Analysis of DNA methylation and microRNA expression in hepatocellular carcinoma

• Project/Area Number: 15K09017
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Yasui Kohichiroh 京都府立医科大学, 医学(系)研究科(研究院), 准教授 (30323695)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 肝細胞癌 / マイクロRNA / DNAメチル化 / エピゲノム異常 / エピゲノム

Outline of Final Research Achievements

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and can act as tumor suppressors or oncogenes. To identify miRNA involved in the development of HCC, a genome-wide miRNA gene expression analysis was performed in paired HCC tumors and non-tumorous liver tissues from patients with primary HCC. We also screened for genes with promoter DNA hypermethylation using a genome-wide DNA methylation microarray analysis in the same samples. We found that miR-214 and miR-199a were significantly down-regulated by aberrant promoter hypermethylation of their host gene, DNM3OS, in HCC tumors compared to the non-tumorous liver tissues.

Research Products

• [Journal Article] Oncogenic miR-96-5p inhibits apoptosis by targeting the caspase-9 gene in hepatocellular carcinoma (2018)
  • Author(s): Iwai Naoto、Yasui Kohichiroh、Tomie Akira、Gen Yasuyuki、Terasaki Kei、Kitaichi Tomoko、Soda Tomohiro、Yamada Nobuhisa、Dohi Osamu、Seko Yuya、Umemura Atsushi、Nishikawa Taichiro、Yamaguchi Kanji、Moriguchi Michihisa、Konishi Hideyuki、Naito Yuji、Itoh Yoshito
  • Journal Title: International Journal of Oncology Volume: 53 Pages: 237-245
  • DOI: 10.3892/ijo.2018.4369
  • Peer Reviewed
• [Journal Article] Multicenter Phase II study of sorafenib in Japanese patients with advanced hepatocellular carcinoma and Child Pugh A and B class (2018)
  • Author(s): Suzuki Eiichiro、Kaneko Shuichi、Okusaka Takuji、Ikeda Masafumi、Yamaguchi Kensei、Sugimoto Rie、Aramaki Takeshi、Asagi Akinori、Yasui Kohichiroh、Sano Keiji、Hosokawa Ayumu、Kato Naoya、Ishii Hiroshi、Sato Tosiya、Furuse Junji
  • Journal Title: Japanese Journal of Clinical Oncology Volume: 48 Issue: 4 Pages: 317
  • DOI: 10.1093/jjco/hyy010
  • Peer Reviewed
• [Journal Article] Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers (2018)
  • Author(s): Kawaguchi T, Shima T, Mizuno M, Mitsumoto Y, Umemura A, Kanbara Y, Tanaka S, Sumida Y, Yasui K, Takahashi M, Matsuo K, Itoh Y, Tokushige K, Hashimoto E, Kiyosawa K, Kawaguchi M, Itoh H, Uto H, Komorizono Y, Shirabe K, Takami S, Takamura T, Kawanaka M, Yamada R, Matsuda F, Okanoue T.
  • Journal Title: PLOS ONE Volume: 13 Issue: 1 Pages: e0185490-e0185490
  • DOI: 10.1371/journal.pone.0185490
  • Peer Reviewed / Open Access
• [Journal Article] Combination of PNPLA3 and TLL1 polymorphism can predict advanced fibrosis in Japanese patients with nonalcoholic fatty liver disease (2018)
  • Author(s): Seko Y, Yamaguchi K, Mizuno N, Okuda K, Takemura M, Taketani H, Hara T, Umemura A, Nishikawa T, Moriguchi M, Yasui K, Kamaguchi M, Nishioji K, Mochizuki N, Kobayashi M, Mori K, Tanaka S, Matsuura K, Tanaka Y, Itoh Y.
