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Overexpression of Cyclooxygenase‐2 in the Liver Promotes Hepatocarcinogenesis
Author(s) -
Li Quiying,
Han Chang,
Xu Lihong,
Lim Kyu,
Wu Tong
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.749.10
Subject(s) - carcinogen , genetically modified mouse , cyclin d1 , hccs , hepatocyte , transgene , stat3 , wild type , medicine , western blot , carcinogenesis , endocrinology , hepatocellular carcinoma , chemistry , biology , cancer research , phosphorylation , cell cycle , cancer , in vitro , biochemistry , organic chemistry , mutant , gene
This study was designed to investigate the role of hepatocyte COX‐2 in carcinogen‐induced hepatocarcinogenesis. We developed transgenic mice with targeted expression of COX‐2 in the liver by using the albumin promoter‐enhancer driven vector. Male COX‐2 transgenic (Tg) and wild type C57/BL6 mice were subjected to standard diethylnitrosamine (DEN)/phenobarbital tumor induction protocol and monitored for the development of hepatocellular proliferative lesions. The incidence of hepatocellular lesions in COX‐2 Tg mice is significantly higher than in wild type mice (p<0.01). The tumor lesions in COX‐2 Tg mice are significantly larger when compared to wild type littermates at both 16 weeks to 27 weeks. Approximately 40% of COX‐2 Tg mice had multiple macroscopic HCCs 27 weeks after injection of DEN, whereas the wild type counterparts had only microscopic nodules. The COX‐2 Tg mice showed higher nodule multiplicity (1.71±1.27 at 16 weeks, 11.10±6.62 at 27 weeks) than wild type mice (0.25±0.46 at 16 weeks, 1.86±1.75 at 27 weeks) (p<0.01). Western blot analysis of the liver tissues showed higher levels of EGFR, gp130, phosphorylated STAT3, and cyclin D1 in COX‐2 Tg mice than in wild type mice. These results demonstrate that hepatocyte COX‐2 promotes hepatocarcinogenesis and this effect involves activation of EGFR and STAT3 signaling pathways.