Analysis of hepatocarcinogenesis based on gender and mitochondrial biogenesis

• Project/Area Number: 23390201
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kawasaki Medical School
• Principal Investigator: HINO Keisuke 川崎医科大学, 医学部, 教授 (80228741)
• Co-Investigator(Kenkyū-buntansha): IKEDA Masanori 岡山大学, 医歯(薬)学総合研究科, 准教授 (30315767) ; KISHI Fumio 川崎医科大学, 医学部, 教授 (40153077) ; KORENAGA Masaaki 川崎医科大学, 医学部, 准教授 (70420536) ; NISHINA Sohji 川崎医科大学, 医学部, 講師 (70550961) ; HARA Yuichi 川崎医科大学, 医学部, 講師 (60550952)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥15,860,000 (Direct Cost: ¥12,200,000、Indirect Cost: ¥3,660,000); Fiscal Year 2013: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2012: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2011: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
• Keywords: ミトコンドリア / 酸化ストレス / 肝発がん / C型肝炎ウイルス / 性差 / Ｃ型肝炎ウイルス / 肝細胞癌 / mitophagy / Parkin / 活性酸素種 / autophagy / エストロゲン

Research Abstract

Oxidative stress plays an important role in hepatocarcinogenesis. Hepatitis C virus (HCV) is well known to induce the production of reactive oxygen species (ROS). In the present study we have shown that hepatitis C virus (HCV) core protein suppresses mitophagy (mitochondrial quality control) , which may lead to continuous induction of ROS production and inhibition of mitochondrial biogenesis. We also demonstrated that hepatic oxidative stress was augumented in ovariectomized transgenic mice expressing the HCV polyprotein by attenuation of antioxidant potential through inhibition of AMPK/PGC-1alpha signaling. These results may account in part for the mechanisms by which HCV-infected women are at high risk for HCC development when some period had passed after menopause.

Research Products

• [Journal Article] Hepatic oxidative stress in ovariectomized transgenic mice expressing the hepatitis C virus polyprotein is augmented through suppression of AMPK/PGC-1alpha signaling (2014)
  • Author(s): Tomiyama Y, Nishina S, Hara Y, Kawase T, Hino K
  • Journal Title: Hepatol Res Volume: (in press) Issue: 10 Pages: 229-39
  • DOI: 10.1111/hepr.12254
  • Peer Reviewed / Open Access
• [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, Kashiwase K, Minami M, Sugiyama M, Seto WK, Yuen MF, Posuwan N, Poovorawan Y, Ahn SH, Han KH, Matsuura K, Tanaka Y, Kurosaki M, Asahina Y, Izumi N, Kang JK, （省略）, Tokunaga K, and Mizokami M
  • Journal Title: PLoS One Volume: 9 Issue: 2 Pages: e86449-e86449
  • DOI: 10.1371/journal.pone.0086449
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondrial reactive oxygen species as a mystery voice in hepatits C (2014)
  • Author(s): Hino K, Hara Y, Nishina S
  • Journal Title: Heparol Res Volume: 44 Pages: 123-32
  • 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, Kashiwase K, Minami M, Sugiyama M, Seto WK, Yuen MF, Posuwan N, Poovorawan Y, Ahn SH, Han KH, Matsuura K, Tanaka Y, Kurosaki M, Asahina Y, Izumi N, Yamamoto K, Sakaida I, Murawaki Y, Itoh Y, Tamori A, Orito E, Honda M, Kaneko S, Mita E, Hino K, Tokunaga K, Mizokami M, et al
  • Journal Title: PLOS One Volume: 9
  • Peer Reviewed
• [Journal Article] Mitochondrial reactive oxygen species as a mystery voice in hepatitis C (2014)
