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

Research Project

Project/Area Number 15K09006
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Gastroenterology
Research InstitutionEhime 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 *help
¥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)
KeywordsProtein 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.

Report

(4 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Research-status Report
  • 2015 Research-status Report
  • Research Products

    (46 results)

All 2018 2017 2016 2015

All Journal Article (21 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 21 results,  Open Access: 17 results,  Acknowledgement Compliant: 5 results) Presentation (14 results) (of which Int'l Joint Research: 12 results) Book (10 results) Patent(Industrial Property Rights) (1 results)

  • [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

    • Related Report
      2017 Annual Research Report
    • 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

    • Related Report
      2017 Annual Research Report
    • 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

    • Related Report
      2017 Annual Research Report
    • 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

    • Related Report
      2017 Annual Research Report
    • 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

    • Related Report
      2017 Annual Research Report
    • 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

    • Related Report
      2017 Annual Research Report
    • 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

    • Related Report
      2017 Annual Research Report
    • 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

    • Related Report
      2017 Annual Research Report
    • 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

    • Related Report
      2017 Annual Research Report
    • 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

    • Related Report
      2017 Annual Research Report
    • 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

    • Related Report
      2017 Annual Research Report
    • 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 levels2017

    • 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

    • Related Report
      2016 Research-status Report
    • 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

    • Related Report
      2016 Research-status Report
    • 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

    • Related Report
      2016 Research-status Report
    • 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

    • Related Report
      2016 Research-status Report
    • 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

    • Related Report
      2016 Research-status Report
    • 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 disease2016

    • 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

    • Related Report
      2015 Research-status Report
    • 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 Disease2016

    • 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

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Usefulness of a New Three-Dimensional Simulator System for Radiofrequency Ablation2016

    • 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

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Effects of long-term entecavir treatment on the incidence of hepatocellular carcinoma in chronic hepatitis B patients2016

    • 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

    • Related Report
      2015 Research-status Report
    • Peer Reviewed
  • [Journal Article] Characterization of the biliary tract by virtual ultrasonography constructed by gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging2015

    • 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

    • Related Report
      2015 Research-status Report
    • 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)
    • Related Report
      2017 Annual Research Report
    • 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)
    • Related Report
      2017 Annual Research Report
    • 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)
    • Related Report
      2017 Annual Research Report
    • 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)
    • Related Report
      2017 Annual Research Report
    • 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)
    • Related Report
      2017 Annual Research Report
    • 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)
    • Related Report
      2017 Annual Research Report
    • 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
    • Related Report
      2016 Research-status Report
    • 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
    • Related Report
      2016 Research-status Report
    • 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
    • Related Report
      2016 Research-status Report
    • 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
    • Related Report
      2016 Research-status Report
    • 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
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Protein kinase R modulates DNA methylation in hepatocellular carcinoma with HCV infection2016

    • 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
    • Related Report
      2015 Research-status Report
    • 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
    • Related Report
      2015 Research-status Report
  • [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
    • Related Report
      2015 Research-status Report
  • [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
    • Related Report
      2017 Annual Research Report
  • [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
    • Related Report
      2017 Annual Research Report
  • [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
    • Related Report
      2017 Annual Research Report
  • [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
    • Related Report
      2017 Annual Research Report
  • [Book] 消化器疾患 最新の治療2017-20182017

    • Author(s)
      阿部雅則、日浅陽一
    • Total Pages
      4
    • Publisher
      南江堂
    • Related Report
      2017 Annual Research Report
  • [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
    • Related Report
      2017 Annual Research Report
  • [Book] 消化器疾患 最新の治療 2017-20182017

    • Author(s)
      阿部雅則、日浅陽一
    • Total Pages
      4
    • Publisher
      南江堂
    • Related Report
      2016 Research-status Report
  • [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
    • Related Report
      2016 Research-status Report
  • [Book] 肝臓クリニカルアップデート vol. 22016

    • Author(s)
      渡辺崇夫、日浅陽一
    • Total Pages
      5
    • Publisher
      医学図書出版株式会社
    • Related Report
      2016 Research-status Report
  • [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
    • Related Report
      2016 Research-status Report
  • [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
    • Related Report
      2017 Annual Research Report

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Published: 2015-04-16   Modified: 2019-03-29  

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