The role of protein kinase R (PKR) for hepatocarcinogenesis and progression of hepatocellular carcinoma during inflammation due to hepatitis C virus infection.

• Project/Area Number: 15K09006
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Ehime University
• Principal Investigator: Hiasa Yoichi 愛媛大学, 医学系研究科, 教授 (70314961)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: Protein kinase R / Hepatocellular carcinoma / C型肝炎ウイルス / eIF2-alpha / PERK / ERストレス / DNMT / MAPK / PKR-like ER kinase / eIF2alpha / AP-1 / hepatitis C virus / hepatocellular carcinoma / DNAメチル化 / JNK1

Outline of Final Research Achievements

Protein kinase R (PKR) is recognized as a key executor of anti-hepatitis C virus (HCV). Moreover, over-expressed PKR up-regulates the mitogen-activated protein kinase (MAPK) signaling pathway, and it promotes hepatocarcinogenesis and progression of hepatocellular carcinoma (HCC) in vitro models. In this study, we investigate the total potential of PKR against the role for HCC by using in vivo models, including human specimens after HCC resection and HCC transplanted nude mice model. In also human specimens, over-expressed PKR enhanced MAPK signaling, and in mice model, PKR inhibitor inhibited progression of HCC. Additionally, PKR has epigenetic roles to regulate DNMTs in HCV infected cells. Moreover, there is not obvious interaction between PKR and PERK, and PKR would regulate the activity of eIF2-alpha cooperated with PERK, which is a key molecule for ER stress and cell inflammation. From those data, PKR could be one of the therapeutic targets to regulate HCC in patients with HCV.

Research Products

• [Journal Article] Transcatheter Arterial Chemoembolization With or Without Radiofrequency Ablation: Outcomes in Patients With Barcelona Clinic Liver Cancer Stage B Hepatocellular Carcinoma. (2018)
  • Author(s): Hirooka M, Hiraoka A, Ochi H, Kisaka Y, Joko K, Michitaka K, Hiasa Y.
  • Journal Title: AJR Am J Roentgenol. Volume: 210 Issue: 4 Pages: 891-898
  • DOI: 10.2214/ajr.17.18177
  • Peer Reviewed
• [Journal Article] Roles of protein kinase R in cancer: Potential as a therapeutic target. (2018)
  • Author(s): Watanabe T, Imamura T, Hiasa Y.
  • Journal Title: Cancer Sci. Volume: 109 Issue: 4 Pages: 919-925
  • DOI: 10.1111/cas.13551
  • Peer Reviewed / Open Access
• [Journal Article] Cigarette smoking is a risk factor for the onset of fatty liver disease in nondrinkers: A longitudinal cohort study. (2018)
  • Author(s): Okamoto M, Miyake T, Kitai K, Furukawa S, Yamamoto S, Senba H, Kanzaki S, Deguchi A, Koizumi M, Ishihara T, Miyaoka H, Yoshida O, Hirooka M, Kumagi T, Abe M, Matsuura B, Hiasa Y.
  • Journal Title: PLoS One. Volume: 13 Issue: 4 Pages: e0195147-e0195147
  • DOI: 10.1371/journal.pone.0195147
  • Peer Reviewed / Open Access
• [Journal Article] Upregulated absorption of dietary palmitic acids with changes in intestinal transporters in non-alcoholic steatohepatitis (NASH) (2017)
  • Author(s): Utsunomiya H, Yamamoto Y, Takeshita E, Tokumoto Y, Tada F, Miyake T, Hirooka M, Abe M, Kumagi T, Matsuura B, Ikeda Y, Hiasa Y
  • Journal Title: J Gastroenterol Volume: 印刷中 Issue: 8 Pages: 940-954
  • DOI: 10.1007/s00535-016-1298-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Predictors of treatment efficacy and ALT non-normalization with sofosbuvir/ribavirin therapy for patients with hepatitis C virus genotype 2. (2017)
  • Author(s): Watanabe T, Tokumoto Y, Joko K, Michitaka K, Horiike N, Tanaka Y, Tada F, Kisaka Y, Nakanishi S, Nonaka T, Yamauchi K, Hirooka M, Abe M, Hiasa Y.