  • Author(s): Hino K, Hara Y, Nishina S
  • Journal Title: Hepatol Res Volume: 44 Issue: 2 Pages: 123-32
  • DOI: 10.1111/hepr.12247
  • Peer Reviewed / Open Access
• [Journal Article] Iron metabolic disorder in chronic hepatitis C. Mechanisms and relevance to hepatocarcinogenesis (2013)
  • Author(s): Hino K, Nishina S, Hara Y
  • Journal Title: J Gastroenterol Hepatol Volume: 28 Suppl 4 Pages: 93-8
  • Peer Reviewed
• [Journal Article] Clinical usefulness of non-protein respiratory quotient measurement in non-alcoholic fatty liver disease (2013)
  • Author(s): Korenaga K, Korenaga M, Hino K, 他9名(12番目)
  • Journal Title: Hepatol Res Volume: 43 Pages: 1284-94
  • Peer Reviewed
• [Journal Article] Iron metabolic disorder in chronic hepatitis C: Mechanisms and relevance to hepatocarcinogenesis (2013)
  • Author(s): Hino K, Nishina S, Hara Y
  • Journal Title: J Gastroenterol Hepatol Volume: 28 Suppl 4 Issue: S4 Pages: 93-8
  • DOI: 10.1111/jgh.12243
  • Peer Reviewed
• [Journal Article] Risk factors for survival and the development of hepatocellular carcinoma in patients with primary biliary cirrhosis (2013)
  • Author(s): Tomiyama Y, Takenaka K, Kodama T, Kawanaka M, sasaki K, Nishina S, Yoshioka N, Hara Y, Hino K
  • Journal Title: Intern Med Volume: 52 Pages: 1553-9
  • NAID: 130003365701
  • Peer Reviewed
• [Journal Article] First jejunal vein oriented mesenteric excision for pancreatoduodenectomy (2013)
  • Author(s): Nakamura M, Nakashima H, Tsutsumi K, Matsumoto H, Muta Y, Ueno D, Yoshida K, Hino K, Urakami A, Tanaka M
  • Journal Title: J Gastroenterol Volume: 48 Issue: 8 Pages: 989-95
  • DOI: 10.1007/s00535-012-0697-6
  • NAID: 10031195125
  • Peer Reviewed
• [Journal Article] Treatment of nonalcoholic steatohepatitis with vitamins E and C: a pilot study (2013)
  • Author(s): Kawanaka M, Nishino K, Suehiro M, Goto D, Urata N, Oka T, Kawamoto H, Nakamura H, Yodoi J, Hino K, Yamada G
  • Journal Title: Hepatic Medicine: Evidence and Research Volume: 5 Pages: 11-16
  • Peer Reviewed
• [Journal Article] Clinical usefulness of non-protein respiratory quotient measurement in non-alcoholic fatty liver disease (2013)
  • Author(s): Korenaga Keiko
  • Journal Title: Hepatol Res Volume: in press
  • Peer Reviewed
• [Journal Article] Risk factors for survival and development of hepatocellular carcinoma in primary biliary cirrhosis (2013)
  • Author(s): Tomiyama Ysuyuki
  • Journal Title: Intern Med Volume: in press
  • Peer Reviewed
• [Journal Article] Treatment of nonalcoholic steatohepatitis with vitamins E and C: a pilot study (2013)
  • Author(s): Kawanaka Miwa
  • Journal Title: Hepatic Medicine: Evidence and Research Volume: in press
  • Peer Reviewed
• [Journal Article] Genome-wide association study confirming association of HLA-DP with protection against chronic hepatitis B and viral clearance in Japanese and Korean. (2012)
  • Author(s): Nishida N, Asahina Y, Mizokami M et al
  • Journal Title: PLoS One Volume: 7 Issue: 6 Pages: 1-8
  • DOI: 10.1371/journal.pone.0039175
  • Peer Reviewed
• [Journal Article] Temperature-Related Effects of Adenosine Triphosphate-Activated Microglia on Pro-Inflammatory Factors (2012)
