Importance of loss-of-function of ARID family proteins in liver cancer

• Project/Area Number: 16K09340
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Chiba University
• Principal Investigator: Chiba Tetsuhiro 千葉大学, 大学院医学研究院, 講師 (00381583)
• Research Collaborator: IWAMA ATSUSHI ; KATO NAOYA
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: エピジェネティクス / 癌

Outline of Final Research Achievements

Epigenetic dysregulation is closely involved in cancer development and progression. ARID family proteins, including ARID1A, ARID1B, and ARID2, are core molecules of SWI/SNF complexes and function as chromatin remodeling factors.
ARID genes function as tumor suppressor in vitro assays. Genome information analyses using TCGA data revealed that 30-40% of patients with liver cancer harbors mutation of ARID genes. Survival of patients with ARID mutation is unfavorable than those without ARID mutation due to at least in part high tumor mutation burden.

Academic Significance and Societal Importance of the Research Achievements

ARID遺伝子群（ARID1A, ARID1B, ARID2）はがん抑制遺伝子として機能し、その機能喪失型変異は肝癌においても、発癌、癌の進行において重要な役割を果たすものと考えられる。今回の検討では、ARID遺伝子群に変異がある場合は、ない場合に比較してtumor mutation burdenが高く、overall survivalが不良であった。特にARID1A変異はミスマッチ修復機構を妨げ、免疫チェックポイント阻害剤(ICI)の効果が高いことも報告されており、ICIの治療効果予測においても有用である可能性が示唆された。