  • Journal Title: J Med Virol. Volume: 89 Issue: 9 Pages: 1567-1573
  • DOI: 10.1002/jmv.24776
  • Peer Reviewed / Open Access
• [Journal Article] Clinical utility of multipolar ablation with a 3-D simulator system for patients with liver cancer. (2017)
  • Author(s): Hirooka M, Koizumi Y, Imai Y, Nakamura Y, Yukimoto A, Watanabe T, Yoshida O, Tokumoto Y, Abe M, Hiasa Y.
  • Journal Title: J Gastroenterol Hepatol. Volume: 32 Issue: 11 Pages: 1852-1858
  • DOI: 10.1111/jgh.13772
  • Peer Reviewed
• [Journal Article] Role of hepatic resection in patients with intermediate-stage hepatocellular carcinoma: A multicenter study from Japan. (2017)
  • Author(s): Tada T, Kumada T, Toyoda H, Tsuji K, Hiraoka A, Itobayashi E, Nouso K, Kariyama K, Ishikawa T, Hirooka M, Hiasa Y.
  • Journal Title: Cancer Sci. Volume: 108 Issue: 7 Pages: 1414-1420
  • DOI: 10.1111/cas.13257
  • Peer Reviewed / Open Access
• [Journal Article] Downregulation of ANP32B exerts anti-apoptotic effects in hepatocellular carcinoma. (2017)
  • Author(s): Ohno Y, Koizumi M, Nakayama H, Watanabe T, Hirooka M, Tokumoto Y, Kuroda T, Abe M, Fukuda S, Higashiyama S, Kumagi T, Hiasa Y.
  • Journal Title: PLoS One. Volume: 12 Issue: 5 Pages: 0177343-0177343
  • DOI: 10.1371/journal.pone.0177343
  • Peer Reviewed / Open Access
• [Journal Article] Antiemetic Effectiveness and Cost-Saving of Aprepitant plus Granisetron Is Superior to Palonosetron in Gastrointestinal Cancer Patients Who Received Moderately Emetogenic Chemotherapy. (2017)
  • Author(s): Toda H, Kawazoe H, Yano A, Yamamoto Y, Watanabe Y, Yamamoto Y, Hiasa Y, Yakushijin Y, Tanaka A, Araki H.
  • Journal Title: J Cancer. Volume: 8 Issue: 8 Pages: 1371-1377
  • DOI: 10.7150/jca.17102
  • Peer Reviewed / Open Access
• [Journal Article] Nonalcoholic fatty liver with a hepatic arterial buffer response strongly associated with future metabolic disease. (2017)
  • Author(s): Hirooka M, Koizumi Y, Miyake T, Watanabe T, Yoshida O, Tokumoto Y, Yukimoto A, Nakamura Y, Imai Y, Abe M, Hiasa Y.
  • Journal Title: Hepatol Commun. Volume: 1 Issue: 7 Pages: 623-633
  • DOI: 10.1002/hep4.1070
  • Peer Reviewed / Open Access
• [Journal Article] Quantitative assessment of liver fibrosis reveals a nonlinear association with fibrosis stage in nonalcoholic fatty liver disease. (2017)
  • Author(s): Masugi Y, Abe T, Tsujikawa H, Effendi K, Hashiguchi A, Abe M, Imai Y, Hino K, Hige S, Kawanaka M, Yamada G, Kage M, Korenaga M, Hiasa Y, Mizokami M, Sakamoto M
  • Journal Title: Hepatol Commun Volume: 27 Issue: 1 Pages: 58-68
  • DOI: 10.1002/hep4.1121
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Differences in the risk of fatty liver for onset of impaired fasting glucose according to baseline plasma glucose levels (2017)
  • Author(s): Miyake T, Hirooka M, Yoshida O, Furukawa S, Kumagi T, Koizumi M, Yamamoto S, Kuroda T, Arimitsu E, Takeshita E, Abe M, Kitai K, Matsuura B, Hiasa Y
  • Journal Title: J Gastroenterol Volume: 52 Issue: 2 Pages: 237-244
  • DOI: 10.1007/s00535-016-1234-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genome-wide Association Study Identifies TLL1 Variant Associated With Development of Hepatocellular Carcinoma After Eradication of Hepatitis C Virus Infection. (2017)
  • Author(s): Matsuura K, Honda M, et al.
