DNA methylation level of 10 CpG sites on 8 specific genes in non-cancerous liver tissues is useful to predict multicentric recurrence of hepatocellular carcinoma after surgical resection

• Project/Area Number: 16K09385
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kurume University
• Principal Investigator: Torimura Takuji 久留米大学, 医学部, 教授 (60197986)
• Co-Investigator(Kenkyū-buntansha): 中村 徹 久留米大学, 医学部, 講師 (30341332) ; 矢野 博久 久留米大学, 医学部, 教授 (40220206) ; 岩本 英希 久留米大学, 医学部, 助教 (40529541) ; 山本 健 久留米大学, 医学部, 教授 (60274528)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 肝細胞癌 / 多中心性再発 / DNAメチル化異常 / 非癌部肝組織 / 肝発がん / DNAメチル化 / CpGアイランド / CpG island / バイオマーカー

Outline of Final Research Achievements

The mechanism of multicentric recurrence after curative treatment of hepatocellular carcinoma (HCC) is not clarified yet. The aim of this study is to clarify the participation of DNA methylation in multicentric recurrence of HCC and also evaluate the possibility of DNA methylation as a biomarker of multicentric recurrence.26 HCC patients recurred multicentrically within 2 years after surgical resection (early recurrence group) and 22 HCC patients without recurrence more than 5 years (no recurrence group) were enrolled. Between 1st and 2nd sets, 10 common DNA methylation sites which showed significantly different methylation level (p<0.001) were identified on 8 genes. 9 sites of 10 common DNA methylation sites showed hypomethylation level in early recurrence group. After curative resection of HCC, the DNA methylation level in non-cancerous liver tissues seems to be a biomarker of multicentric recurrence of HCC.

Academic Significance and Societal Importance of the Research Achievements

本研究は肝細胞癌の多中心性再発予測を可能にすることを目指した研究である。無再発群と早期再発群のDNAメチル化レベルの差を検定した結果両群間で差を認める部位を8遺伝子領域10箇所に同定した。これら10箇所のメチル化レベルを用いた分析により、無再発群と早期再発群の識別が可能であった。8遺伝子には転写因子、シグナル伝達分子、細胞増殖関連分子などが含まれていた。以上から、同定した非癌部肝組織のDNAメチル化領域のメチル化レベルは肝細胞癌の根治切除後の多中心性再発を予測する有用なマーカーになり得ること。さらにその領域に位置する遺伝子群は、多中心性再発の原因の遺伝子候補となり得ることが示唆された。

