The FXR Agonist, Obeticholic Acid, Suppresses HCC Proliferation & Metastasis: Role of IL-6/STAT3 Signalling Pathway

Abstract

The nuclear receptor, farnesoid X receptor (FXR), has been recently considered as a tumor suppressor in HCC. IL-6/Janus kinase 2 (Jak-2)/signal transducer and activator of transcription 3 (STAT3) pathway has been implicated as a key player in many cancer types. This study aimed at investigating the potential effect of the FXR agonist, obeticholic acid (OCA), on HCC and the involvement of IL-6/ STAT3 pathway. The potential regulation of STAT3 by its main feedback inhibitor target gene, the suppressor of cytokine signaling 3 (SOCS3), triggered by OCA was also explored. Cytotoxicity studies were performed on HepG2, Huh7, and SNU-449 cell lines using OCA alone and combined with the FXR antagonist guggulsterone (Gugg). OCA cytotoxic effect was significantly hampered in presence of Gugg. OCA also caused cell cycle arrest and inhibited invasion and migration of HCC cells. Decrease in STAT3 phosphorylation and SOCS3 upregulation were also observed. Moreover, Jak-2, IL-1β, and IL-6 levels were decreased. These results were correlated with an upregulation of FXR and small heterodimer partner (SHP) levels. Effects of OCA on IL-6/STAT3 main key players were reversed in presence of Gugg. Overall, these findings suggest a potential effect of OCA in HCC via interfering with IL-6/STAT3 signalling pathway in vitro.Hepatocellular carcinoma (HCC) is the sixth most prevalent type of cancer and the third most common cause of cancer-related death worldwide. It accounts for about 85% of primary liver cancer where its incidence has dramatically increased during the past two decades 1

Farnesoid X Receptor Activation Enhances Transforming Growth Factor β-Induced Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma Cells

“…FXR agonist treatment inhibits proliferation of SK-GI-18 cells, which are FXR-overexpressing SK-Hep-1 cells, and suppresses tumor growth and metastasis in an orthotopic xenograft model with these cells in nude mice [ 22 ]. Recently, OCA was reported to suppress proliferation, migration, and invasion of HepG2 cells and HuH-7 cells [ 23 ]. Our preliminary experiments showed higher concentrations of CDCA, GS, GW4064, and OCA inhibited cell proliferation.…”

STAT3 and STAT5 Activation in Solid Cancers

“…It is also possible to consider treatments that re-express SOCS1/3 in tumors. Indeed, in liver cancer SOCS3 gene expression can be re-established by drugs that activate the Farnesoid X receptor (FXR) [163,164]. Gene therapy strategies are also under development to re-express SOCS1 or SOCS3 in tumors [165,166,167].…”

Successful stories of drug repurposing for cancer therapy in hepatocellular carcinoma

“…OCA is a synthetically modified bile acid agonist for the nuclear farnesoid X receptor (FXR). A cross talk between IL-6/STAT3 pathway and the hepatic FXR in HCC was previously reported [ 94 ]. In this study, activating FXR using OCA interfered with HCC cell growth by downregulating IL-6/STAT3 pathway in vitro.…”