  • Journal Title: Gastroenterology. Volume: - Issue: 6 Pages: 1383-1394
  • DOI: 10.1053/j.gastro.2017.01.041
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Simeprevir with peginterferon/ribavirin for patients with hepatitis C virus genotype 1: high frequency of viral relapse in elderly patients. (2016)
  • Author(s): Watanabe T, Joko K, Hiasa Y, et al.
  • Journal Title: Springerplus Volume: 26 Issue: 1 Pages: 518-518
  • DOI: 10.1186/s40064-016-2190-9
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Interleukin-34 as a fibroblast-derived marker of liver fibrosis in patients with non-alcoholic fatty liver disease. (2016)
  • Author(s): Shoji H, Yoshio S, Mano Y, Kumagai E, Sugiyama M, Korenaga M, Arai T, Itokawa N, Atsukawa M, Aikata H, Hyogo H, Chayama K, Ohashi T, Ito K, Yoneda M, Nozaki Y, Kawaguchi T, Torimura T, Abe M, Hiasa Y, Kamiyama T, Fukai M, Taketomi A, Mizokami M, Kanto T*
  • Journal Title: Scientific Reports Volume: 6:28814 Issue: 1 Pages: 1-10
  • DOI: 10.1038/srep28814
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Low alcohol consumption increases the risk of impaired glucose tolerance in patients with non-alcoholic fatty liver disease. (2016)
  • Author(s): Teruki Miyake
  • Journal Title: Journal of Gastroenterology Volume: 印刷中 Issue: 11 Pages: 1090-1100
  • DOI: 10.1007/s00535-016-1194-0
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Low alcohol consumption increases the risk of impaired glucose tolerance in patients with non-alcoholic fatty liver disease (2016)
  • Author(s): Miyake T, Kumagi T, Hirooka M, Furukawa S, Yoshida O, Koizumi M, Yamamoto S, Watanabe T, Yamamoto Y, Tokumoto Y, Takeshita E, Abe M, Kitai K, Matsuura B, Hiasa Y.
  • Journal Title: Journal of Gastroenterology Volume: Epub ahead of print
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Characterization of Liver Monocytic Myeloid-Derived Suppressor Cells and Their Role in a Murine Model of Non-Alcoholic Fatty Liver Disease (2016)
  • Author(s): Yao L, Abe M, Kawasaki K, Akbar SM, Matsuura B, Onji M, Hiasa Y.
  • Journal Title: PLoS One Volume: 11 Issue: 2 Pages: e0149948-e0149948
  • DOI: 10.1371/journal.pone.0149948
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Usefulness of a New Three-Dimensional Simulator System for Radiofrequency Ablation (2016)
  • Author(s): Hirooka M, Koizumi Y, Imai Y, Miyake T, Watanabe T, Yoshida O, Takeshita E, Tokumoto Y, Abe M, Hiasa Y.
  • Journal Title: PLoS One Volume: 11 Issue: 2 Pages: e0148298-e0148298
  • DOI: 10.1371/journal.pone.0148298
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Effects of long-term entecavir treatment on the incidence of hepatocellular carcinoma in chronic hepatitis B patients (2016)
  • Author(s): Watanabe T, Tokumoto Y, Joko K, Michitaka K, Mashiba T, Hiraoka A, Ochi H, Koizumi Y, Tada F, Hirooka M, Yoshida O, Imai Y, Abe M, Hiasa Y.
  • Journal Title: Hepatology International Volume: 10 Issue: 2 Pages: 320-327
  • DOI: 10.1007/s12072-015-9647-8
  • Peer Reviewed
• [Journal Article] Characterization of the biliary tract by virtual ultrasonography constructed by gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (2015)
  • Author(s): Koizumi Y, Hirooka M, Ochi H, Tokumoto Y, Takechi M, Hiraoka A, Ikeda Y, Kumagi T, Matsuura B, Abe M, Hiasa Y.