  • Journal Title: Journal of Gastroenterology Volume: 53 Issue: 3 Pages: 438-448
  • DOI: 10.1007/s00535-017-1372-8
  • Peer Reviewed
• [Journal Article] Real-world efficacy of daclatasvir and asunaprevir with respect to resistance-associated substitutions (2017)
  • Author(s): Fujii Hideki、Umemura Atsushi、Nishikawa Taichiro、Yamaguchi Kanji、Moriguchi Michihisa、Nakamura Hideki、Yasui Kohichiroh、Minami Masahito、Tanaka Saiyu、Ishikawa Hiroki、Kimura Hiroyuki、Takami Shiro、Nagao Yasuyuki、Shima Toshihide、Itoh Yoshito
  • Journal Title: World Journal of Hepatology Volume: 9 Issue: 25 Pages: 1064-1064
  • DOI: 10.4254/wjh.v9.i25.1064
  • Peer Reviewed
• [Journal Article] Insulin resistance increases the risk of incident type 2 diabetes mellitus in patients with non-alcoholic fatty liver disease (2017)
  • Author(s): Seko Yuya、Sumida Yoshio、Tanaka Saiyu、Mori Kojiroh、Taketani Hiroyoshi、Ishiba Hiroshi、Hara Tasuku、Okajima Akira、Umemura Atsushi、Nishikawa Taichiro、Yamaguchi Kanji、Moriguchi Michihisa、Kanemasa Kazuyuki、Yasui Kohichiroh、Imai Shunsuke、Shimada Keiji、Itoh Yoshito
  • Journal Title: Hepatology Research Volume: 48 Issue: 3
  • DOI: 10.1111/hepr.12925
  • Peer Reviewed
• [Journal Article] Loss of PAR-3 protein expression is associated with invasion, lymph node metastasis, and poor survival in esophageal squamous cell carcinoma. (2017)
  • Author(s): Kitaichi T, Yasui K, Gen Y, Dohi O, Iwai N, Tomie A, Yamada N, Terasaki K, Umemura A, Nishikawa T, Yamaguchi K, Moriguchi M, Sumida Y, Mitsuyoshi H, Naito Y, Zen Y, Itoh Y.
  • Journal Title: Hum Pathol Volume: 62 Pages: 134-140
  • DOI: 10.1016/j.humpath.2017.01.009
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Hepatic nucleotide binding oligomerization domain-like receptors pyrin domain-containing 3 inflammasomes are associated with the histologic severity of non-alcoholic fatty liver disease. (2017)
  • Author(s): Mitsuyoshi H, Yasui K, Hara T, Taketani H, Ishiba H, Okajima A, Seko Y, Umemura A, Nishikawa T, Yamaguchi K, Moriguchi M, Minami M, Itoh Y.
  • Journal Title: Hepatol Res Volume: - Issue: 13 Pages: 1459-1468
  • DOI: 10.1111/hepr.12883
  • Peer Reviewed
• [Journal Article] Effect of sodium glucose cotransporter 2 inhibitor on liver function tests in Japanese patients with non-alcoholic fatty liver disease and type 2 diabetes mellitus. (2017)
  • Author(s): Seko Y, Sumida Y, Tanaka S, Mori K, Taketani H, Ishiba H, Hara T, Okajima A, Umemura A, Nishikawa T, Yamaguchi K, Moriguchi M, Kanemasa K, Yasui K, Imai S, Shimada K, Itoh Y.
  • Journal Title: Hepatol Res Volume: 47 Issue: 10 Pages: 1072-1078
  • DOI: 10.1111/hepr.12834
  • Peer Reviewed
• [Journal Article] Liver stiffness measurement to platelet ratio index predicts the stage of liver fibrosis in non-alcoholic fatty liver disease. (2017)
  • Author(s): Okajima A, Sumida Y, Taketani H, Hara T, Seko Y, Ishiba H, Nishimura T, Umemura A, Nishikawa T, Yamaguchi K, Moriguchi M, Mitsuyoshi H, Ysui K, Minami M, Itoh Y.
  • Journal Title: Hepatology Research Volume: 47(8) Issue: 8 Pages: 721-730
  • DOI: 10.1111/hepr.12793
  • Peer Reviewed
• [Journal Article] p62, Upregulated during Preneoplasia, Induces Hepatocellular Carcinogenesis by Maintaining Survival of Stressed HCC-Initiating Cells. (2016)
  • Author(s): Umemura A, He F, Taniguchi K, Nakagawa H, Yamachika S, Font-Burgada J, Zhong Z, Subramaniam S, Raghunandan S, Duran A, Linares JF, Reina-Campos M, Umemura S, Valasek MA, Seki E, Yamaguchi K, Koike K, Itoh Y, Diaz-Meco MT, Moscat J, Karin M.
  • Journal Title: Cancer Cell Volume: 29 Pages: 935-948
  • DOI: 10.1016/j.canlet.2017.04.002
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Sorafenib plus Hepatic Arterial Infusion Chemotherapy with Cisplatin vs. Sorafenib for Advanced Hepatocellular Carcinoma: Randomized Phase II Trial. (2016)
  • Author(s): Ikeda M, Shimizu S, Sato T, Morimoto M, Kojima Y, Inaba Y, Hagihara A, Kudo M, Nakamori, Kaneko S, Sugimoto R, Tahara T, Ohmura T, Yasui K, Sato K, Ishii H, Furuse J, Okusaka T.
