Deletion of IFNγ enhances hepatocarcinogenesis in FXR knockout mice

JOURNAL OF HEPATOLOGY

卷:57

Article

Meng, Zhipeng^2,5  Wang, Xiaoqiong^3,4  Gan, Yichao¹  Zhang, Yunfeng¹  Zhou, Hong¹  Van Ness, Carl⁵  Wu, Jun⁷  Lou, Guiyu^5,8  Yu, Hua^2,6  He, Chao^3,4  Xu, Rongzhen¹  Huang, Wendong^2,5 

[1] Zhejiang Univ, Sch Med, Affiliated Hosp 2, Dept Hematol, Hangzhou 310009, Zhejiang, Peoples R China

[2] City Hope Natl Med Ctr, Irell & Manella Grad Sch Biol Sci, Duarte, CA 91010 USA

[3] Zhejiang Univ, Sch Med, Sir Run Run Shaw Hosp, Dept Colorectal Surg, Hangzhou 310016, Zhejiang, Peoples R China

[4] Zhejiang Univ, Sch Med, Sir Run Run Shaw Hosp, Biomed Res Ctr, Hangzhou 310016, Zhejiang, Peoples R China

[5] City Hope Natl Med Ctr, Beckman Res Inst, Div Gene Regulat & Drug Discovery, Duarte, CA 91010 USA

[6] City Hope Natl Med Ctr, Beckman Res Inst, Dept Canc Immunotherapeut & Tumor Immunol, Duarte, CA 91010 USA

[7] City Hope Natl Med Ctr, Beckman Res Inst, Dept Comparat Med, Duarte, CA 91010 USA

[8] Third Mil Med Univ, Dept Biochem & Mol Biol, Chongqing 400038, Peoples R China

关键词: FXR;    HCC;    STAT3;    JNK;    NF-kappa B;    p53;   

DOI  :  10.1016/j.jhep.2012.06.016

来源: Elsevier

【 摘 要 】

Background & Aims: Liver tumor, especially hepatocellular carcinoma (HCC), is closely associated with chronic inflammation. We previously showed that farnesoid X receptor knockout (FXR-/-) mice displayed chronic inflammation and developed spontaneous liver tumors when they aged. However, the mechanism by which inflammation leads to HCC in the absence of FXR is unclear. Because IFN gamma is one of the most upregulated proinflammatory cytokines in FXR-/- livers, we generated IFN gamma-/-FXR-/- double knockout mice to determine IFN gamma's roles in hepatocarcinogenesis. Methods: IFN gamma(-/-) mice were crossed with an FXR-/- C57BL/6 background or injected i.p. with the hepatocarcinogen diethylnitrosamine (DEN). Hepatocarcinogenesis was analyzed with biochemical and histological methods. Results: IFN gamma deletion accelerated spontaneous hepatocarcinogenesis in FXR-/- mice and increased the susceptibility to DEN-induced hepatocarcinogenesis. IFN gamma deletion enhanced activation of HCC promoters STAT3 and JNK/c-Jun, but abolished induction of p53 in IFNy(-/-) livers after acute DEN-induced injury. Furthermore, hepatic p53 expression increased in aged wild type mice but not in aged IFN gamma(-/-) and IFN gamma-/-FXR-/- mice, while activation of STAT3 and JNK/c-Jun was enhanced in aged IFNy(-/-) and IFN gamma-/-FXR-/- mice. In addition, IFN gamma inhibited liver cancer xenograft growth and impaired IL-6-induced STAT3 phosphorylation by inducing SOCS1/3 expression. Conclusions: Increased IFN gamma expression in FXR-/- livers represents a protective response of the liver against chronic injury and tumorigenesis. IFN gamma suppresses hepatocarcinogenesis by inducing p53 expression and preventing STAT3 activation. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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