  • Journal Title: Journal of Medical Ultrasonics Volume: 42 Issue: 2 Pages: 185-193
  • DOI: 10.1007/s10396-014-0598-9
  • NAID: 130005465200
  • Peer Reviewed / Open Access
• [Presentation] Patients with HBV and HCV chronic liver disease under surveillance for HCC have a favorable long-term outcome for pancreatic cancer due to early diagnosis and high resection rate. (2017)
  • Author(s): Kumagi T, Terao T, Hiasa Y, et al.
  • Organizer: American Association for the Study of Liver Diseases (AASLD)
  • Int'l Joint Research
• [Presentation] Increased frequency of myeloid-derived suppressor cells in patients with non-alcoholic fatty liver disease. (2017)
  • Author(s): Abe M, Nakamura Y, Hiasa Y, et al.
  • Organizer: American Association for the Study of Liver Diseases (AASLD)
  • Int'l Joint Research
• [Presentation] Comparison with Child-Pugh, liver damage and newly proposed ALBI-grade for assessment of hepatic function and predicting prognosis of Japanese patients with hepatocellular carcinoma. (2017)
  • Author(s): Hiraoka A, Kumada T, Hiasa Y, et al.
  • Organizer: American Association for the Study of Liver Diseases (AASLD)
  • Int'l Joint Research
• [Presentation] No-touch radio frequency ablation is an ideal method to prevent intrahepatic metastasis of hepatocellular carcinoma. (2017)
  • Author(s): Hiraoka m, Hiraoka A, Hiasa Y, et al.
  • Organizer: American Association for the Study of Liver Diseases (AASLD)
  • Int'l Joint Research
• [Presentation] Increase of serum chylomicron triglyceride concentration associated with intestinal overproduction of chylomicron triglyceride in nonobese, nondiabetic and normolipidemic NASH patients. (2017)
  • Author(s): Utsunomiya H, Hanayama M, Hiasa Y, et al.
  • Organizer: American Association for the Study of Liver Diseases (AASLD)
  • Int'l Joint Research
• [Presentation] Validation of the GLOBE score and the UK-PBC risk score in Japanese patients. (2017)
  • Author(s): Yoshida O, Abe M, Hiasa Y, et al.
  • Organizer: American Association for the Study of Liver Diseases (AASLD)
  • Int'l Joint Research
• [Presentation] The roles of protein kinase R and its possibility as a therapeutic target in hepatocellular carcinoma with hepatitis C virus infection. (2016)
  • Author(s): Watanabe T, Tokumoto Y, Hiasa Y, et al.
  • Organizer: The Liver Meeting of American Association for the Study of Liver Diseases
  • Place of Presentation: Boston, MA, USA
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] Down-regulated acidic leucine-rich nuclear phosphoprotein 32 family member B (ANP32B) has a role in suppression of apoptosis, and is associated with poor prognosis in patients with hepatocellular carcinoma. (2016)
  • Author(s): Ohio Y, Koizumi M, Hiasa Y, et al.
  • Organizer: The Liver Meeting of American Association for the Study of Liver Diseases
  • Place of Presentation: Boston, MA, USA
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] Unregulated palmitic acid absorption with altered intestinal transporters in non-alcoholic steatohepatitis (NASH). (2016)
  • Author(s): Utsunomiya H, Yamamoto Y, Hiasa Y, et al.
  • Organizer: The Liver Meeting of American Association for the Study of Liver Diseases
  • Place of Presentation: Boston, MA, USA
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] The efficacy of radio frequency ablation combined with trans catheter hepatic chemoembolization for patients with BCLC stage B hepatocellular carcinoma. (2016)
  • Author(s): Hirooka M, Hiraoka A, Hiasa Y, et al.