  • Author(s): Tomohiro MATSUI, et al
  • Journal Title: Neurocrit.Care Volume: (in press) Issue: 2 Pages: 293-300
  • DOI: 10.1007/s12028-011-9639-z
  • Peer Reviewed
• [Journal Article] No association for Chinese HBV-related hepatocellular carcinoma susceptibility SNP in other East Asian populations. (2012)
  • Author(s): Sawai H, Asahina Y, Tokunaga K et al
  • Journal Title: BMC Med Genet Volume: 13 Issue: 1 Pages: 47-47
  • DOI: 10.1186/1471-2350-13-47
  • Peer Reviewed
• [Journal Article] Iron metabolic disorder: insights from recent evidence (2012)
  • Author(s): Hino Keisuke
  • Journal Title: Cin J Gastroenterol Volume: 5 Issue: 4 Pages: 251-256
  • DOI: 10.1007/s12328-012-0323-4
  • Peer Reviewed
• [Journal Article] Genome-wide association study identified ITPA/DDRGK1 variants reflecting thrombocytopenia in pegylated interferon and ribavirin therapy for chronic hepatitis C (2011)
  • Author(s): Tanaka Y, Kurosaki M, Hino K, 他19名
  • Volume: 20
  • Pages: 3507-16
  • Peer Reviewed
• [Journal Article] A glycyrrhizin-containing preparation reduces hepatic steatosis induced by hepatitis C virus protein and iron in mice (2011)
  • Author(s): Korenaga M, Hidaka I, Nishina S, Sakai A, Shinozaki A, Gondo T, Furutani T, Kawano H< sakaida I, Hino K
  • Journal Title: Liver Int Volume: 31 Pages: 552-60
  • Peer Reviewed
• [Journal Article] Focal Nodular Hyperplasia-Like Nodule with Reduced Expression of Organic Anion Transporter 1B3 in Alcoholic Liver Cirrhosis (2011)
  • Author(s): Doi Nubuko
  • Journal Title: Internal Medicine Volume: 50 Pages: 1193-9
  • Peer Reviewed
• [Journal Article] Type I interferon receptor in peripheral blood mononuclear cells may predict reapoonse to intraarterial 5-fluorouracil/interferon combination therapy for advanced hepatocellular carcinoma-a pilot study- (2011)
  • Author(s): Tomiyama Yasuyuki
  • Journal Title: Hepatic Medicine : Evidence and Research Volume: 3 Pages: 45-52
  • Peer Reviewed
• [Journal Article] A glycyrrhizin-containing preparation reduces hepatic steatosis induced by hepatitis C virus protein and iron in mice (2011)
  • Author(s): Korenaga Masaaki
  • Journal Title: Liver International Volume: 31 Pages: 552-60
  • Peer Reviewed
• [Journal Article] Recommendation of lamivudine-to-entecavir switching treatment in chronic hepatitis B responders : Randomized controlled trial (2011)
  • Author(s): Matsuura Kentaro
  • Journal Title: Hepatology Research Volume: 41 Pages: 505-11
  • Peer Reviewed
• [Journal Article] The rs8099917 Polymorphism, When Detemined by a Suitable Genotyping Method, Is a Better Predictor for Response to Pegylated Alpha Interferon/Ribavirin Therapy in Japanese Patients than Other Single Nucleotide Polymorphisms Associated with Interleukin-28B (2011)
  • Author(s): Ito Kiyoaki
  • Journal Title: Journal of Clinical Mirobiology Volume: 49 Pages: 1853-60
  • Peer Reviewed
• [Journal Article] Genome-wide association study identified ITPA/DDRGK1 variants reflecting thrombocytopenia in pegylated interferon and ribavirin therapy for chronic hepatitis C (2011)
  • Author(s): Tanaka Y, Sakamoto N, et al.
