Involvement of Cytoglobin expressed in hepatic stellate cells in the development of cancer derived from inflamed liver.

• Project/Area Number: 25293177
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Osaka City University
• Principal Investigator: KAWADA NORIFUMI 大阪市立大学, 大学院医学研究科, 教授 (30271191)
• Co-Investigator(Kenkyū-buntansha): Le Thuy 大阪市立大学, 大学院医学研究科, 特任助教 (10572175) ; Enomoto Masaru 大阪市立大学, 大学院医学研究科, 准教授 (20423874) ; Tamori Akihiro 大阪市立大学, 大学院医学研究科, 准教授 (30291595)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥15,860,000 (Direct Cost: ¥12,200,000、Indirect Cost: ¥3,660,000); Fiscal Year 2015: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2014: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2013: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000)
• Keywords: 肝がん / サイトグロビン / 肝硬変 / 肝癌 / 線維芽細胞 / 動物モデル

Outline of Final Research Achievements

We have shown Cygb's anti-oxidative properties.Here,we clarified the role of Cygb in the development of liver fibrosis and cancer with different aetiologies.Model 1;25ppm DEN treatment for 25 weeks induced liver tumor formation in 100% of Cygb-/- mice compared to 44% in WT mice. Background liver developed fibrosis together with the augmented inflammatory reactions and oxidative stress conditions in Cygb-/- mice. Model 2;8-16 weeks of CDAA treatment provoked more steatohepatitis,fibrosis,and accumulated neutrophils in Cygb-/- mice than in WT.Interestingly,100% of Cygb-/- mice fed CDAA for 32 weeks developed liver cancer,while no tumor was found in WT.HSCs isolated from Cygb-/- mice exhibited the priming condition and the senescence-like phenotype with upregulated chemokine and cytokine mRNA expression and superoxide production.Thus,Cygb deficiency detetiorated liver fibrosis and cancer development caused by different etiologies,indicating the protective role of Cygb in organ insult.

Research Products

• [Journal Article] Pathophysiological role of cytoglobin, the fourth globin in mammals, in liver diseases. (2016)
  • Author(s): Thuy Le TT, Hai NT, Hai H, Kawada N.
  • Journal Title: Histol Histopathol. Volume: 31 Pages: 257-267
• [Journal Article] Cytoglobin as a Marker of Hepatic Stellate Cell-derived Myofibroblasts. (2015)
  • Author(s): Kawada N.
  • Journal Title: Front Physiol. Volume: 6 Pages: 329-329
  • DOI: 10.3389/fphys.2015.00329
• [Journal Article] Cytoglobin Deficiency Promotes Liver Cancer Development from Hepatosteatosis through Activation of the Oxidative Stress Pathway. (2015)
  • Author(s): Thuy le TT, Matsumoto Y, Thuy TT, Hai H, Suoh M, Urahara Y, Motoyama H, Fujii H, Tamori A, Kubo S, Takemura S, Morita T, Yoshizato K, Kawada N
  • Journal Title: The American Journal of Pathology Volume: 185 Issue: 4 Pages: 1045-1060
  • DOI: 10.1016/j.ajpath.2014.12.017
  • Peer Reviewed
• [Journal Article] Involvement of hepatic stellate cell cytoglobin in acute hepatocyte damage through the regulation of CYP2E1-mediated xenobiotic metabolism (2015)
  • Author(s): Yuga Teranishi, Tsutomu Matsubara, Kristopher W Krausz, Thi T T Le, Frank J Gonzalez, Katsutoshi Yoshizato,Kazuo Ikeda and Norifumi Kawada
  • Journal Title: Laboratory Investigation Volume: 00 Pages: 1-10
• [Journal Article] Cytoglobin Deficiency Promotes Liver Cancer Development from Hepatosteatosis through Activation of the Oxidative Stress Pathway (2015)
  • Author(s): Thuy le TT, Matsumoto Y, Thuy TT, Hai H, Suoh M, Urahara Y, Motoyama H, Fujii H, Tamori A, Kubo S, Takemura S, Morita T, Yoshizato K, Kawada N.
  • Journal Title: Am J Pathol. Volume: 185 Pages: 1045-1060
• [Journal Article] Cytoglobin is expressed in hepatic stellate cells, but not in myofibroblasts, in normal and fibrotic human liver. (2014)
  • Author(s): Motoyama H, Komiya T, Thuy le TT, Tamori A, Enomoto M, Morikawa H, Iwai S,Uchida-Kobayashi S, Fujii H, Hagihara A, Kawamura E, Murakami Y, Yoshizato K,Kawada N.
  • Journal Title: Lab Invest. Volume: 94 Pages: 192-207
• [Presentation] Loss of Cytoglobin Exacerbates Liver Fibrosis and Cancer Development in Steatohepatitis by Activating the Oxidative Stress Pathway (2015)
  • Author(s): Le, Thuy T、Matsumoto, Yoshinari、Tuong Thi Van Thuy、Hoang Hai、Yoshizato, Katsutoshi、Kawada, Norifumi
  • Organizer: American Association for the Study of Liver Diseases
  • Place of Presentation: San Francisco(U S A)
  • Year and Date: 2015-11-13
  • Int'l Joint Research
• [Presentation] Evolution of hepatic fibrosis reserch (2015)
  • Author(s): Kawada N
  • Organizer: Asian Pacific Association for the Study of the Liver
  • Place of Presentation: Istanbul (Turkey)
  • Year and Date: 2015-03-13
  • Invited
• [Remarks] 大阪市立大学大学院医学研究科肝胆膵病態内科学 医局ホームページ
  • URL: http://www.med.osaka-cu.ac.jp/liver/index.html
• [Remarks] 大阪市立大学大学院医学研究科肝胆膵病態内科学医局ホームページ
  • URL: http://www.med.osaka-cu.ac.jp/liver/index.html
• [Remarks] 大阪市立大学大学院医学研究科肝胆膵病態内科学医局ホームページ
  • URL: http://www.med.osaka-cu.ac.jp/liver/index.html