  • Journal Title: Ann Oncol Volume: 27 Issue: 11 Pages: 2090-2096
  • DOI: 10.1093/annonc/mdw323
  • Peer Reviewed
• [Journal Article] Effect of 12-week dulaglutide therapy in Japanese patients with biopsy-proven non-alcoholic fatty liver disease and type 2 diabetes mellitus. (2016)
  • Author(s): Seko Y, Sumida Y, Tanaka S, Mori K, Taketani H, Ishiba H, Hara T, Okajima A, Umemura A, Nishikawa T, Yamaguchi K, Moriguchi M, Kanemasa K, Yasui K, Imai S, Shimada K, Itoh Y.
  • Journal Title: Hepatol Res Volume: 印刷中 Issue: 11 Pages: 1206-1211
  • DOI: 10.1111/hepr.12837
  • Peer Reviewed
• [Journal Article] Development of hepatocellular carcinoma in Japanese patients with biopsy-proven non-alcoholic fatty liver disease: Association between PNPLA3 genotype and hepatocarcinogenesis/fibrosis progression. (2016)
  • Author(s): Seko Y, Sumida Y, Tanaka S, Mori K, Taketani H, Ishiba H, Hara T, Okajima A, Umemura A, Nishikawa T, Yamaguchi K, Moriguchi M, Kanemasa K, Yasui K, Imai S, Shimada K, Itoh Y.
  • Journal Title: Hepatol Res Volume: - Issue: 11 Pages: 1083-1092
  • DOI: 10.1111/hepr.12840
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Genome-wide DNA methylation analysis in hepatocellular carcinoma. (2016)
  • Author(s): Yamada N, Yasui K, Dohi O, Gen Y, Tomie A, Kitaichi T, Iwai N, Mitsuyoshi H, Sumida Y, Moriguchi M, Yamaguchi K, Nishikawa T, Umemura A, Naito Y, Tanaka S, Arii S, Itoh Y.
  • Journal Title: Oncol Rep. Volume: 35 Issue: 4 Pages: 2228-2236
  • DOI: 10.3892/or.2016.4619
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association of coronary artery calcification with liver fibrosis in Japanese patients with NAFLD. (2016)
  • Author(s): Ishiba H, Sumida Y, Kataoka S, Kuroda M, Akabame S, Tomiyasu K, Tanaka M, Arai M, Taketani H, Seko Y, Okajima A, Hara T, Umemura A, Nishikawa T, Yamaguchi K, Moriguchi M, Mitsuyoshi H, Yasui K, Itoh Y.
  • Journal Title: Hepatol Res Volume: 46 Issue: 11 Pages: 1107-1117
  • DOI: 10.1111/hepr.12665
  • Peer Reviewed
• [Journal Article] EVI1, a target gene for amplification at 3q26, antagonizes transforming growth factor-β-mediated growth inhibition in hepatocellular carcinoma. (2015)
  • Author(s): Yasui K, Konishi C, Gen Y, Endo M, Dohi O, Tomie A, Kitaichi T, Yamada N, Iwai N, Nishikawa T, Yamaguchi K, Moriguchi M, Sumida Y, Mitsuyoshi H, Tanaka S, Arii S, Itoh Y.
  • Journal Title: Cancer Sci. Volume: 106 Issue: 7 Pages: 929-937
  • DOI: 10.1111/cas.12694
  • Peer Reviewed / Open Access
• [Journal Article] Effect of PNPLA3 rs738409 variant (I148M) on hepatic steatosis, necroinflammation, and fibrosis in Japanese patients with chronic hepatitis C. (2015)
  • Author(s): Yasui K, Kawaguchi T, Shima T, Mitsuyoshi H, Seki K, Sendo R, Mizuno M, Itoh Y, Matsuda F, Okanoue T.
  • Journal Title: J Gastroenterol. Volume: 50 Issue: 8 Pages: 887-893
  • DOI: 10.1007/s00535-014-1018-z
  • Peer Reviewed / Open Access
• [Journal Article] Helicobacter pylori infection might have a potential role in hepatocyte ballooning in nonalcoholic fatty liver disease. (2015)
  • Author(s): Sumida Y, Kanemasa K, Imai S, Mori K, Tanaka S, Shimokobe H, Kitamura Y, Fukumoto K, Kakutani A, Ohno T, Taketani H, Seko Y, Ishiba H, Hara T, Okajima A, Yamaguchi K, Moriguchi M, Mitsuyoshi H, Yasui K, Minami M, Itoh Y.
