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 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.
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 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.
Authors: Guobin He; Guann-Yi Yu; Vladislav Temkin; Hisanobu Ogata; Christian Kuntzen; Toshiharu Sakurai; Wolfgang Sieghart; Markus Peck-Radosavljevic; Hyam L Leffert; Michael Karin Journal: Cancer Cell Date: 2010-03-16 Impact factor: 31.743
Authors: Fiona C McGillicuddy; Elise H Chiquoine; Christine C Hinkle; Roy J Kim; Rachana Shah; Helen M Roche; Emer M Smyth; Muredach P Reilly Journal: J Biol Chem Date: 2009-09-23 Impact factor: 5.157
Authors: L Lin; R Amin; G I Gallicano; E Glasgow; W Jogunoori; J M Jessup; M Zasloff; J L Marshall; K Shetty; L Johnson; L Mishra; A R He Journal: Oncogene Date: 2009-01-12 Impact factor: 9.867
Authors: Guodong Li; Yan Zhu; Ossama Tawfik; Bo Kong; Jessica A Williams; Le Zhan; Karen M Kassel; James P Luyendyk; Li Wang; Grace L Guo Journal: Am J Physiol Gastrointest Liver Physiol Date: 2013-10-03 Impact factor: 4.052
Authors: Guodong Li; Bo Kong; Yan Zhu; Le Zhan; Jessica A Williams; Ossama Tawfik; Karen M Kassel; James P Luyendyk; Li Wang; Grace L Guo Journal: Toxicol Appl Pharmacol Date: 2013-06-26 Impact factor: 4.219
Authors: Z Meng; X Ma; J Du; X Wang; M He; Y Gu; J Zhang; W Han; Z Fang; X Gan; C Van Ness; X Fu; D E Schones; R Xu; W Huang Journal: Oncogene Date: 2016-11-07 Impact factor: 9.867