogramming factors SALL4 and KLF52012

    • Author(s)
      Fujii, Y.
    • Journal Title

      Proc Natl Acad Sci U S A

      Volume: 109 Pages: 20584-20589

    • DOI

      10.1073/pnas.1208651109

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] TNF alpha signals through specialized factories where responsive coding and miRNA genes are transcribed.2012

    • Author(s)
      Papantonis, A., Kohro, T., Baboo, S., Larkin, J.D., Deng, B., Short, P., Tsutsumi, S., Taylor, S.,Kanki, Y., Kobayashi, M., Li, G., Poh, H., Ruan,X., Aburatani, H., Ruan, Y., Kodama, T., Wada,Y., and Cook, P. R.
    • Journal Title

      EMBO J

      Volume: 31 Pages: 4404-14

    • DOI

      10.1038/emboj.2012.288

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Sox21 promotes hippocampal adult neurogenesis via the transcriptional repression of the Hes5 gene.2012

    • Author(s)
      Matsuda S
    • Journal Title

      J Neurosci

      Volume: 32 Pages: 12543-57

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Dynamic change of chromatin conformation in response to hypoxia enhances the expression of GLUT3 (SLC2A3) by cooperative interaction of hypoxia-inducible factor 1 and KDM3A.2012

    • Author(s)
      Mimura I
    • Journal Title

      Mol Cell Biol

      Volume: Aug;32(15) Pages: 3018-3032

    • DOI

      10.1128/mcb.06643-11

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Presentation] Identification of aberrant pathways by integrated analysis in stepwise hepatocarcinogenesis2014

    • Author(s)
      Midorikawa Y, Yamamoto S, Tatsuno K, Takayama T, Aburatani H.
    • Organizer
      第73回日本癌学会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2014-09-05 – 2014-09-07
    • Related Report
      2014 Annual Research Report
  • [Presentation] 次世代シークエンサー・包括的エピゲノム解析による早期肝癌の統合的ゲノム解析2014

    • Author(s)
      緑川 泰、高山忠利、山本尚吾、辻 真吾、永江玄太、辰野健二、油谷浩幸
    • Organizer
      第50回日本肝癌研究会
    • Place of Presentation
      国立京都国際会館(京都府京都市)
    • Year and Date
      2014-06-05 – 2014-06-06
    • Related Report
      2014 Annual Research Report
  • [Presentation] Identification of inactivating mutations in stepwise hepatocarcinogenesis using next generation sequencer2014

    • Author(s)
      Midorikawa Y, Yamamoto S, Tatsuno K, Takayama T, Aburatani H.
    • Organizer
      AACR Annual Meeting 2014
    • Place of Presentation
      サンディエゴ(アメリカ)
    • Year and Date
      2014-04-05 – 2014-04-09
    • Related Report
      2014 Annual Research Report
  • [Presentation] RNAシークエンシングエクソームシークエンスによる肝癌多段階発癌メカニズムの解明2013

    • Author(s)
      緑川 泰
    • Organizer
      第113回日本外科学会
    • Place of Presentation
      福岡
    • Related Report
      2013 Annual Research Report
  • [Presentation] Identification of mutation patterns using exome sequencing for stepwise progression of hepatocarcinogenesis2013

    • Author(s)
      緑川 泰
    • Organizer
      第72回日本癌学会
    • Place of Presentation
      横浜
    • Related Report
      2013 Annual Research Report
  • [Presentation] ランダムフォレストを用いたFOLFOX療法感受性予測による個別化医療への臨床応用2012

    • Author(s)
      緑川泰
    • Organizer
      第23回日本消化器癌発生学会
    • Place of Presentation
      徳島
    • Related Report
      2012 Annual Research Report
  • [Presentation] Integrative analysis of methylation and expression profiles for discovering functional key molecules in colorectal cancer.2012

    • Author(s)
      Midorikawa Y
    • Organizer
      第71回日本癌学会
    • Place of Presentation
      札幌
    • Related Report
      2012 Annual Research Report
  • [Book] 最新肝癌学2014

    • Author(s)
      緑川 泰、山本尚吾、高山忠利、油谷浩幸
    • Total Pages
      4
    • Publisher
      日本臨床
    • Related Report
      2014 Annual Research Report
  • [Book] 肝細胞がん治療のpractice2014

    • Author(s)
      緑川 泰、高山忠利
    • Total Pages
      4
    • Publisher
      メジカルビュー
    • Related Report
      2014 Annual Research Report
  • [Book] The Liver Cancer Journal2014

    • Author(s)
      緑川 泰、山本尚吾、高山忠利、油谷浩幸
    • Total Pages
      4
    • Publisher
      メディカルレビュー
    • Related Report
      2014 Annual Research Report
  • [Book] メタボ案癌2013

    • Author(s)
      緑川泰、高山忠利
    • Publisher
      アークメディア
    • Related Report
      2013 Annual Research Report
  • [Book] 肝癌診療Q&A2013

    • Author(s)
      緑川泰、高山忠利
    • Publisher
      中外医学社
    • Related Report
      2013 Annual Research Report
  • [Book] 肝細胞癌のすべて2012  治療法の進歩2012

    • Author(s)
      緑川泰
    • Total Pages
      6
    • Publisher
      アークメディア
    • Related Report
      2012 Annual Research Report

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Published: 2013-05-15   Modified: 2019-07-29  

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