Investigation of hepatocarcinogenic mechanisms by comprehensive ahalysis of cellular signaling responding to oxidative stress

• Project/Area Number: 26293179
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• 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): 原 裕一 川崎医科大学, 医学部, 講師 (60550952) ; 仁科 惣治 川崎医科大学, 医学部, 講師 (70550961) ; 岸 文雄 川崎医科大学, 医学部, 教授 (40153077) ; 池田 正徳 鹿児島大学, 医歯学域医学系, 教授 (30315767)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥15,080,000 (Direct Cost: ¥11,600,000、Indirect Cost: ¥3,480,000); Fiscal Year 2016: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2015: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2014: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
• Keywords: 酸化ストレス / 活性酸素種 / 細胞内シグナル / ミトコンドリア / オートファジー / マイトファジー / 鉄 / ミトコンドリアフェリチン / 肝癌 / リン酸化 / リン酸化シグナル / C型肝炎ウイルス

Outline of Final Research Achievements

We investigated the mechanisms underlying oxidative stress induces hepatocarcinogenesis in terms of cellular signaling and mitochondria quality control. Oxidative stress modified cellular signaling for glycolysis and apoptosis through activation of several kinase. These changes were cancelled by antioxidant, N-acetyl cysteine. Mitochondria is the main site of ROS production. Therefore, mitochondria quality control is critical for controlling oxidative stress. We found that iron loss reduces the development of liver tumors in NASH-rerlated hepatocarcinogenic mouse model through induction of mitochondria quality control.

Research Products

• [Journal Article] Key HLA-DRB1-DQB1 haplotypes and role of the BTNL2 gene for response to a hepatitis B vaccine (2019)
  • Author(s): Nishida N, Sugiyama M, Sawai H, Nishina S, Sakai A, Ohashi J, Khor SS, Kakisaka K, Tsuchiura T, Hino K, Sumazaki R, Takikawa Y, Murata K, Kanda T, Yokosuka O, Tokunaga K, Mizokami M
  • Journal Title: Hepatology Volume: 印刷中 Pages: 1-1
  • DOI: 10.1002/hep.29876
  • Peer Reviewed / Open Access
• [Journal Article] Quantitative assessment of liver fibrosis reveals a nonlinear association with fibrosis stage in nonalcoholic fatty liver disease (2018)
  • 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: Hepatology Communications Volume: 27 Pages: 58-68
  • DOI: 10.1002/hep4.1121
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sorafenib plus low-dose cisplatin and fluorouracil hepatic arterial infusion chemotherapy versus sorafenib alone in patients with advanced hepatocellular carcinoma (SILIUS): a randomised, open label, phase 3 trial. (2018)
  • Author(s): Kudo M、Ueshima K、Yokosuka O、Ogasawara S、Obi S、Izumi N、Aikata H、Nagano H、Hatano E、Sasaki Y、Hino K、Kumada T、Yamamoto K、Imai Y、Iwadou S、Ogawa C、Okusaka T、Kanai F、Akazawa K、Yoshimura K、Johnson P、Arai Y
  • Journal Title: Lancet Gastroenterol Hepatol. 2018 Jun;3(6):424-432 Volume: 3 Pages: 424-432
  • DOI: 10.1016/s2468-1253(18)30078-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Wisteria floribunda agglutinin-positive Mac-2 binding protein predicts the development of hepatocellular carcinoma in patients with nonalcoholic fatty liver disease (2018)
  • Author(s): Miwa Kawanaka, Yasuyuki Tomiyama, Hideyuki Hyogo, Masahiko Koda, Toshihide Shima, Hiroshi Tobita, Akira Hiramatsu, Ken Nishino, Toshiaki Okamoto, Shuichi Sato, Yuichi Hara, Sohji Nishina, Hirofumi Kawamoto, Kazuaki Chayama, Takeshi Okanoue, Keisuke Hino.
  • Journal Title: Hepatol Res Volume: 1 Pages: 13054-13054
  • DOI: 10.1111/hepr.13054
  • Peer Reviewed
• [Journal Article] Combinational use of hepatitis B viral antigens predicts responses to nucleos(t)ide analogue/peg-interferon sequential therapy. (2018)
  • Author(s): Matsumoto A, Nishiguchi S, Enomoto H, kang JH, tanak Y, Shinkai N, Hino K, et al.