Research Products

• [Journal Article] Transarterial chemoembolization with miriplatin vs. epirubicin for unresectable hepatocellular carcinoma: a phase III randomized trial. (2018)
  • Author(s): Ikeda M, Kudo M, Aikata H, Nagamatsu H, Ishii H, Yokosuka O, Torimura T, Morimoto M, Ikeda K, Kumada H, Sato T, Kawai I, Yamashita T, Horio H, Okusaka T; Miriplatin TACE Study Group
  • Journal Title: J Gastroenterol Volume: 53 Issue: 2 Pages: 281-290
  • DOI: 10.1007/s00535-017-1374-6
  • NAID: 120006878534
  • Open Access
• [Journal Article] STAT3 deficiency prevents hepatocarcinogenesis and promotes biliary proliferation in thioacetamide-induced liver injury. (2017)
  • Author(s): Abe M, Yoshida T, Akiba J, Ikezono Y, Wada F, Masuda A, Sakaue T, Tanaka T, Iwamoto H, Nakamura T, Sata M, Koga H, Yoshimura A, Torimura T.
  • Journal Title: World J Gastroenterol Volume: 23 Issue: 37 Pages: 6833-6844
  • DOI: 10.3748/wjg.v23.i37.6833
  • Peer Reviewed / Open Access
• [Journal Article] Effects of in-hospital exercise on liver function, physical ability, and muscle mass during treatment of hepatoma in patients with chronic liver disease. (2017)
  • Author(s): Koya S, Kawaguchi T, Hashida R, Goto E, Matsuse H, Saito H, Hirota K, Taira R, Matsushita Y, Imanaga M, Nagamatsu A, Shirono T, Shimose S, Iwamoto H, Niizeki T, Kuromatsu R, Miura H, Shiba N, Torimura T.
  • Journal Title: Hepatol Res Volume: 47 Issue: 3
  • DOI: 10.1111/hepr.12718
  • Peer Reviewed / Open Access
• [Journal Article] Diffusion-weighted magnetic resonance imaging predicts malignant potential in small hepatocellular carcinoma (2016)
  • Author(s): Okamura S, Sumie S, Tonan T, Nakano M, Satani M, Shimose S, Shirono T, Iwamoto H, Aino H, Niizeki T, Tajiri N, Kuromatsu R, Okuda K, Nakashima O, Torimura TOkamura S, Sumie S, Tonan T, Nakano M, Satani M, Shimose S, Shirono T, Iwamoto H, Aino H, Niizeki T, Tajiri N, Kuromatsu R, Okuda K, Nakashima O, Torimura T
  • Journal Title: Dig Liver Dis Volume: 48 Pages: 945-952
  • Peer Reviewed / Open Access
• [Journal Article] The systemic inflammatory response as a prognostic factor for advanced hepatocellular carcinoma with extrahepatic metastasis (2016)
  • Author(s): Aino H, Sumie S, Niizeki T, Kuromatsu R, Tajiri N, Nakano M, Satani M, Okamura S, Shimose S, Miyahara K, Torimura T
  • Journal Title: Mol Clin Oncol Volume: 5 Issue: 1 Pages: 83-88
  • DOI: 10.3892/mco.2016.879
  • Peer Reviewed / Open Access
• [Journal Article] Antiangiogenic and Antitumor Activities of Aflibercept, a Soluble VEGF Receptor-1 and -2, in a Mouse Model of Hepatocellular Carcinoma. (2016)
  • Author(s): Torimura T, Iwamoto H, Nakamura T, Abe M, Ikezono Y, Wada F, Sakaue T, Masuda H, Hashimoto O, Koga H, Ueno T, Yano H.
  • Journal Title: Neoplasia Volume: 18 Issue: 7 Pages: 413-424
  • DOI: 10.1016/j.neo.2016.05.001
  • Peer Reviewed / Open Access
• [Journal Article] Alternative treatments in advanced hepatocellular carcinoma patients with progressive disease after sorafenib treatment: a prospective multicenter cohort study. (2016)
  • Author(s): Nakano M, Tanaka M, Kuromatsu R, Nagamatsu H, Satani M, Niizeki T, Okamura S, Iwamoto H, Shimose S, Shirono T, Noda Y, Koga H, Torimura T; Kurume Liver Cancer Study Group Of Japan.
  • Journal Title: Oncotarget Volume: 7 Issue: 39 Pages: 64400-64409
  • DOI: 10.18632/oncotarget.10794
  • Peer Reviewed / Open Access
