肝細胞癌におけるＰＫＲの役割とその宿主細胞機能修飾

2014 Fiscal Year Annual Research Report

• Project/Area Number: 24590980
• Research Institution: Ehime University
• Principal Investigator: 日浅 陽一 愛媛大学, 医学(系)研究科(研究院), 教授 (70314961)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: PKR / 肝細胞癌 / C型肝炎ウイルス / c-Jun / c-Fos / リン酸化c-Jun / リン酸化c-Fos / MAPK

Outline of Annual Research Achievements

Protein kinase R (PKR)は、非癌部の肝組織に比べてHCV関連肝細胞癌において強発現している。しかし強発現したPKRのHCV関連肝細胞癌の発癌と進展における役割については不明であった。昨年度までの研究で、HCV感染肝癌細胞株を用いて、PKRがHCV関連肝細胞癌において細胞増殖能を亢進させており、その作用はErk1/2→c-Fos, JNK→c-JunのMAPK経路に依存していることを同定した。本年度は手術あるいは肝生検時に得られたヒト肝細胞癌組織34例(HCV陽性17例、陰性17例)より、mRNAを抽出し、PKR mRNAの中央値からPKR高発現群と低発現群に分けた。次に3.で同定し得た細胞内癌関連遺伝子について、mRNAおよび蛋白をリアルタイムRT-PCR、ウエスタンブロット法で測定し、PKR発現量によって増減するかどうかを検討した。またHCV陽性群と陰性群に分けて検討を加えた。
その結果、肝細胞癌でPKR高発現群においてPKR低発現群よりc-Jun mRNAが増加していた。その差は、HCV陰性例ではみられず、HCV陽性例で有意差がみられた。また、Western blotによる検討で、PKR高発現群ではPKR低発現群よりリン酸化c-Fosとリン酸化c-Junの発現が増加しており、in vitroのデーターと合致した。つまり、特にHCV陽性肝細胞癌において高発現するPKRはc-Fos、c-Junを活性化しており、腫瘍の増殖、進展に関わる可能性が示唆された。これらの結果より、HCV関連肝細胞癌においてPKRは治療標的となり得ると考えられた。

