2015 Fiscal Year Annual Research Report
非アルコール性脂肪性肝炎の病態形成におけるサイトグロビンの関与
| Project/Area Number |
25860554
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| Research Institution | Osaka City University |
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Principal Investigator |
LE THUY 大阪市立大学, 大学院医学研究科, 特任助教 (10572175)
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| Project Period (FY) |
2013-04-01 – 2016-03-31
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| Keywords | 遺伝子 / ｻｲﾄｸﾞﾛﾋﾞﾝ |
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| Outline of Annual Research Achievements |
We claify the role of cytoglobin in the development of the liver fibrosis and cancer in humans and in a mouse model of non-alcoholic steatohepatitis.CYGB was expressed in HSCs of intact human livers,and its expression was reduced in NASH and HCC patients.In Cygb-/-mice,71.3% of those aged 1 to 2 years spontaneously exhibited abnormalities and cancer development in multiple organs,including the liver,lung,lymph nodes and heart,compared with 5.8% in WT mice.In the NASH model,CDAA treatment for 8weeks induced rubust inflammation,fibrosis,and prominent expression of γ-H2AX,a marker of oxidative stress-related DNA double-stranded breaks,in Cygb-/- livers. Interestingly,100% of Cygb-/- mice fed CDAA developed liver cancer,while no tumors were found in WT controls.An imbalance between oxidative stress and antioxidant defense in Cygb-/- mice fed CDAA was demonstrated by the altered expression of 31 ROS metabolism genes,including myeloperoxidase and glutathione peroxidase2,both of which are involved in H2O2 production.In addition,Cygb-/- mice exhibited induction of nitric oxide synthase,high levels of nitrotyrosine formation,and an increased number of hypoxic hepatocytes,as determined by pimonidzole staining.NAC treatment rescued oxidative stress conditions in HSCs in primary culture and attenuated liver tumor formation in CDAA-treated Cygb-/- mice.Conclution:These results indicate that CYGB may control ROS production in chronically inflamed liver and provide important insights into the role of CYGB expressed in HSCs in liver hemeostasis,fibrosis and cancer development.
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[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 Tuong TV, Hai H,Suoh M,Urahara Y,Motoyama H,Fujii H,Tamori A,Kubo S,Takemura S,Morita T,Yoshizato K, and Kawada N.
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Journal Title
Am J Pathol.
Volume: 185
Pages: 1045-1060
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