  • Journal Title: Human Molecular Genetics Volume: 20(17) Issue: 17 Pages: 3507-3516
  • DOI: 10.1093/hmg/ddr249
  • Peer Reviewed
• [Presentation] HCV とミトコンドリアバイオジェネシスとの関連性 (2014)
  • Author(s): 原 裕一, 仁科惣治, 日野啓輔
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 2014-05-30
• [Presentation] Hepatitis C virus core protein suppresses mitophagy by interacting with Parkin (2013)
  • Author(s): Hara Y, Nishina S, Hino K, et al
  • Organizer: The 64th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Washington DC
  • Year and Date: 2013-11-02
• [Presentation] Ovariectomized transgenic mice expressing hepatitis C virus poltprotein develop hepatic steatosis through suppression of AMPK/PGCα signaling (2013)
  • Author(s): Tomiyama Y, Nishina S, Hara Y, Hino K
  • Organizer: The 64th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Washington DC
  • Year and Date: 2013-11-02
• [Presentation] The hepatitis C virus core protein suppresses mitophagy by interacting with Parkin (2013)
  • Author(s): Hara Y, Nishina S, Hino K, et al
  • Organizer: Cell symposium Mitochondria : from signaling to disease
  • Place of Presentation: Lisbon
  • Year and Date: 2013-05-05
• [Presentation] Hepatitis C virus proteins suppress compensatory induction of reactive oxygen species-detoxifying enzymes following oxidative stress in the absence of estrogen (2012)
  • Author(s): Tomiyama Yasuyuki
  • Organizer: Annual Meeting of American Association for the Study of Liver Diseases
  • Place of Presentation: Hynes Convention Center, Boston, USA
• [Presentation] Hepatitis C virus core protein suppresses mitophagy by interacting with Parkin (2012)
  • Author(s): Hara Yuichi
  • Organizer: Annual Meeting of American Association for the Study of Liver Diseases
  • Place of Presentation: Hynes Convention Center, Boston, USA
• [Presentation] Anti-Interferon-α neutralizing antibody interacts with viral response to interferon in patient with hepatitis C virus with interferon sensitive of IL28B single nucleotide polymorphisms (2012)
  • Author(s): Korenaga Masaaki
  • Organizer: Annual Meeting of American Association for the Study of Liver Diseases
  • Place of Presentation: Hynes Convention Center, Boston, USA
• [Presentation] Supplementation with branched-chain amino acids improves HCV induced iron metabolic disorder via upregulation of antioxidant potential by restoring mitochondrial complex I function in iron overloaded transgenic mice expressing hepatitis C virus polyprotein (2012)
  • Author(s): Korenaga Masaaki
  • Organizer: Annual Meeting of American Association for the Study of Liver Diseases
  • Place of Presentation: Hynes Convention Center, Boston, USA
• [Presentation] Dietary supplementation with branched chain amino acids reduces hepatic iron accumulation in iron overloaded transgenic mice expressing hepatitis C virus polyprotein (2011)
  • Author(s): Korenaga Masaaki
  • Organizer: The 62nd Annual Meeting of the American Association for the Study of Liver Disease
  • Place of Presentation: San Francisco
  • Year and Date: 2011-11-05
• [Presentation] BCAA顆粒はHCVTgMにおける肝内鉄過剰と酸化ストレスを抑制する (2011)
  • Author(s): 是永匡紹
  • Organizer: 第47回日本肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 2011-06-02
• [Presentation] The hepatitis C virus core protein suppresses mitophagy by affecting Parkin
