Hepatic tumor and Nrf2 activation by impaired autophagy(Fostering Joint International Research)

• Project/Area Number: 15KK0325
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research)
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Tohoku University
• Principal Investigator: Taguchi Keiko 東北大学, 医学系研究科, 講師 (20466527)
• Research Collaborator: Kensler Thomas W. ジョンズホプキンス大学, Environmental Health Science, 名誉教授 ; Columbano Amedeo カリアリ大学, Scienze Biomediche, 教授 ; Cuadrado Antonio マドリード自治大学, Bioquimica, 教授
• Project Period (FY): 2016 – 2018
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥14,560,000 (Direct Cost: ¥11,200,000、Indirect Cost: ¥3,360,000)
• Keywords: Nrf2 / 肝臓 / 化学発がん / 肝臓がん

Outline of Final Research Achievements

Nrf2 knockout rats were used to examine contribution of a transcription factor Nrf2 in three kinds of chemical hepatocarcinogenesis models. Partial hepatectomy and DNA extraction from tissue sections by laser capture microdissection were learned from Professor Amedeo Columbano in University of Cagliari, Italy. Keap1-independent Nrf2 activation was discussed with Professor Antonio Cuadrado in Autonomous University of Madrid in Madrid, Spain. Nrf2 activation in Aflatoxin B1-induced liver tumor models was discussed with Professor Thomas Kensler in Johns Hopkins University in Baltimore, USA.

Academic Significance and Societal Importance of the Research Achievements

アメリカ・イタリア・スペインの３カ国において、最新のNrf2研究に携わる研究者と共に、３年にわたって本研究を遂行できたことは大変意義深い。古くから実験モデルとして確立している化学肝発がんモデルをNrf2欠失ラットに適用することで、Nrf2がいかに毒物に対する防御系に寄与しているかを示すことができた。また、発がんにはNrf2の体性変異を獲得した細胞が生存して増殖することが示唆され、ヒトがんにおけるNrf2の活性化を治療標的とする今後の研究が期待される。