Research Products

• [Journal Article] Genome-Wide Mapping of Bivalent Histone Modifications in Hepatic Stem/Progenitor Cells (2019)
  • Author(s): Kanayama K, Chiba T, Oshima Kanzaki H, Koide S, Saraya A, Miyagi S, Mimura N, Kusakabe Y, Saito T, Ogasawara S, Suzuki E, Ooka Yoshihiko, Maruyama H, Iwama A, Kato N.
  • Journal Title: Stem Cells Int Volume: 2019 Pages: 9789240-9789240
  • DOI: 10.1155/2019/9789240
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A nationwide survey on non-B, non-C hepatocellular carcinoma in Japan: 2011-2015 update. (2019)
  • Author(s): Tateishi R, Uchino K, Fujiwara N, Takehara T, Okanoue T, Seike M, Yoshiji H, Yatsuhashi H, Shimizu M, Torimura T, Moriyama M, Sakaida I, Okada H, Chiba T, Chuma M, Nakao K, Isomoto H, Sasaki Y, Kaneko S, Masaki T, Chayama K, Koike K.
  • Journal Title: J Gastroenterol. Volume: 54 Issue: 4 Pages: 367-376
  • DOI: 10.1007/s00535-018-1532-5
  • Peer Reviewed / Open Access
• [Journal Article] Epigenetic dysregulation in hepatocellular carcinoma: an up-to-date review. (2019)
  • Author(s): Nakamura M, Chiba T, Kanayama K, Kanzaki H, Saito T, Kusakabe Y, Kato N.
  • Journal Title: Hepatol Res. Volume: 49 Issue: 1 Pages: 3-13
  • DOI: 10.1111/hepr.13250
  • Peer Reviewed
• [Journal Article] Prediction of the very early occurrence of HCC right after DAA therapy for HCV infection. (2018)
  • Author(s): Ooka Y, Miho K, Shuntaro O, Nakamura M, Ogasawara S, Suzuki E, Yasui S, Chiba T, Arai M, Kanda T, Maruyama H, Yokosuka O, Kato N, Mochizuki H, Omata M.
  • Journal Title: Hepatol Int. Volume: 12 Issue: 6 Pages: 523-530
  • DOI: 10.1007/s12072-018-9895-5
  • Peer Reviewed
• [Journal Article] Transarterial chemoembolization as a substitute to radiofrequency ablation for treating barcelona clinic liver cancer stage 0/A hepatocellular carcinoma. (2018)
  • Author(s): Ishikawa K, Chiba T, Ooka Y, Suzuki E, Ogasawara S, Maeda T, Yokoyama M, Inoue M, Wakamatsu T, Kusakabe Y, Saito T, Tawada A, Arai M, Kanda T, Maruyama H, Imazeki F, Kato N.
  • Journal Title: Oncotarget Volume: －
  • Peer Reviewed / Open Access
• [Journal Article] Successful retreatment with sofosbuvir plus ledipasvir for cirrhotic patients with hepatitis C virus genotype 1b, who discontinued the prior treatment with asunaprevir plus daclatasvir: A case series and review of the literature. (2018)
  • Author(s): Haga Y, Kanda T, Yasui S, Nakamura M, Ooka Y, Takahashi K, Wu S, Nakamoto S, Arai M, Chiba T, Maruyama H, Yokosuka O, Takada N, Moriyama M, Imazeki F, Kato N.
  • Journal Title: Oncotarget Volume: 9 Pages: 5509-5513
  • Peer Reviewed / Open Access
• [Journal Article] Association of IFNL3 Genotype with Hepatic Steatosis in Chronic Hepatitis C Patients Treated with Peginterferon and Ribavirin Combination Therapy. (2017)
  • Author(s): Nakamoto S, Imazeki F, Kanda T, Wu S, Nakamura M, Yasui S, Tawada A, Mikata R, Chiba T, Arai M, Yokosuka O, Shirasawa H.
  • Journal Title: Int J Med Sci Volume: 14 Pages: 1088-1093
  • Peer Reviewed / Open Access
• [Journal Article] Characteristics of patients with sorafenib-treated advanced hepatocellular carcinoma eligible for second-line treatment. (2017)
  • Author(s): Ogasawara S, Chiba T, Ooka Y, Suzuki E, Maeda T, Yokoyama M, Wakamatsu T, Inoue M, Saito T, Kobayashi K, Kiyono S, Nakamura M, Nakamoto S, Yasui S, Tawada A, Arai M, Kanda T, Maruyama H, Yokosuka O, Kato N.
  • Journal Title: Invest New Drugs Volume: － Issue: 2 Pages: 332-339
  • DOI: 10.1007/s10637-017-0507-3
  • Peer Reviewed / Open Access
• [Journal Article] Application of transcutaneous ultrasonography for the diagnosis of muscle mass loss in patients with liver cirrhosis. (2017)
  • Author(s): Kobayashi K, Maruyama H, Kiyono S, Ogasawara S, Suzuki E, Ooka Y, Chiba T, Kato N, Yamaguchi T.
  • Journal Title: J Gastroenterol Volume: － Issue: 5 Pages: 652-659
  • DOI: 10.1007/s00535-017-1378-2
  • Peer Reviewed / Open Access
• [Journal Article] A randomized placebo-controlled trial of prophylactic dexamethasone for transcatheter arterial chemoembolization. (2017)
  • Author(s): Ogasawara S, Chiba T, Ooka Y, Kanogawa N, Motoyama T, Suzuki E, Tawada A, Nagai K, Nakagawa T, Sugawara T, Hanaoka H, Kanai F, Yokosuka O
  • Journal Title: Hepatology Volume: － Issue: 2 Pages: 575-585
  • DOI: 10.1002/hep.29403
  • Peer Reviewed / Open Access
• [Journal Article] Histone lysine methyltransferase G9a is a novel epigenetic target for the treatment of hepatocellular carcinoma (2017)
  • Author(s): Yokoyama M, Chiba T, Zen Y, Oshima M, Kusakabe Y, Noguchi Y, Yuki K, Koide S, Tara S, Saraya A, Aoyama K, Mimura N, Miyagi S, et al.
  • Journal Title: Oncotarget Volume: 8 Issue: 13 Pages: 21315-21326
  • DOI: 10.18632/oncotarget.15528
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Presence of non-hypervascular hypointense nodules on Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging in patients with hepatocellular carcinoma. (2017)
  • Author(s): Inoue M, Ogasawara S, Chiba T, Ooka Y, Wakamatsu T, Kobayashi K, Suzuki E, Tawada A, Yokosuka O.
  • Journal Title: J Gastroenterol Hepatol Volume: 32 Issue: 4 Pages: 908-915
  • DOI: 10.1111/jgh.13622
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Setdb1 maintains hematopoietic stem and progenitor cells by restricting the ectopic activation of non-hematopoietic genes. (2016)
  • Author(s): Koide S, Oshima M, Takubo K, Yamazaki S, Nitta E, Saraya A, Aoyama K, Kato Y, Miyagi S, Nakajima-Takagi Y, Chiba T, Matsui H, Arai F, Suzuki Y, Kimura H, Nakauchi H, Suda T, Shinkai Y,Iwama A.
  • Journal Title: Blood Volume: 128(5) Issue: 5 Pages: 638-649
  • DOI: 10.1182/blood-2016-01-694810
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prognostic Significance of Concurrent Hypovascular and Hypervascular Nodules in Patients with Hepatocellular Carcinoma. (2016)
  • Author(s): Ogasawara S, Chiba T, Motoyama T, Kanogawa N, Saito T, Shinozaki Y, Suzuki E, Ooka Y, Tawada A, Kato H, Okabe S, Kanai F, Yoshikawa M, Yokosuka O.
  • Journal Title: PLoS One Volume: 11 Issue: 9 Pages: e0163119-e0163119
  • DOI: 10.1371/journal.pone.0163119
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Analysis of Sorafenib Outcome: Focusing on the Clinical Course in Patients with Hepatocellular Carcinoma. (2016)
  • Author(s): Analysis of Sorafenib Outcome: Focusing on the Clinical Course in Patients with Hepatocellular Carcinoma.
  • Journal Title: PLoS One Volume: 11 Issue: 8 Pages: e0161303-e0161303
  • DOI: 10.1371/journal.pone.0161303
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 胎生肝幹 / 前駆細胞の分化制御から見た新規肝癌治療法の可能性の検討. (2018)
  • Author(s): 千葉哲博, 日下部裕子, 加藤直也.
  • Organizer: 第104回日本消化器病学会総会
• [Presentation] 肝癌におけるポリコーム群遺伝子EZH1およびEZH2の役割. (2018)
  • Author(s): 日下部裕子, 千葉哲博, 加藤直也.
  • Organizer: 第104回日本消化器病学会総会
• [Presentation] 非アルコール性脂肪肝疾患における肝炎症及び肝線維化に対するmicroRNA-200bの重要性. (2018)
  • Author(s): 中村昌人, 千葉哲博, 加藤直也.
  • Organizer: 第104回日本消化器病学会総会
• [Presentation] 肝癌に対する分子標的治療におけるFGF19/FGFR4シグナル制御の意義. (2018)
  • Author(s): 神崎洋彰, 千葉哲博, 加藤直也.
  • Organizer: 第26回日本消化器病関連学会週間
• [Presentation] Patient preferences regarding treatment for hepatocellular carcinoma (HCC) in Japan: A best-worst scaling approach (2017)
  • Author(s): 千葉哲博
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] 肝細胞癌におけるG9aの機能解析 (2017)
  • Author(s): 横山昌幸, 千葉哲博
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] 肝細胞癌におけるEZH1/2の治療標的分子としての有用性 (2017)
  • Author(s): 日下部裕子, 千葉哲博
  • Organizer: 第53回日本肝臓学会総会