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Deletion of IFN? enhances hepatocarcinogenesis in FXR knockout mice.


ABSTRACT: 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? is one of the most upregulated pro-inflammatory cytokines in FXR(-)(/)(-) livers, we generated IFN?(-)(/)(-)FXR(-)(/)(-) double knockout mice to determine IFN?'s roles in hepatocarcinogenesis.IFN?(-)(/)(-) 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.IFN? deletion accelerated spontaneous hepatocarcinogenesis in FXR(-)(/)(-) mice and increased the susceptibility to DEN-induced hepatocarcinogenesis. IFN? deletion enhanced activation of HCC promoters STAT3 and JNK/c-Jun, but abolished induction of p53 in IFN?(-)(/)(-) livers after acute DEN-induced injury. Furthermore, hepatic p53 expression increased in aged wild type mice but not in aged IFN?(-)(/)(-) and IFN?(-)(/)(-)FXR(-)(/)(-) mice, while activation of STAT3 and JNK/c-Jun was enhanced in aged IFN?(-)(/)(-) and IFN?(-)(/)(-)FXR(-)(/)(-) mice. In addition, IFN? inhibited liver cancer xenograft growth and impaired IL-6-induced STAT3 phosphorylation by inducing SOCS1/3 expression.Increased IFN? expression in FXR(-)(/)(-) livers represents a protective response of the liver against chronic injury and tumorigenesis. IFN? suppresses hepatocarcinogenesis by inducing p53 expression and preventing STAT3 activation.

SUBMITTER: Meng Z 

PROVIDER: S-EPMC3477276 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Deletion of IFNγ enhances hepatocarcinogenesis in FXR knockout mice.

Meng Zhipeng Z   Wang Xiaoqiong X   Gan Yichao Y   Zhang Yunfeng Y   Zhou Hong H   Ness Carl Van CV   Wu Jun J   Lou Guiyu G   Yu Hua H   He Chao C   Xu Rongzhen R   Huang Wendong W  

Journal of hepatology 20120621 5


<h4>Background & aims</h4>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 IFNγ is one of the most upregulated pro-inflammatory cytokines in FXR(-)(/)(-) livers, we generated IFNγ(-)  ...[more]

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