• [Presentation] 非癌部肝組織のDNAメチル化の変化は肝細胞癌の多中心性発生のバイオマーカーになり得る (2018)
  • Author(s): 岩本英希 古賀浩徳 山本健 鳥村拓司
  • Organizer: 第42回日本肝臓学会東部会
• [Presentation] DNA methylation level of 10 CpG sites on 8 specific genes in non-cancerous liver tissues is useful to predict multicentric recurrence of hepatocellular carcinoma after surgical resection (2018)
  • Author(s): Takuji Torimura, Hironori Koga, Toru Nakamura, Hideki Iwamoto, Yasuko Imamura, Hiroshi Suzuki, Takahiko Sakaue, Mitsuhiko Abe, Atsutaka Masuda, Toshimitsu Tanaka, Hirohisa Yano, Ken Yamamoto
  • Organizer: AASLD The liver meeting 2018
  • Int'l Joint Research
• [Presentation] 当院における肉眼的脈管浸潤を合併する進行肝細胞癌の予後因子と治療戦略 (2017)
  • Author(s): 新関 敬, 古賀浩徳, 鳥村拓司
  • Organizer: 第103回日本消化器病学会総会
• [Presentation] ACE不応stage3肝癌症例へのDEB-TACE局所制御の検討 (2017)
  • Author(s): 下瀬茂男, 新関 敬, 城野智毅, 岩本英希, 田中正俊, 古賀浩徳, 鳥村拓司
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] 進行肝細胞癌に対するソラフェニブ治療の予後予測における肝線維化評価方法（FIB-4）の有用性 (2017)
  • Author(s): 中野聖士, 古賀浩徳, 鳥村拓司
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] 血管新生抑制剤の中止は肝類洞のRevascularizationを引き起こす (2017)
  • Author(s): 岩本英希, 古賀浩徳, 鳥村拓司
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] DAA治療開始後に肝細胞癌を発症したC型肝炎症例の検討 (2017)
  • Author(s): 森田 俊, 永松洋明, 德重貴彦, 小岡洋平, 堤 翼, 平井真吾, 清水基規, 立石秀夫, 井出達也, 鳥村拓司
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] 非Ｂ非Ｃ肝がん患者の長期生存に関連する因子 (2017)
  • Author(s): 野田 悠, 川口 巧, 鳥村拓司
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] 肝癌根治後DAA施行例における肝癌再発についての検討 (2017)
  • Author(s): 黒松亮子, 井出達也, 中野聖士, 佐谷 学, 岡村修祐, 野田 悠, 有永照子, 古賀浩徳, 鳥村拓司
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] 当科における進行肝細胞癌に対する治療戦略 (2017)
  • Author(s): 新関 敬, 古賀浩徳, 鳥村拓司
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] C-TACEとDEB-TACEの直接治療効果から、その選択を考察する (2017)
  • Author(s): 下瀬茂男, 新関 敬, 田中正俊, 城野智毅, 岩本英希, 野田 悠, 岡村修祐, 中野聖士, 佐谷 学, 黒松亮子, 古賀浩徳, 鳥村拓司
  • Organizer: 第53回日本肝癌研究会
• [Presentation] 当院における肉眼的脈管浸潤を伴う進行肝細胞癌に対する肝動注化学療法とsorafenibの比較 (2017)
  • Author(s): 新関 敬, 中野聖士, 岩本英希, 下瀬茂男, 城野智毅, 相野 一, 黒松亮子, 古賀浩徳, 鳥村拓司
  • Organizer: 第53回日本肝癌研究会
• [Presentation] HES1はWNTシグナル改変肝癌細胞においてスフィア形成能や造腫瘍能を決定的に制御する (2017)
  • Author(s): 古賀浩徳, 中村 徹, 和田史孝, 岩本英希, 増田篤高, 阪上尊彦, 田中俊光, 安倍満彦, 秋葉 純, 矢野博久, 鳥村拓司
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] C型肝疾患でのDAAs-SVR例の肝発癌の検討 (2017)
  • Author(s): 井出達也, 江口有一郎, 原田 大, 岩根伸治, 宮原千賀, 本間雄一, 有永照子, 宮島一郎, 桑原礼一郎, 天野恵介, 川口俊弘, 鳥村拓司
  • Organizer: 25th JDDW（第21回日本肝臓学会大会）
• [Presentation] Inhibition of hypoxia inducible factor via upregulation of von Hippel-Lindau protein induces ‘Angiogenic switch off’ in a mouse hepatoma model (2017)
  • Author(s): Iwamoto H,, Koga H, Torimura T
  • Organizer: The 68th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)
• [Presentation] STAT3 deficiency prevents hepatocarcinogenesis and promotes transdifferentiation of hepatocytes into biliary cells in chronic liver injury of mice (2017)
  • Author(s): be M, Yoshida T, Akiba J, Ikezono Y, Wada F, Masuda A, Sakaue T, Tanaka T, Iwamoto H, Nakamura T, Sata M, Koga H, Yoshimura A, Torimura T
  • Organizer: The 68th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)
• [Presentation] Prognostic Impact of Fibroblast-derived Cytokine, IL-34 in Non-hepatitis B virus-, Non-hepatitis C virus-related Hepatocellular Carcinoma Patients with Chronic Liver Disease (2017)
  • Author(s): Yu Noda, Kawaguchi T, Korenaga M, Nakano M, Niizeki T, Koga H,Kanto T, Torimura T