  • Journal Title: Journal of Gastroenterology Volume: 53 Pages: 247-257
  • DOI: 10.1007/s00535-017-1360-z
  • Peer Reviewed / Open Access
• [Journal Article] Assessment of clinical and MRI features of de novo hypervascular HCC using gadoxetic acid-enhanced MRI (2017)
  • Author(s): Tamada, T. Korenaga, M. Yamamoto, A. Higaki, A. Kanki, A. Nishina, S. Hino, K. Ito, K
  • Journal Title: Hepatology Research Volume: 47 Pages: 152-160
  • DOI: 10.1111/hepr.12742
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Acyl/free carnitine ratio is a risk factor for hepatic steatosis after pancreatoduodenectomy and total pancreatectomy (2017)
  • Author(s): Nakamura, M. Nakata, K. Matsumoto, H. Ohtsuka, T. Yoshida, K. Tokunaga, S. Hino, K
  • Journal Title: Pancreatology Volume: 17 Pages: 135-138
  • DOI: 10.1016/j.pan.2016.11.007
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Assessment of hepatic fibrosis with superb microvascular imaging in hepatitis C virus-associated chronic liver diseases (2017)
  • Author(s): Koyama, N. Hata, J. Sato, T. Tomiyama, Y. Hino, K
  • Journal Title: Hepatology Research Volume: 47 Pages: 593-597
  • DOI: 10.1111/hepr.12776
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Emergent laparoscopic cholecystectomy for acute acalculous cholecystitis revisited (2016)
  • Author(s): Ueno, D. Nakashima, H. Higashida, M. Yoshida, K. Hino, K. Irei, I. Moriya, T. Matsumoto, H. Hirai, T. Nakamura, M
  • Journal Title: Surg Today Volume: 46 Pages: 309-312
  • DOI: 10.1007/s00595-015-1173-8
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Genome-Wide Association Study Identifies ZNF354C Variants Associated with Depression from Interferon-Based Therapy for Chronic Hepatitis C (2016)
  • Author(s): Matsunami K, Nishida N, Kaneko N, Ikeo K, Licht Toyo-oka, Takeuchi H, Matsuura K, Tamori A, Nomura H, Yoshiji H, Imamura M, Masaki N, Hayakawa T, Ide T, Shimada N, Ikeda F, Hino K, Nishiguchi S, Okuse C, Nojiri S, Sawamoto K, Tokunaga K, Joh T, Tanaka
  • Journal Title: PLoS One Volume: 11 Pages: 1-18
  • DOI: 10.1371/journal.pone.0164418
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A Series of microRNA in the Chromosome 14q32.2 Maternally Imprinted Region Related to Progression of Non-Alcoholic Fatty Liver Disease in a Mouse Model (2016)
  • Author(s): Okamoto K, Koda M, Okamoto T, Onoyama T, Miyoshi K, Kishina M, Kato J, Tokunaga S, Sugihara TA, Hara Y, Hino K, Murawaki Y
  • Journal Title: PLoS One Volume: 11
  • DOI: 10.1371/journal.pone.0154676
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Understanding of HLA-conferred susceptibility to chronic hepatitis B infection requires HLA genotypingbased association analysis (2016)
  • Author(s): Nishida N, Ohashi J, Hino K, Tokunaga K, Mizokami M, et al.
  • Journal Title: Sci Rep Volume: 6 Pages: 24767-24767
  • DOI: 10.1038/srep24767
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] L-Carnitine Supplementation Improved Hepatic Steatosis After Pancreatectomy (2016)
  • Author(s): Nakamura M, Matsumoto H, Nakashima H, Ando Y, Hirai T, Yoshida K, Hino K
  • Journal Title: Pancreas Volume: 45
  • DOI: 10.1097/mpa.0000000000000508
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition), (2016)
  • Author(s): Klionsky DJ., Abdelmohsen K., Abe A., Abedin MJ.,Inomata M., et al.
  • Journal Title: Autophagycineol. Volume: 12(1) Pages: 1-122
  • DOI: 10.1080/15548627.2015.1100356
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Branched-chain amino acids reduce hepatic iron accumulation and oxidative stress in hepatitis C virus polyprotein-expressing mice (2015)
  • Author(s): Korenaga M, Nishina S, Korenaga K, Tomiyama Y, Yoshioka N, Hara Y, Sasaki Y, Shimonaka Y, Hino K.
