Deletion of IFNγ enhances hepatocarcinogenesis in FXR knockout mice.
OBJECTIVE
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(-)(/)(-)FXR(-)(/)(-) double knockout mice to determine IFNγ's roles in hepatocarcinogenesis.


METHODS
IFNγ(-)(/)(-) 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
IFNγ deletion accelerated spontaneous hepatocarcinogenesis in FXR(-)(/)(-) mice and increased the susceptibility to DEN-induced hepatocarcinogenesis. IFNγ deletion enhanced activation of HCC promoters STAT3 and JNK/c-Jun, but abolished induction of p53 in IFNγ(-)(/)(-) livers after acute DEN-induced injury. Furthermore, hepatic p53 expression increased in aged wild type mice but not in aged IFNγ(-)(/)(-) and IFNγ(-)(/)(-)FXR(-)(/)(-) mice, while activation of STAT3 and JNK/c-Jun was enhanced in aged IFNγ(-)(/)(-) and IFNγ(-)(/)(-)FXR(-)(/)(-) mice. In addition, IFNγ inhibited liver cancer xenograft growth and impaired IL-6-induced STAT3 phosphorylation by inducing SOCS1/3 expression.


CONCLUSIONS
Increased IFNγ expression in FXR(-)(/)(-) livers represents a protective response of the liver against chronic injury and tumorigenesis. IFNγ suppresses hepatocarcinogenesis by inducing p53 expression and preventing STAT3 activation.
Irell & Manella Graduate School of Biological Sciences, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, United States.
Zhipeng
Z
Meng
Xiaoqiong
X
Wang
Yichao
Y
Gan
Yunfeng
Y
Zhang
Hong
H
Zhou
Carl Van
CV
Ness
Jun
J
Wu
Guiyu
G
Lou
Hua
H
Yu
Chao
C
He
Rongzhen
R
Xu
Wendong
W
Huang
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000453:epidemiology* / Q000235:genetics*; D004052:Diethylnitrosamine / Q000009:adverse effects; D004195:Disease Models, Animal; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced / Q000453:epidemiology* / Q000235:genetics*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D012307:Risk Factors; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D004052:Diethylnitrosamine; D007371:Interferon-gamma; D048670:MAP Kinase Kinase 4; D016328:NF-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D050796:STAT3 Transcription Factor; D016159:Tumor Suppressor Protein p53; D000099150:Receptor, Farnesoid X-Activated