Identification of aberrant pathways by integrated analysis in stepwise hepatocarcinogenesis

• Project/Area Number: 24249068
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Nihon 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: ¥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.

Research Products

• [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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Peer Reviewed
• [Journal Article] CDX1 directs gastric intestinal metaplasia via induction of stemness-associated reprogramming factors SALL4 and KLF5 (2012)
  • Author(s): Fujii, Y.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 109 Pages: 20584-20589
  • DOI: 10.1073/pnas.1208651109
  • 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
  • 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
  • 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
  • Peer Reviewed
• [Presentation] Identification of aberrant pathways by integrated analysis in stepwise hepatocarcinogenesis (2014)
  • 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
• [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
• [Presentation] Identification of inactivating mutations in stepwise hepatocarcinogenesis using next generation sequencer (2014)
  • 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
• [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
• [Presentation] Identification of mutation patterns using exome sequencing for stepwise progression of hepatocarcinogenesis (2013)
  • Author(s): 緑川 泰
  • Organizer: 第72回日本癌学会
  • Place of Presentation: 横浜
• [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
• [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
• [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
• [Book] 肝細胞がん治療のpractice (2014)
  • Author(s): 緑川 泰、高山忠利
  • Total Pages: 4
  • Publisher: メジカルビュー
• [Book] The Liver Cancer Journal (2014)
  • 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
• [Book] メタボ案癌 (2013)
  • Author(s): 緑川泰、高山忠利
  • Publisher: アークメディア
• [Book] 肝癌診療Q&A (2013)
  • Author(s): 緑川泰、高山忠利
  • Publisher: 中外医学社
• [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