  • Journal Title: Liver International Volume: 35 Pages: 1303-14
  • DOI: 10.1111/liv.12675
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Fibroblast activation protein-alpha-expressing fibroblasts promote the progression of pancreatic ductal adenocarcinoma (2015)
  • Author(s): Kawase T, Yasui Y, Nishina S, Hara Y, Yanatori I, Tomiyama Y, Nakashima Y, Yoshida K, Kishi F, Nakamura M, Hino K
  • Journal Title: BMC Gastroenterology Volume: 15 Pages: 109-109
  • DOI: 10.1186/s12876-015-0340-0
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Association between Wisteria floribunda agglutinin-positive Mac-2 binding protein and the fibrosis stage of non-alcoholic fatty liver disease (2015)
  • Author(s): Abe M, Miyake T, Kuno A, Imai Y, Sawai Y, Hino K, Hara Y, Hige S, Sakamoto M, Yamada G, Kage M, Korenaga M, Hiasa Y, Mizokami M, Narimatsu H
  • Journal Title: Journal of Gastroenterology Volume: 50 Pages: 776-784
  • DOI: 10.1007/s00535-014-1007-2
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Effects of HLA-DPB1 genotypes on chronic hepatitis B infection in Japanese (2015)
  • Author(s): N. Nishida, J. Ohashi, M. Sugiyama, T. Tsuchiura, K. Yamamoto, K. Hino, M. Honda, S. Kaneko, H. Yatsuhashi, K. Koike, O. Yokosuka, E. Tanaka, A. Taketomi, M. Kurosaki, N. Izumi, N. Sakamoto, Y. Eguchi, T. Sasazuki, K. Tokunaga, and M. Mizokami
  • Journal Title: Tissue Antigens Volume: 5 Pages: 406-12
  • DOI: 10.1111/tan.12684
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Genome-wide association study identifies a PSMD3 variant associated with neutropenia in interferon-based therapy for chronic hepatitis C (2015)
  • Author(s): Iio E, Matsuura K, Nishida N, Maekawa S, Enomoto N, Nakagawa M, Sakamoto N, Yatsuhashi H et al.
  • Journal Title: Human Genetics Volume: 134 Pages: 279-289
  • DOI: 10.1007/s00439-014-1520-7
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hepatic oxidative stress in ovariectomized transgenic mice expressing the hepatitis C virus polyprotein is augmented through suppression of adenosine monophosphate-activated protein kinase/proliferator-activated receptor gamma co-activator 1 alpha signaling (2014)
  • Author(s): Tomiyama Y, Nishina S, Hara Y, Kawase T, Hino K
  • Journal Title: Hepatology research : the official journal of the Japan Society of Hepatology Volume: (in press) Pages: 229-39
  • DOI: 10.1111/hepr.12254
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mitochondrial reactive oxygen species as a mystery voice in hepatitis C. (2014)
  • Author(s): Hino K, Hara Y, Nishina S
  • Journal Title: Hepatology research : the official journal of the Japan Society of Hepatology Volume: 44 Pages: 123-32
  • DOI: 10.1111/hepr.12247
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hepatitis C virus core protein suppr 1 esses mitophagy by interacting with Parkin in the context of mitochondrial depolarization. (2014)
  • Author(s): Hara Y, Yanatori I, Ikeda M, Kiyokage E, Nishina S, Tomiyama Y, Toida K, Kishi F, Kato N, Imamura M, Chayama K, Hino K.