  • Organizer: The 68th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)
• [Presentation] Prognosis of Patients with Non-hepatitis B virus-, Non-hepatitis C virus-related Hepatocellular Carcinoma: A Comparison with Hepatitis C virus-related Hepatocellular Carcinoma Patients (2017)
  • Author(s): Noda, Kawaguchi T, Nakano M, Niizeki T, Kuromatsu R, Koga H, Torimura T
  • Organizer: The 68th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)
• [Presentation] Targeting CD44v9-xCT system by sulfasalazine to overcome cisplatin resistance in human liver cancer cells (2017)
  • Author(s): Wada F, Koga H, Jun Akiba, Yu Ikezono, Nakamura T, Abe M, Iwamoto H, Sakaue T, Masuda A, Tanaka T, Yano H, Torimura T
  • Organizer: The 68th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)
• [Presentation] The Wnt Target Gene CLAUDIN-2 Regulates Tumorigenesis of Combined Hepatocellular- Cholangiocarcinoma Cells (2017)
  • Author(s): Koga H, Imamura Y, Wada F, Ikezono Y, Abe M,, Iwamoto H, Nakamura T, Sakaue T, Tanaka T, Yano H, Torimura T
  • Organizer: The 68th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)
• [Presentation] DPP4 inhibitor suppressed Warburg-Dickens pathway and HCC progression in a mouse model of NASH: A metabolomic analysis (2016)
  • Author(s): Kawaguchi T, Taniguchi E, Koga H, Torimura T
  • Organizer: The 67th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)
  • Place of Presentation: Boston, USA
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] DNA methylation level of non-cancerous liver tissue has potential for being a biomarker of multicentric recurrence of hepatocellular carcinoma (2016)
  • Author(s): Torimura T, Koga H, Nakamura T, Iwamoto H, Imamura Y, Ikezono Y, Sakaue T, Wada F, Masuda A, Tanaka T, Yano H, Ueno T, Yamamoto K
  • Organizer: The 67th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)
  • Place of Presentation: Boston, USA
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] The Wnt effector T-CELL FACTOR-4 isoform activates Notch signaling via upregulating CLAUDIN-2 in human liver cancer cells (2016)
  • Author(s): Koga H, Kim M, Imamua Y, Ikezono Y, Wada F, Iwamoto H, Nakamura T, Sakaue T, Masuda A, Tanaka T, Yano H, Wands JR, Torimura T
  • Organizer: The 67th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)
  • Place of Presentation: Boston, USA
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] DDP4阻害剤がNASHモデルマウスの肝癌におよぼす影響 (2016)
  • Author(s): 川口 巧、谷口英太郎、鳥村拓司
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: ホテルニューオタニ幕張、他 千葉市
  • Year and Date: 2016-05-19
• [Presentation] マウス肝癌モデルを用いたNotch抑制剤の効果検討 (2016)
  • Author(s): 岩本英希、鳥村拓司、古賀浩徳
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: ホテルニューオタニ幕張、他 千葉市
  • Year and Date: 2016-05-19
• [Presentation] 進行肝細胞癌に対するソラフェニブ治療の予後予測におけるInflammation-based prognostic score (Glasgow prognostic score： GPS)の有用性 (2016)
  • Author(s): 中野聖士、田中正俊、黒松亮子、永松洋明、古賀浩徳、鳥村拓司
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: ホテルニューオタニ幕張、他 千葉市
  • Year and Date: 2016-05-19
• [Presentation] 脈管侵襲を有する進行肝細胞癌に対するNew FP療法：長期生存を目標としたCancer -Freeへの条件 (2016)
  • Author(s): 永松洋明、新関 敬、鳥村拓司
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: ホテルニューオタニ幕張、他 千葉市
  • Year and Date: 2016-05-19
• [Presentation] 進行肝細胞癌に対するNew FP療法を中心とした集学的治療の検討：延命から治癒への挑戦 (2016)
  • Author(s): 永松洋明、新関 敬、鳥村拓司
  • Organizer: 第102回日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル 東京
  • Year and Date: 2016-04-21