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.

FXR and liver carcinogenesis

“…The level of SHP expression was much lower in aging FXR -/-mice with HCC compared to young FXR -/-mice [19] . In human HCC specimens, expression of FXR and SHP are both markedly decreased [23,25] , and the FXR mRNA level was significantly and positively correlated with the SHP mRNA level in HCC tissues [23] . Those studies demonstrate that loss of SHP may contribute to liver carcinogenesis in livers deficient in FXR.…”

“…The elevated levels of proinflammatory cytokines, such as TNFα, IL-1β, and IL-6, in both FXR -/-mice [19,20] and in most human HCC patients [25,88] , may reduce the FXR expression via inhibiting the transactivity of hepatic nuclear factor 1α (HNF1α) on the FXR gene promoter [25] . TNFα and IL-1β alter the relative expression of FXRα1 and FXRα2, which leads to an increase in the FXRα1/ FXRα2 ratio and subsequent reduction of BSEP, indicting a potential interaction between FXR alternative splicing procedure and the inflammatory-cytokine mediated signal pathway [88] .…”

“…Interest in the potential function of FXR in cancer surged thereafter. Compared with matched normal tissues, FXR expression is significantly reduced in human tumor specimens [21][22][23][24][25] , and the downregulation of FXR is associated with malignant clinicopathological characteristics [23,26] . Loss of FXR leads to early mortality and/or promotes intestinal carcinogenesis in the mice with either a mutated APC gene (APC min/+ ) or chronic colitis [26][27][28] .…”

Farnesoid X Receptor Agonist as a new treatment option for Non-Alcoholic Fatty Liver disease: A Review

“…FXR knockout mice have been shown to develop liver tumours with aging [69,70], and FXR expression has been found to be signifi cantly decreased in many human tumour specimens [71][72][73][74]. In FXR knockout mice excessive BA accumulation has been considered to have cytotoxic effects, thus favouring tumorigenesis [69,70,75].…”

Regulation of N-Myc downstream regulated gene 2 by bile acids

“…Since two independent groups reported that the loss of FXR in Fxr-null mice resulted in spontaneous hepatocarcinogenesis [7,8], considerable research efforts have been focused on the identification of the underlying mechanisms of liver cancer inhibition by FXR and its relevance in the pathogenesis of human HCC. Subsequently, it has shown that FXR expression in human HCC samples was decreased compared to normal liver tissues [9].…”