  • Journal Title: Amer J Pathol Volume: 184 Pages: 3026-3629
  • DOI: 10.1016/j.ajpath.2014.07.024
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 肝発癌抑制機構としてのmitophagy誘導 (2018)
  • Author(s): 原 裕一、仁科惣治、日野啓輔
  • Organizer: 第104回日本消化器病学会総会
• [Presentation] ミトコンドリア内鉄欠乏によるmitophagy誘導機構 (2017)
  • Author(s): 原 裕一、仁科惣治、日野啓輔
  • Organizer: 第42回日本肝臓学会西部会
• [Presentation] Los of iron up regulates mitochondria ferritin and triggers mitophagy (2017)
  • Author(s): Hara Y, Sasaki K, Nishina S, Hino K
  • Organizer: The Annual Meeting of American Association for the Study of Liver Diseases
  • Int'l Joint Research
• [Presentation] NASH肝発癌抑制機構としてのmitophagy誘導 (2017)
  • Author(s): 原 裕一、仁科惣治、日野啓輔
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] 肝細胞癌治療標的としてのCD26(DPP4) の意義 (2016)
  • Author(s): 仁科惣治, 山内明, 小山展子, 富山恭行, 吉岡奈穂子, 原裕一, 日野啓輔
  • Organizer: 第113回日本内科学会総会
  • Place of Presentation: 東京国際フォーラム
• [Presentation] NASH肝発癌抑制機構としてのmitophagy誘導 (2016)
  • Author(s): 原裕一, 仁科惣治, 日野啓輔
  • Organizer: 第102回日本消化器病学会総会
  • Place of Presentation: 東京京王プラザホテル
• [Presentation] 鉄キレートはC型肝炎ウイルスによるmitophagyの抑制を回復させる (2016)
  • Author(s): 原 裕―, 仁科惣治, 日野啓輔
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: 千葉幕張メッセ
• [Presentation] 肝細胞癌進展抑制におけるDPP4阻害薬の分子学的機序 (2016)
  • Author(s): 仁科惣治, 山内明, 富山恭行, 吉岡奈穂子, 原裕一, 日野啓輔
  • Organizer: JDDW2016
  • Place of Presentation: 神戸ポートピアホテル
• [Presentation] Iron chelator suppresses hepatocarcinogenesis through mitophagy induction in STAM mice (2016)
  • Author(s): Yuichi Hara, Kyo Sasaki, Soji Nishina, Keisuke Hino
  • Organizer: Annual Meeting of AASLD
  • Place of Presentation: Boston（米国）
  • Int'l Joint Research
• [Presentation] Dipeptidyl peptidase 4 (DPP4) inhibitor enhances natural killer cell chemotaxis, improving tumor immunity against hepatocellular carcinoma (2016)
  • Author(s): Sohji Nishina, Akira Yamauchi, Yuichi Hara, Kyo Sasaki, Keisuke Hino
  • Organizer: Annual Meeting of AASLD
  • Place of Presentation: Boston（米国）
  • Int'l Joint Research
• [Presentation] DPP-4 inhibitor, anagliptin suppresses the progression of Hepatocellular carcinoma (2015)
  • Author(s): Nishina S, Yamauchi A, Tomiyama Y, Hara Y, Hino K
  • Organizer: Annual Meeting of American Association for the Study of Liver Diseases 2015
  • Place of Presentation: San Francisco
  • Year and Date: 2015-11-17
  • Int'l Joint Research
• [Presentation] Iron chelation restores mitophagy suppressed by hepatitis C virus (2015)
  • Author(s): Hara Y, Nishina S, Hirayama T, Nagasawa H, Hino K
  • Organizer: Annual Meeting of American Association for the Study of Liver Diseases 2015
  • Place of Presentation: San Francisco
  • Year and Date: 2015-11-16
  • Int'l Joint Research
• [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, Kawanaka M, Miyake T, Abe M, Yamashita S, Tobita H, Sato S, Hiasa Y, Chayama K, Hino K
  • Organizer: The 65th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Hynes Convention Center, Boston, USA
  • Year and Date: 2014-11-09
• [Presentation] Hepatitis C virus core protein suppresses mitophagy by interacting with Parkin in the context of mitochondrial depolarization (2014)
  • Author(s): Hara Y, Yanatori I, Ikeda M, Kiyokage E, Nishina S, Tomiyama Y, Toida K, Kishi F, Kato N, Imamura M, Chayama K, Hino K
  • Organizer: 5th World Congress on Targeting Mitochondria
  • Place of Presentation: Ritz Carlton Hotel, Berlin, Germany
  • Year and Date: 2014-10-30
• [Presentation] HCVとミトコンドリアのバイオジェネーシスとの関連性 (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: ホテルニューオータニ、東京
  • Year and Date: 2014-05-30
• [Book] The liver in systemic diseases (2016)
  • Author(s): Keisuke Hino, Masaru Harada
  • Total Pages: 343
  • Publisher: Springer
• [Book] HEPATOLOGY PRACTICE（第３巻） (2014)
  • Author(s): 原裕一, 日野啓輔
  • Total Pages: 321
  • Publisher: 文光堂
• [Book] 酸化ストレスの医学 (2014)
  • Author(s): 原裕一, 日野啓輔
  • Total Pages: 444
  • Publisher: 診断と治療社
• [Book] HEPATOLOGY PRACTICE（第４巻） (2014)
  • Author(s): 仁科惣治, 日野啓輔
  • Total Pages: 340
  • Publisher: 文光堂
• [Patent(Industrial Property Rights)] 肝細胞癌の予防又は治療のための医薬 (2015)
  • Inventor(s): 仁科惣治、日野啓輔、後藤守兄、秦 克美
  • Industrial Property Rights Holder: 仁科惣治、日野啓輔、後藤守兄、秦 克美
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-04-27