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

2017 Fiscal Year Annual Research Report

• Project/Area Number: 15K09006
• Research Institution: Ehime University
• Principal Investigator: 日浅 陽一 愛媛大学, 医学系研究科, 教授 (70314961)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: PKR-like ER kinase / Protein kinase R / eIF2alpha / AP-1 / ERストレス

Outline of Annual Research Achievements

C型肝炎ウイルス (HCV)関連肝細胞癌の癌部において過剰発現し、AP-1シグナルを活性化することで癌の進展に寄与するProtein kinase R (PKR)は、その下流にあるeIF2alphaを活性化する。同様にeIF2alphaを下流に持つ細胞内分子として、PKR-like endoplasmic reticulum (ER) kinase (PERK)がある。PERKは肝炎症によって生じるERストレスに影響され、PKRと同様に抗ウイルス作用を持つことが示されている。また、PERKはPKRとともにp53発現を低下させることから癌に関与しているが示唆される。PKRと下流分子を共有するPERKは、C型肝炎における炎症による発癌および癌進展にPKRと何らかの相互作用が想定されるが、肝細胞癌との関連については不明である。そのため(1)PERKの変化による細胞増殖への影響を調べるため肝癌細胞株にPERK inhibitorであるGSK2656157を投与し, 細胞増殖アッセイを用いて細胞増殖能を観察した。(2)同様に肝細胞癌株を用いて、Tunicamycinによる小胞体ストレスを誘導し、PERKに与える影響について確認した。(3)作成したPKR siRNAとPERK siRNAを肝癌細胞株にトランスフェクションしてPKR, PERKの発現を低下させ、mRNAおよび蛋白の変化をリアルタイムRT-PCR、ウエスタンブロット法で測定した。(4) PKR,PERKをコードしたプラスミド(pPKR, pPERK)を肝癌細胞株にトランスフェクションしてPKR、 PERKを過剰発現させ、mRNAおよび蛋白の変化を測定した。これらの検討の結果、PKRおよびPERKの抑制あるいは過剰発現により、PKRからPERK発現、PERKからPKR発現への影響は見られるものの軽微であり、両者は独立してeIF2alphaなど下流シグナルに影響を与えている実態が明らかになった。また、PERKはその阻害によって細胞増殖能の低下がみられ、癌の進展に寄与している可能性が示唆された。

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 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 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 Pages: 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: 52 Pages: 940-954
  • DOI: 10.1007/s00535-016-1298-6.
  • Peer Reviewed
• [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 Pages: 1567-1573
  • DOI: 10.1002/jmv.24776.
  • Peer Reviewed
• [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 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 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 Pages: e0177343
  • DOI: 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 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 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: 2 Pages: 58-68
  • DOI: 10.1002/hep4.1121.
  • 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
• [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: 978-4-7849-4650-1
• [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
• [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: 特願2017-138047