title: Hepatocarcinogenesis in FXR-/- mice mimics human HCC progression that operates through HNF1α regulation of FXR expression.
abstract: 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.
authors.affiliation: Division of Gene Regulation and Drug Discovery, Beckman Research Institute, City of Hope National Medical Center, Duarte, California 91010, USA.
authors.forename: Nian
authors.initials: N
authors.lastname: Liu
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Meng
authors.forename: Guiyu
authors.initials: G
authors.lastname: Lou
authors.forename: Weiping
authors.initials: W
authors.lastname: Zhou
authors.forename: Xiaoqiong
authors.initials: X
authors.lastname: Wang
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Zhang
authors.forename: Lisheng
authors.initials: L
authors.lastname: Zhang
authors.forename: Xiyong
authors.initials: X
authors.lastname: Liu
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
authors.forename: Lily
authors.initials: L
authors.lastname: Lai
authors.forename: Barry M
authors.initials: BM
authors.lastname: Forman
authors.forename: Zhonggao
authors.initials: Z
authors.lastname: Xu
authors.forename: Rongzhen
authors.initials: R
authors.lastname: Xu
authors.forename: Wendong
authors.initials: W
authors.lastname: Huang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008113:Liver Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D016207:Cytokines; D051538:Hepatocyte Nuclear Factor 1-alpha; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D000099150:Receptor, Farnesoid X-Activated