Research Products

• [Journal Article] Nonalcoholic Fatty Liver Disease: Portal Hypertension Due to Outflow Block in Patients without Cirrhosis. (2015)
  • Author(s): Hirooka M, Koizumi Y, Miyake T, Ochi H, Tokumoto Y, Tada F, Matsuura B, Abe M, Hiasa Y.
  • Journal Title: Radiology Volume: 274 Pages: 597-604
  • DOI: 10.1148/radiol.14132952.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Significance of exercise in nonalcoholic fatty liver disease in men: a community-based large cross-sectional study. (2015)
  • Author(s): Miyake T, Kumagi T, Hirooka M, Furukawa S, Kawasaki K, Koizumi M, Todo Y, Yamamoto S, Nunoi H, Tokumoto Y, Ikeda Y, Abe M, Kitai K, Matsuura B, Hiasa Y.
  • Journal Title: J Gastroenterol Volume: 50 Pages: 230-237
  • DOI: 10.1007/s00535-014-0959-6.
  • Peer Reviewed
• [Journal Article] Pancreatic congestion in liver cirrhosis correlates with impaired insulin secretion. (2014)
  • Author(s): Kuroda T, Hirooka M, Koizumi M, Ochi H, Hisano Y, Bando K, Matsuura B, Kumagi T, Hiasa Y.
  • Journal Title: J Gastroenterol Volume: Epub Pages: Epub
  • DOI: 10.1007/s00535-014-1001-8
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Hyperuricemia is a risk factor for the onset of impaired fasting glucose in men with a high plasma glucose level: a community-based study. (2014)
  • Author(s): Miyake T, Kumagi T, Furukawa S, Hirooka M, Kawasaki K, Koizumi M, Todo Y, Yamamoto S, Abe M, Kitai K, Matsuura B, Hiasa Y.
  • Journal Title: PLoS One Volume: 9 Pages: e107882
  • DOI: 10.1371/journal.pone.0107882.
  • Peer Reviewed / Open Access
• [Journal Article] Short sleep duration reduces the risk of nonalcoholic fatty liver disease onset in men: a community-based longitudinal cohort study. (2014)
  • Author(s): Miyake T, Kumagi T, Furukawa S, Hirooka M, Kawasaki K, Koizumi M, Todo Y, Yamamoto S, Tokumoto Y, Ikeda Y, Abe M, Kitai K, Matsuura B, Hiasa Y.
  • Journal Title: J Gastroenterol Volume: Epub Pages: Epub
  • DOI: 10.1007/s00535-014-0989-0
  • Peer Reviewed
• [Journal Article] New susceptibility and resistance HLA-DP alleles to HBV-related diseases identified by a trans-ethnic association study in Asia. (2014)
  • Author(s): Nishida N, Sawai H, Hiasa Y, et al.
  • Journal Title: PLoS One Volume: 9 Pages: e86449
  • DOI: 10.1371/journal.pone.0086449.
  • Peer Reviewed / Open Access
• [Journal Article] Interleukin 28B polymorphism predicts interferon plus ribavirin treatment outcome in patients with hepatitis C virus-related liver cirrhosis: A multicenter retrospective study in Japan. (2014)
  • Author(s): Shakado S, Sakisaka S, Okanoue T, Chayama K, Izumi N, Toyoda J, Tanaka E, Ido A, Takehara T, Yoshioka K, Hiasa Y, Nomura H, Seike M, Ueno Y, Kumada H.
  • Journal Title: Hepatol Res Volume: 44 Pages: 983-992
  • DOI: 10.1111/hepr.12280.
  • Peer Reviewed / Open Access
• [Journal Article] 18F-FDG-PET/CT predicts the distribution of microsatellite lesions in hepatocellular carcinoma. (2014)
  • Author(s): Ochi H, Hirooka M, Hiraoka A, Koizumi Y, Abe M, Sogabe I, Ishimaru Y, Furuya K, Miyagawa M, Kawasaki H, Michitaka K, Takada Y, Mochizuki T, Hiasa Y.
  • Journal Title: Mol Clin Oncol Volume: 2 Pages: 798-804
  • DOI: 10.3892/mco.2014.328
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Maximum standardized uptake value in 18F-fluoro-2-deoxyglucose positron emission tomography is associated with advanced tumor factors in esophageal cancer. (2014)
  • Author(s): Kajiwara T, Hiasa Y, Nishina T, Matsumoto T, Hori S, Nadano S, Iguchi H, Takeji S, Tsubouchi E, Ikeda Y, Onji M.
  • Journal Title: Mol Clin Oncol Volume: 2 Pages: 313-321
  • DOI: 10.3892/mco.2014.238
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Portal hypertension due to outflow block in non-cirrhotic patients with nonalcoholic fatty liver disease. (2014)
  • Author(s): Koizumi Y, Hirooka M, Hiasa Y, et al.
  • Organizer: The 65th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-07 – 2014-11-11
• [Presentation] Branched-chain amino acids improve intestinal malabsorption of dietary long-chain fatty acids and preserve intestinal fatty acid transporters in liver cirrhosis. (2014)
  • Author(s): Yamamoto Y, Utsunomiya H, Hiasa Y, et al.
  • Organizer: The 65th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-07 – 2014-11-11
• [Presentation] Pancreatic congestion in liver cirrhosis correlates with impaired insulin secretion. (2014)
  • Author(s): Kuroda T, Hirooka M, Hiasa Y, et al.
  • Organizer: The 65th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-07 – 2014-11-11
• [Presentation] Wisteria floribunda agglutinin-positive Mac-2 binding protein as a predictor of liver fibrosis in patients with non-alcoholic fatty liver disease. (2014)
  • Author(s): Abe M, Miyake T, Hiasa Y, et al.
  • Organizer: The 65th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-07 – 2014-11-11
• [Presentation] Oral glucose tolerance test predicts hepatic fibrosis in nonalcoholic fatty liver disease patients without overt diabetes mellitus. (2014)
  • Author(s): Nishina S, Hyogo H, Hiasa Y, et al.
  • Organizer: The 65th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-07 – 2014-11-11