  • Journal Title: J Gastroenterol. Volume: 50 Issue: 9 Pages: 996-1004
  • DOI: 10.1007/s00535-015-1039-2
  • Peer Reviewed / Open Access
• [Journal Article] Predictors of malignancies and overall mortality in Japanese patients with biopsy-proven non-alcoholic fatty liver disease (2014)
  • Author(s): Seko Y, Sumida Y, Tanaka S, Taketani H, Kanemasa K, Ishiba H, Okajima A, Nishimura T, Yamaguchi K, Moriguchi M, Mitsuyoshi H, Yasui K, Minami M, Itoh Y
  • Journal Title: Hepatol Res Volume: - Issue: 7 Pages: 728-738
  • DOI: 10.1111/hepr.12407
  • Peer Reviewed / Open Access
• [Presentation] Epigenetic silencing of miR-214-3p is associated with resistance to p53-induced apoptosis through up-regulation of gankyrin expression in hepatocellular carcinoma. (2017)
  • Author(s): Yasui K, Iwai N, Terasaki K, Gen Y, Itoh Y.
  • Organizer: Annual Meeting 2017 of the American Association for Cancer Research
  • Int'l Joint Research
• [Presentation] SOX2 promotes cell proliferation of esophageal squamous cell carcinoma through the miR-17-92 cluster /PTEN/AKT/mTORC1 pathway. (2017)
  • Author(s): Terasaki K, Gen Y, Yasui K, Iwai N, Dohi O, Itoh Y.
  • Organizer: Annual Meeting 2017 of the American Association for Cancer Research
  • Int'l Joint Research
• [Presentation] miR-96-5p functions as an oncogenic miRNA by inhibiting apoptosis in hepatocellular carcinoma. (2017)
  • Author(s): 2.Iwai N, Yasui K, Tomie A, Terasaki K, Kitaichi T, Dohi O, Gen Y, Itoh Y.
  • Organizer: Annual Meeting 2017 of the American Association for Cancer Research
  • Int'l Joint Research
• [Presentation] Epigenetic silencing of miR-199a-3p is associated with increased cell survival, enhanced cell motility, and sensitivity to tivantinib through regulation of c-Met expression in hepatocellular carcinoma. (2016)
  • Author(s): Yasui K, Tomie A, Iwai N, Kitaichi T, Dohi O, Gen Y, Itoh Y.
  • Organizer: Annual Meeting 2016 of the American Association for Cancer Research (AACR)
  • Place of Presentation: New Orleans, USA
  • Int'l Joint Research
• [Presentation] 肝細胞癌におけるtumor suppressor miR-199a-3pのエピジェネティックな不活化はc-Metの発現調節を介してc-Met阻害薬tivantinibへの感受性に関与する (2016)
  • Author(s): 安居幸一郎、伊藤 義人
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: 幕張
• [Presentation] Epigenetic silencing of miR-214 and miR-199a is associated with cell survival and motility in hepatocellular carcinoma (2016)
  • Author(s): Kohichiroh Yasui, Akira Tomie, Naoto Iwai, Tomoko Kitaichi, Kei Terasaki, Osamu Dohi, Yasuyuki Gen, Yoshito Itoh.
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] EVI1 is a target for gene amplification at 3q26 and suppresses growth inhibition by transforming growth factor-β in hepatocellular carcinoma. (2015)
  • Author(s): Yasui K, Umemura A, Nishikawa T, Yamaguchi K, Moriguchi M, Sumida Y, Mitsuyoshi H, Tanaka S, Arii S, Itoh Y.
  • Organizer: 65th Annual Meeting of the American Association for the Study of Liver Disease (AASLD).
  • Place of Presentation: San Francisco, USA.
  • Year and Date: 2015-11-17
  • Int'l Joint Research
• [Presentation] miRNAとDNAメチル化の統合的エピゲノム解析による肝細胞癌の病態解明 (2015)
  • Author(s): 安居幸一郎，伊藤義人
  • Organizer: 日本人類遺伝学会第60回大会
  • Place of Presentation: 東京
  • Year and Date: 2015-10-16
• [Presentation] EVI1, a target gene for amplification at 3q26, antagonizes TGF-β-mediated growth inhibition in hepatocellular carcinoma. (2015)
  • Author(s): Kohichiroh Yasui, Yasuyuki Gen, Tomoko Kitaichi, Naoto Iwai, Shinji Tanaka, Shigeki Arii, Yoshito Itoh.
  • Organizer: 第74回日本癌学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] Amplification and overexpression of EVI1 suppresses growth inhibition mediated by TGF-β in hepatocellular carcinoma. (2015)
  • Author(s): Yasui K, Gen Y, Dohi O, Tomie A, Kitaichi T, Itoh Y.
  • Organizer: Annual Meeting 2015 of the American Association for Cancer Research (AACR).
  • Place of Presentation: Philadelphia, USA.
  • Year and Date: 2015-04-20
  • Int'l Joint Research
• [Remarks] 京都府立医科大学消化器内科学教室
  • URL: http://www.f.kpu-m.ac.jp/k/syokanai/index.html