Research Products

• [Int'l Joint Research] ジョンズホプキンス大学(米国) (2018)
• [Int'l Joint Research] ピッツバーグ大学(米国) (2017)
  • Year and Date: 2017-03-05
• [Int'l Joint Research] マドリード自治大学(スペイン) (2016)
  • Year and Date: 2016-10-15
• [Int'l Joint Research] カリアリ大学(イタリア) (2016)
  • Year and Date: 2016-06-04
• [Journal Article] NRF2 in liver toxicology (2019)
  • Author(s): Keiko Taguchi, Thomas W. Kensler
  • Journal Title: Archives of Pharmacal Research Volume: 印刷中
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Genetic inactivation of Nrf2 prevents clonal expansion of initiated cells in a nutritional model of rat hepatocarcinogenesis (2018)
  • Author(s): Orru Claudia、Szydlowska Marta、Taguchi Keiko、Zavattari Patrizia、Perra Andrea、Yamamoto Masayuki、Columbano Amedeo
  • Journal Title: Journal of Hepatology Volume: 69 Issue: 3 Pages: 635-643
  • DOI: 10.1016/j.jhep.2018.05.010
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The KEAP1-NRF2 system in cancer. (2017)
  • Author(s): Taguchi K, Yamamoto M.
  • Journal Title: Frontiers in Oncology Volume: 7 Pages: 85-85
  • DOI: 10.3389/fonc.2017.00085
  • Peer Reviewed / Open Access
• [Journal Article] Generation of a new model rat: Nrf2 knockout rats are sensitive to aflatoxin B1 toxicity. (2016)
  • Author(s): Taguchi K, Takaku M, Egner PA, Morita M, Kaneko T, Mashimo T, Kensler TW, Yamamoto M.
  • Journal Title: Toxicol Sci Volume: in press Issue: 1 Pages: 40-52
  • DOI: 10.1093/toxsci/kfw065
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming (2016)
  • Author(s): Saito T, Ichimura Y, Taguchi K, Suzuki T, Mizushima T, Takagi K, Hirose Y, Nagahashi M, Iso T, Fukutomi T, Ohishi M, Endo K, Uemura T, Nishito Y, Okuda S, Obata M, Kouno T, Imamura R, Tada Y, Obata R, Yasuda D, Takahashi K, Fujimura T, Pi J, Lee MS, Ueno T, Ohe T, Mashino T, Wakai T, Kojima H, Okabe T, Nagano T et al.
  • Journal Title: Nature Commun Volume: 7 Issue: 1 Pages: 12030-12030
  • DOI: 10.1038/ncomms12030
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Partial contribution of the Keap1-Nrf2 system to cadmium-mediated metallothionein expression in vascular endothelial cells. (2016)
  • Author(s): Shinkai Y, Kimura T, Itagaki A, Yamamoto C, Taguchi K, Yamamoto M, Kumagai Y, Kaji T.
  • Journal Title: Toxicol Appl Pharmacol Volume: 295 Pages: 37-46
  • DOI: 10.1016/j.taap.2016.01.020
  • Peer Reviewed / Open Access
• [Presentation] Keap1欠失ラットは転写因子Nrf2の活性化により重篤な肝障害を引き起こす (2019)
  • Author(s): 田口恵子、小山内七重、佐藤由莉、宮坂佳樹、真下知士、山本雅之
  • Organizer: 平成30年度先端モデル動物支援プラットフォーム成果発表会
• [Presentation] Keap1-Nrf2 system: Findings using animal models (2019)
  • Author(s): Keiko Taguchi
  • Organizer: National Institute on Aging/National Institute of Health (NIA/NIH) seminar
  • Int'l Joint Research / Invited
• [Presentation] Aflatoxin B1 induces fibrosis and cirrhosis in Nrf2 knockout rats (2019)
  • Author(s): Keiko Taguchi, Nanae Osanai, Eriko Naganuma, Thomas W. Kensler, Masayuki Yamamoto
  • Organizer: 58th Annual Meeting of Society of Toxicology
  • Int'l Joint Research
• [Presentation] The Nrf2 knockout rat as a toxicological tool (2017)
  • Author(s): Keiko Taguchi, Misaki Takaku, Patricia A. Egner, Thomas W. Kensler, Masayuki Yamamoto
  • Organizer: Society of Toxicology 56th Annual Meeting
  • Place of Presentation: Baltimore, USA
  • Year and Date: 2017-03-12
  • Int'l Joint Research
• [Presentation] Nrf2 activation-acquired Liver cancer (2017)
  • Author(s): Keiko Taguchi, Masayuki Yamamoto
  • Organizer: Closed seminar at Profs. Bruce Freeman & Thomas Kensler’s laboratories in University of Pittsburgh
  • Place of Presentation: Pittsburgh, USA
  • Year and Date: 2017-03-07
  • Int'l Joint Research / Invited
• [Presentation] 毒性学におけるNrf2欠失ラットの貢献 (2017)
  • Author(s): 田口恵子、山本雅之
  • Organizer: 第10回ラットリソースリサーチ研究会
  • Place of Presentation: 京都大学芝蘭会館稲盛ホール（京都）
  • Year and Date: 2017-02-03
  • Invited
• [Presentation] オートファジーとKeap1-Nrf2システム (2017)
  • Author(s): 田口恵子
  • Organizer: 第44回日本毒性学会学術年会
• [Presentation] 毒性学における転写因子Nrf2の貢献 (2017)
  • Author(s): 田口恵子、山本雅之
  • Organizer: 第44回日本毒性学会学術年会
  • Invited
• [Presentation] Pten欠失肝臓がんにおけるNrf2活性獲得の意義 (2017)
  • Author(s): 田口恵子、一戸理沙、山本雅之
  • Organizer: 第5回がんと代謝研究会
  • Invited
• [Presentation] Nrf2 activation acquired in a transition from steatosis to liver cancer (2017)
  • Author(s): Keiko Taguchi, Risa Ichinohe, Masayuki Yamamoto
  • Organizer: 2017 International Congress Obesity and Metabolic Syndrome (ICOMES2017)
  • Int'l Joint Research / Invited
• [Presentation] オートファジーの破綻による肝腫瘍とKeap1-Nrf2システム (2016)
  • Author(s): 田口恵子、小松雅明、山本雅之
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター（仙台）
  • Year and Date: 2016-09-25
• [Presentation] Nrf2 is a critical factor for hepatocellular adenoma in impaired autophagy (2016)
  • Author(s): Keiko Taguchi, Masaaki Komatsu, Masayuki Yamamoto
  • Organizer: 41st NAITO Conference
  • Place of Presentation: CHATERAISE Gateaux Kingdom SAPPORO（札幌）
  • Year and Date: 2016-07-05
  • Int'l Joint Research
• [Presentation] Nrf2の恒常的活性化はヘム合成阻害剤による肝毒性を軽減する (2016)
  • Author(s): 田口恵子、増井紗帆、山本雅之
  • Organizer: 第43回日本毒性学会学術年会
  • Place of Presentation: ウィンクあいち（名古屋）
  • Year and Date: 2016-06-29
• [Presentation] Nrf2 activation in liver cancer model mice (2016)
  • Author(s): Keiko Taguchi, Masayuki Yamamoto
  • Organizer: Closed seminar at Prof. Amedeo Columbano laboratory in University of Cagliari
  • Place of Presentation: Cagliari, Italy
  • Year and Date: 2016-06-13
  • Int'l Joint Research / Invited
• [Remarks] 東北大学 大学院医学系研究科 医化学分野
  • URL: http://www.dmbc.med.tohoku.ac.jp/official/index.html