Downregulation of nuclear receptor FXR is associated with multiple malignant clinicopathological characteristics in human hepatocellular carcinoma

Abstract

The nuclear receptor farnesoid X receptor (FXR) acts as a liver protector by regulating normal liver homeostasis. Spontaneously developed liver tumors have been found in FXR-null mice. However, the role of FXR in the tumorigenesis of human hepatocellular carcinoma (HCC) is still poorly understood. In this study, we measured the expression of FXR and its primary target gene, small heterodimer partner, and analyzed the clinical significance of FXR expression in HCC patients. A lentiviral vector that selectively overexpresses FXR was used to investigate the function of FXR in HCC cell proliferation both in vitro and in vivo. Our data showed that in human HCC, FXR expression was significantly reduced and was positively correlated with multiple malignant clinicopathological characteristics. Lentivirus-mediated exogenous FXR expression resulted in a marked increase of small heterodimer partner expression, significant repression of liver cancer cell proliferation, and tumor growth in nude mice. These results suggest that FXR may be of clinical and pharmacological importance as a promising biomarker of HCC. farnesoid X receptor; small heterodimer partner; tumor suppressor; proliferation HUMAN HEPATOCELLULAR CARCINOMA (HCC) is one of the most common human malignancies in the world and is prevalent in developing countries. In China, HCC has become the second highest cancer-related cause of death since the 1990s and accounts for 53% of all liver cancer deaths worldwide (12). The high mortality of HCC is due in large part to the lack of good biomarkers for early diagnosis and treatment assessment. Patients are often diagnosed at advanced stages, when most available therapies have only limited efficacy.The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors and is highly expressed in the liver. FXR controls the expression of various genes involved in bile acid, lipid, and glucose metabolism (21). In recent years, the understanding of the role of FXR in the liver has developed from that as a metabolic regulator to the novel function as a cell protector implicated in liver regeneration (9, 23) and hepatocarcinogenesis (22). In 2007, we first reported that in the absence of FXR, mice displayed spontaneous development of liver tumors (22). In parallel, Kim et al. (10) published very similar observations showing that aged FXR-null mice had a high incidence of liver tumors. However, limited information was available regarding the role of FXR in the development and progression of human HCC.The nuclear receptor small heterodimer partner (SHP) is an important modulator of metabolic signaling pathways (1,8,20) and is a primary FXR target gene. One of the well-characterized mechanisms by which FXR regulates gene expression in the liver is through the induction of SHP. Recent studies (24, 25) have revealed the role of SHP in the inhibition of cellular proliferation. However, combined loss of FXR and SHP expression in human HCC has not been previously reported.In this 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.…”

“…SHP is considered a tumor suppressor [80] in addition to a metabolic regulator [81] . SHP null mice spontaneously develop HCC at 12 to 15 months of age [82] , and SHP expression is diminished in human HCC samples and cell lines [23,83] . SHP represses tumor growth via the inhibition of cellular proliferation [82,83] and the activation of apoptotic signals [84,85] .…”

“…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] .…”

“…FXR deficiency also facilitates the progression of colorectal adenocarcinoma in C57BL/6 mice treated with the colon carcinogen azoxymethane [28] . A gain-of-function study using a xenograft mouse model showed that overexpression of FXR or treatment with FXR agonists represses cancer cell proliferation in vitro and xenograft growth in nude mice in vivo [23,27,29] . Interestingly, long-lived little mice have high levels of FXR and do not develop liver cancer after treatment with the chemical carcinogen diethylnitrosamine (DEN) [24] .…”

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].…”