FXR induces SOCS3 and suppresses hepatocellular carcinoma

Abstract

Suppressor of cytokine signaling 3 (SOCS3) is regarded as a vital repressor in the liver carcinogenesis mainly by inhibiting signal transducer and activator of transcription 3 (STAT3) activity. Farnesoid X Receptor (FXR), highly expressed in liver, has an important role in protecting against hepatocellular carcinoma (HCC). However, it is unclear whether the tumor suppressive activity of FXR involves the regulation of SOCS3. In the present study, we found that activation of FXR by its specific agonist GW4064 in HCC cells inhibited cell growth, induced cell cycle arrest at G1 phase, elevated p21 expression and repressed STAT3 activity. The above anti-tumor effects of FXR were dramatically alleviated by knockdown of SOCS3 with siRNA. Reporter assay revealed that FXR activation enhanced the transcriptional activity of SOCS3 promoter. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay displayed that FXR directly bound to IR9 DNA motif within SOCS3 promoter region. The in vivo study in nude mice showed that treatment with FXR ligand GW4064 could decelerate the growth of HCC xenografts, up-regulate SOCS3 and p21 expression and inhibit STAT3 phosphorylation in the xenografts. These results suggest that induction of SOCS3 may be a novel mechanism by which FXR exerts its anti-HCC effects, and the FXR-SOCS3 signaling may serve as a new potential target for the prevention/treatment of HCC.

Effect of obeticholic acid on liver regeneration following portal vein embolization in an experimental model

“…Tumours in the liver are at the same time exposed to the potent agonistic effects of FXR. Several reports have suggested that direct FXR stimulation of tumours poses no oncological concerns, and the increase in circulating FGF‐19 levels induced by OCA is not expected to increase the growth of tumours expressing Fgfr4. Pharmacological safety studies in mice have revealed that 2 years' exposure to a dose (25 mg per kg per day) exceeding that used in the present study and in ongoing clinical trials did not result in OCA‐related neoplasms (personal communication; L. Adorini, Intercept Pharmaceuticals, based on the toxicology report by WIL Research, Ashland, Ohio, USA).…”

Multifunctional Effects of a Small-Molecule STAT3 Inhibitor on NASH and Hepatocellular Carcinoma in Mice

“…FXR is highly expressed in liver and has an important role in protecting against HCC by inhibiting cell growth and inducing cell cycle arrest at G1 phase (49). Genomic analysis also identified HNF4a, a major hepatocytic transcription factor, as the main upstream regulator in liver and other liver specification genes upregulated in liver and tumor, suggesting that C188-9 induced hepatocytic differentiation in both liver and tumor.…”

Farnesoid X receptor regulates the growth of renal adenocarcinoma cells without affecting that of a normal renal cell-derived cell line

“…Thus, the stimulation of growth of renal adenocarcinoma cells by FXR ligand may arise from the down-regulation of p53 translation in a miR-21-dependent manner. There are several reports that state FXR regulates the proliferation of hepatocellular and other carcinoma cells (Zhang et al, 2012;He et al, 2015;Guo et al, 2015;Guan et al, 2013;Xie et al, 2016). Zhang et al (2012) and He et al (2015) have reported FXR inhibits the proliferation of hepatocellular carcinoma cell line HepG2 based on the data showing FXR ligand GW4064 reduced the value of MTT assay.…”

“…Thus, in these cells treated with the FXR ligand, the value of MTT assay does not reflect proliferation. Guo et al (2015) have also reported the FXR ligand inhibits the proliferation of HepG2 cells by showing cell cycle arrest caused by the FXR ligand, however, they performed the FXR ligand treatment in the medium containing very low concentration of FBS. Since our previous study in HepG2 cells (Fujino et al, 2012) and the present study have been performed in the medium containing 10% FCS sufficient for cell growth, our data is not comparable with the data obtained from Guo et al Consistent with our previous study (Fujino et al, 2012), Xie et al (2016) have reported FXR ligand GW4064 stimulates cell proliferation of HepG2 cells by analyzing DNA synthesis.…”