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Hepatocarcinogenesis in FXR-/- mice mimics human HCC progression that operates through HNF1α regulation of FXR expression.

Liu, Nian; Meng, Zhipeng; Lou, Guiyu; Zhou, Weiping; Wang, Xiaoqiong; Zhang, Yunfeng; Zhang, Lisheng; Liu, Xiyong; Yen, Yun; Lai, Lily; Forman, Barry M; Xu, Zhonggao; Xu, Rongzhen; Huang, Wendong.
Mol Endocrinol; 26(5): 775-85, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22474109
Farnesoid X receptor (FXR) (nuclear receptor subfamily 1, group H, member 4) is a member of nuclear hormone receptor superfamily, which plays essential roles in metabolism of bile acids, lipid, and glucose. We previously showed spontaneously hepatocarcinogenesis in aged FXR(-/-) mice, but its relevance to human hepatocellular carcinoma (HCC) is unclear. Here, we report a systematical analysis of hepatocarcinogenesis in FXR(-/-) mice and FXR expression in human liver cancer. In this study, liver tissues obtained from FXR(-/-) and wild-type mice at different ages were compared by microarray gene profiling, histological staining, chemical analysis, and quantitative real-time PCR. Primary hepatic stellate cells and primary hepatocytes isolated from FXR(-/-) and wild-type mice were also analyzed and compared. The results showed that the altered genes in FXR(-/-) livers were mainly related to metabolism, inflammation, and fibrosis, which suggest that hepatocarcinogenesis in FXR(-/-) mice recapitulated the progression of human liver cancer. Indeed, FXR expression in human HCC was down-regulated compared with normal liver tissues. Furthermore, the proinflammatory cytokines, which were up-regulated in human HCC microenvironment, decreased FXR expression by inhibiting the transactivity of hepatic nuclear factor 1α on FXR gene promoter. Our study thereby demonstrates that the down-regulation of FXR has an important role in human hepatocarcinogenesis and FXR(-/-) mice provide a unique animal model for HCC study.
Selo DaSilva