  • Author(s): Yuichi Hara, Izumi Yanatori , Masanori Ikeda, Sohji Nishina, Yasuyuki Tomiyama, Fumio Kishi, Kazunori Toida, Nobuyuki Kato, Kazuaki Chayama , Keisuke Hino
  • Organizer: Cell Symposium Mitochondria:from Signaling to Disease
  • Place of Presentation: Sheraton Lisboa, Lisbon, Portugal
• [Presentation] Fibroblast Activation Protein (FAP) Expression of Cancer-Associated Fibroblast Predicts Poor Prognosis in Patients With Pancreatic Adenocarcinoma
  • Author(s): Tomoya Kawase, Koji Yoshida, Keisuke Hino
  • Organizer: DDW2013(American Gastroenterological Association)
  • Place of Presentation: Orange Country Convention Center, Orlando FL, USA
• [Presentation] HCVコア蛋白とParkinとの相互作用によるマイトファジーの抑制
  • Author(s): 原裕一，仁科惣治，日野啓輔
  • Organizer: 第49回日本肝臓学会総会
  • Place of Presentation: 京王プラザホテル、東京
• [Presentation] HCVタンパクはエストロゲン欠乏起因性酸化ストレスに対する抗酸化機構を抑制する
  • Author(s): 富山恭行，小山展子，佐々木恭，仁科惣治，吉岡奈穂子，原 裕一，日野啓輔
  • Organizer: 第49回日本肝臓学会総会
  • Place of Presentation: 京王プラザホテル、東京
• [Presentation] Splenectomy causes hepatic inflammation and oxidative stress through activation of Kupffer cells in iron-overloaded mice
  • Author(s): Sohji Nishina, Yuichi Hara, Yasuyuki Tomiyama, Keisuke Hino
  • Organizer: 17th International Symposium on Cells of the Hepatic Sinusoid
  • Place of Presentation: Osaka International Convention Center, Osaka, Japan
• [Presentation] Splenectomy causes hepatic inflammation and oxidative stress through activation of Kupffer cells in iron-overloaded mice
  • Author(s): Sohji Nishina, Yuichi Hara, Yasuyuki Tomiyama, Keisuke Hino
  • Organizer: The 64th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: WALTER E. Washington Convention Center Washington,DC.USA
• [Presentation] Ovariectomized transgenic mice expressing hepatitis C virus polyprotein develop hepatic steatosis through suppression of AMPK/PGC1a signaling
  • Author(s): Yasuyuki Tomiyama, Sohji Nishina , Yuichi Hara, Keisuke Hino
  • Organizer: The 64th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: WALTER E. Washington Convention Center Washington,DC.US
• [Presentation] Hepatitis C virus core protein suppresses mitophagy by interacting with Parkin
  • Author(s): Yuhichi Hara, Izumi Yanatori, EmiKiyokage, Sohji Nishina, Yasuyuki Tomiyama, Kazunori Toida, Masanori Ikeda, Fumio Kishi, Nobuyuki Kato, Keisuke Hino
  • Organizer: The 64th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: WALTER E. Washington Convention Center Washington,DC.US
• [Book] C型肝炎の診療を極める基本から最前線まで (2014)
  • Author(s): 原裕一, 日野啓輔
  • Publisher: 文光堂
• [Book] 診断と治療 ウイルス肝炎の新展開 (2013)
  • Author(s): 原 裕一、日野啓輔
  • Total Pages: 190
  • Publisher: 診断と治療社
• [Book] わが国における急性肝炎の現状 (2012)
  • Author(s): 日野啓輔
  • Total Pages: 180
  • Publisher: 中外医学社
• [Book] 症例に学ぶNASH/NAFLDの診断と治療 (2012)
  • Author(s): 是永匡紹
  • Total Pages: 213
  • Publisher: 診断と治療社
• [Book] 病気の分子形態学 (2011)
  • Author(s): 日野啓輔
  • Publisher: 学際企画
• [Patent(Industrial Property Rights)] C型慢性肝炎治療効果予測のための検査方法及び検査用キット (2012)
  • Inventor(s): 加藤宣之, 池田正徳, 是永匡紹, 日野啓輔
  • Industrial Property Rights Holder: 国立大学法人 岡山大学, 学校法人川崎学園
  • Industrial Property Rights Type: 特許
  • Acquisition Date: 2012-08-31
• [Patent(Industrial Property Rights)] C型慢性肝炎治療効果予測のための検査方法及び検査用キット (2011)
  • Inventor(s): 加藤宣之、池田正徳、是永匡紹、日野啓輔
  • Industrial Property Rights Holder: 加藤宣之、池田正徳、是永匡紹、日野啓輔
  • Industrial Property Rights Type: 特許
  • Filing Date: 2011-04-27
  • Acquisition Date: 2012-08-31