Activation of FXR modulates SOCS3/Jak2/STAT3 signaling axis in a NASH-dependent hepatocellular carcinoma animal model
Attia, Yasmeen M.; Tawfiq, Rasha A.; Gibriel, Abdullah A.; Ali, Aya A.; Kassem, Dina; Hammam, Olfat A.; Elmazar, Mohamed M.;
Abstract
Despite the recent substantial progress in the treatment of hepatocellular carcinoma (HCC) from viral etiology, non-alcoholic steatohepatitis (NASH) is on a trajectory to become the fastest growing indication for HCC-related liver transplantation. The Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily with multifaceted roles in several metabolic disorders, particularly NASH. Its role as a tumor suppressor was also highlighted. Herein, we investigated the effect of obeticholic acid (OCA), as an FXR agonist, on NASH-associated HCC (NASH-HCC) animal model induced by diethylnitrosamine and high fat choline-deficient diet, exploring the potential impact on the suppressor of cytokine signaling 3 (SOCS3)/Janus kinase 2 (Jak2)/signal transducer and activator of transcription 3 (STAT3) pathway. Results indicated that OCA treatment upregulated FXR and its key mediator, small heterodimer partner (SHP), with remarkable amelioration in the dysplastic foci observed in the NASH-HCC group. This was paralleled with noticeable downregulation of alpha fetoprotein along with reduction in interferon gamma and transforming growth factor beta-1 hepatic levels besides caspase-3 and p53 upregulation. Moreover, sirtuin-1 (SIRT-1), a key regulator of FXR that controls the regenerative response of the liver, was elevated following OCA treatment. Modulation in the SOCS3/Jak2/STAT3 signaling axis was also reported. In conclusion, OCA attenuated the development and progression of NASH-dependent HCC possibly by interfering with SOCS3/Jak2/STAT3 pathway suggesting the potential use of FXR activators in NASH-related disorders, even at later stages of the disease, to impede its progression to the more deteriorating condition of HCC.
Other data
Title | Activation of FXR modulates SOCS3/Jak2/STAT3 signaling axis in a NASH-dependent hepatocellular carcinoma animal model | Authors | Attia, Yasmeen M.; Tawfiq, Rasha A.; Gibriel, Abdullah A.; Ali, Aya A.; Kassem, Dina ; Hammam, Olfat A.; Elmazar, Mohamed M. | Keywords | FXR;Hepatocellular carcinoma;Non-alcoholic steatohepatitis;SOCS3;STAT3 | Issue Date | 1-Apr-2021 | Publisher | PERGAMON-ELSEVIER SCIENCE LTD | Journal | Biochemical Pharmacology | Volume | 186 | ISSN | 00062952 | DOI | 10.1016/j.bcp.2021.114497 | PubMed ID | 33675775 | Scopus ID | 2-s2.0-85103762500 | Web of science ID | WOS:000640417600001 |
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