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

Research Project

Project/Area Number 26293179
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field Gastroenterology
Research InstitutionKawasaki 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 *help
¥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.

Report

(5 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • 2014 Annual Research Report

Research Products

(42 results)

All 2021 2019 2018 2017 2016 2015 2014

All Journal Article (22 results) (of which Int'l Joint Research: 14 results,  Peer Reviewed: 22 results,  Open Access: 16 results,  Acknowledgement Compliant: 9 results) Presentation (15 results) (of which Int'l Joint Research: 5 results) Book (4 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)2021

    • 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

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [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

    • 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.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

    • Related Report
      2017 Annual Research Report
    • 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 trial2018

    • 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

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 1.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

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Combinational use of2018

    • Author(s)
      Matsumoto A, Nishiguchi S, Enomoto H, Kang JH, Tanaka Y, Shinkai N, Kurosaki M, Enomoto M, Kanda T, Yokosuka O, Yatsuhashi H, Nagaoka S, Okuse C, Kagawa T, Mine T, Takaguchi K, Saito S, Hino K, Ikeda F, Sakisaka S, Morihara D, Miyase S, Tsuge M, Chayama K, Hiramatsu N, Suzuki Y, Murata K, Tanaka E
    • Journal Title

      Journal of Gastroenterology

      Volume: 53 Pages: 247-257

    • DOI

      10.1007/s00535-017-1360-z

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Assessment of clinical and MRI features of de novo hypervascular HCC using gadoxetic acid-enhanced MRI2017

    • 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

    • Related Report
      2016 Annual Research Report
    • 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 pancreatectomy2017

    • 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

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Assessment of hepatic fibrosis with superb microvascular imaging in hepatitis C virus-associated chronic liver diseases2017

    • 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

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Emergent laparoscopic cholecystectomy for acute acalculous cholecystitis revisited2016

    • 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

    • Related Report
      2016 Annual Research Report
    • 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 C2016

    • 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

    • Related Report
      2016 Annual Research Report
    • 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 Model2016

    • 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

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Understanding of HLA-conferred susceptibility to chronic hepatitis B infection requires HLA genotyping-based association analysis.2016

    • Author(s)
      N. Nishida (他37名, 山本31番目)
    • Journal Title

      Sci Rep

      Volume: 6 Pages: 24767-24767

    • DOI

      10.1038/srep24767

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] L-Carnitine Supplementation Improved Hepatic Steatosis After Pancreatectomy2016

    • 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

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [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

    • Related Report
      2015 Annual Research Report 2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Fibroblast activation protein-alpha-expressing fibroblasts promote the progression of pancreatic ductal adenocarcinoma2015

    • 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

    • Related Report
      2015 Annual Research Report
    • 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 disease2015

    • 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

    • Related Report
      2015 Annual Research Report 2014 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Effects of HLA-DPB1 genotypes on chronic hepatitis B infection in Japanese individuals.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

    • Related Report
      2015 Annual Research Report
    • 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

    • Related Report
      2015 Annual Research Report
    • 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 AMPK/PGC-1alpha signaling2014

    • 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

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Mitochondrial reactive oxygen species as a mystery voice in hepatitis C2014

    • 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

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] 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.
    • Journal Title

      Amer J Pathol

      Volume: 184 Pages: 3026-3629

    • DOI

      10.1016/j.ajpath.2014.07.024

    • Related Report
      2014 Annual Research Report
    • 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
    • Related Report
      2017 Annual Research Report
  • [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
    • Related Report
      2017 Annual Research Report
  • [Presentation] Los of iron up regulates mitochondria ferritin and triggers mitophagy2017

    • Author(s)
      Hara Y, Sasaki K, Nishina S, Hino K
    • Organizer
      The Annual Meeting of American Association for the Study of Liver Diseases
    • Related Report
      2017 Annual Research Report
    • 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
    • Related Report
      2017 Annual Research Report
  • [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
    • Related Report
      2016 Annual Research Report
  • [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
    • Related Report
      2016 Annual Research Report
  • [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
    • Related Report
      2016 Annual Research Report
  • [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
    • Related Report
      2016 Annual Research Report
  • [Presentation] Iron chelator suppresses hepatocarcinogenesis through mitophagy induction in STAM mice2016

    • Author(s)
      Yuichi Hara, Kyo Sasaki, Soji Nishina, Keisuke Hino
    • Organizer
      Annual Meeting of AASLD
    • Place of Presentation
      Boston(米国)
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Dipeptidyl peptidase 4 (DPP4) inhibitor enhances natural killer cell chemotaxis, improving tumor immunity against hepatocellular carcinoma2016

    • Author(s)
      Sohji Nishina, Akira Yamauchi, Yuichi Hara, Kyo Sasaki, Keisuke Hino
    • Organizer
      Annual Meeting of AASLD
    • Place of Presentation
      Boston(米国)
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] DPP-4 inhibitor, anagliptin suppresses the progression of Hepatocellular carcinoma2015

    • 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
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Iron chelation restores mitophagy suppressed by hepatitis C virus2015

    • 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
    • Related Report
      2015 Annual Research Report
    • 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
    • Related Report
      2014 Annual Research Report
  • [Presentation] Hepatitis C virus core protein suppresses mitophagy by interacting with Parkin in the context of mitochondrial depolarization2014

    • 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
    • Related Report
      2014 Annual Research Report
  • [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
    • Related Report
      2014 Annual Research Report
  • [Book] The liver in systemic diseases2016

    • Author(s)
      Keisuke Hino, Masaru Harada
    • Total Pages
      343
    • Publisher
      Springer
    • Related Report
      2016 Annual Research Report
  • [Book] HEPATOLOGY PRACTICE(第3巻)2014

    • Author(s)
      原裕一, 日野啓輔
    • Total Pages
      321
    • Publisher
      文光堂
    • Related Report
      2014 Annual Research Report
  • [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
    • Related Report
      2014 Annual Research Report
  • [Book] HEPATOLOGY PRACTICE(第4巻)2014

    • Author(s)
      仁科惣治, 日野啓輔
    • Total Pages
      340
    • Publisher
      文光堂
    • Related Report
      2014 Annual Research Report
  • [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
    • Related Report
      2015 Annual Research Report

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Published: 2014-04-04   Modified: 2019-03-29  

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