  • Organizer: The Liver Meeting of American Association for the Study of Liver Diseases
  • Place of Presentation: Boston, MA, USA
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] Patients with HBV and HCV chronic liver disease under surveillance for HCC are diagnosed with pancreatic cancer at early stages. (2016)
  • Author(s): Kumagi T, Terao T, Hiasa Y, et al.
  • Organizer: The Liver Meeting of American Association for the Study of Liver Diseases
  • Place of Presentation: Boston, MA, USA
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] Protein kinase R modulates DNA methylation in hepatocellular carcinoma with HCV infection (2016)
  • Author(s): Takao Watanabe, Yoshio Tokumoto, Masashi Hirooka, Osamu Yoshida, Yohei Koizumi, Yusuke Imai, Yoshiko Nakamura, Masanori Abe, Yoichi Hiasa
  • Organizer: 25th Conference of the Asian pacific association for the study of the liver
  • Place of Presentation: グランドプリンスホテル新高輪、東京都港区
  • Year and Date: 2016-02-20
  • Int'l Joint Research
• [Presentation] C型肝細胞癌におけるProtein kinase Rの役割-c-Fos, c-Jun活性化を介した細胞増殖促進作用 (2015)
  • Author(s): 渡辺崇夫、小泉光仁、日浅陽一
  • Organizer: 日本がん分子標的治療学会第19回学術集会
  • Place of Presentation: 松山全日空ホテル、愛媛県松山市
  • Year and Date: 2015-06-10
• [Presentation] HCV関連肝細胞癌におけるProtein kinase Rの役割 (2015)
  • Author(s): 渡辺崇夫、日浅陽一
  • Organizer: 第25回抗ウイルス療法学会総会
  • Place of Presentation: 国立感染症研究所、東京都新宿区
  • Year and Date: 2015-05-22
• [Book] 第31回犬山シンポジウム -B型肝炎・C型肝炎・肝癌 (2018)
  • Author(s): 渡辺崇夫、徳本良雄、日浅陽一
  • Total Pages: 4
  • Publisher: 犬山シンポジウム記録刊行会
• [Book] 消化器疾患のための栄養療法の手引き (2018)
  • Author(s): 仙波英徳、日浅陽一
  • Total Pages: 3
  • Publisher: 日本消化器病学会
• [Book] 1336専門家による私の治療 2017-18年度版 (2017)
  • Author(s): 徳本良雄、日浅陽一
  • Total Pages: 2
  • Publisher: 日本医事新報社
  • ISBN: 9784784946501
• [Book] 今日の治療指針2017年度版 (2017)
  • Author(s): 日浅陽一
  • Total Pages: 2
  • Publisher: 医学書院
• [Book] 消化器疾患 最新の治療2017-2018 (2017)
  • Author(s): 阿部雅則、日浅陽一
  • Total Pages: 4
  • Publisher: 南江堂
• [Book] 肝疾患治療マニュアル (2017)
  • Author(s): 徳本良雄、日浅陽一
  • Total Pages: 9
  • Publisher: 南江堂
• [Book] 消化器疾患 最新の治療 2017-2018 (2017)
  • Author(s): 阿部雅則、日浅陽一
  • Total Pages: 4
  • Publisher: 南江堂
• [Book] 臨牀消化器内科 10月号 (2016)
  • Author(s): 徳本良雄、日浅陽一
  • Total Pages: 9
  • Publisher: 日本メディカルセンター
• [Book] 肝臓クリニカルアップデート vol. 2 (2016)
  • Author(s): 渡辺崇夫、日浅陽一
  • Total Pages: 5
  • Publisher: 医学図書出版株式会社
• [Book] Modern Physician 11月号 (2016)
  • Author(s): 吉田理、三宅映己、日浅陽一
  • Total Pages: 6
  • Publisher: 株式会社 新興医学出版社
• [Patent(Industrial Property Rights)] B型肝炎ワクチン (2017)
  • Inventor(s): 小原道法、真田崇弘、日浅陽一、小原恭子、郷保正、織田康則
  • Industrial Property Rights Holder: 小原道法、真田崇弘、日浅陽一、小原恭子、郷保正、織田康則
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-138047
  • Filing Date: 2017