Journal Article

Farnesoid X receptor activation induces antitumour activity in colorectal cancer by suppressing JAK2/STAT3 signalling via transactivation of SOCS3 gene

Zheng, Jianbao, Li, Shan, Xu, Zhengshui, Yu, Junhui, Guo, Jing, Sun, Xuejun

2020

Overview

Farnesoid X receptor (FXR, encoded by NR1H4), a bile acid‐activated nuclear receptor, is widely implicated in human tumorigenesis. The FXR agonist obeticholic acid (OCA) has preliminarily displayed tumour suppressor potential. However, the anticancer effects of this agent on colorectal cancer (CRC) remain unclear. In this study, the treatment of colon cancer cells with OCA inhibited cell proliferation and invasion in vitro, retarded tumour growth in vivo and prevented the G0/G1 to S phase transition. Moreover, the expression of active caspase‐3, p21 and E‐cadherin was up‐regulated and the expression of cyclin D1, c‐Myc, vimentin, N‐cadherin and MMP9 was down‐regulated in OCA‐treated colon cancer cells. Mechanistic studies indicated that OCA treatment suppressed the activity of JAK2/STAT3 pathway by up‐regulating SOCS3 expression. Colivelin, an agonist of JAK2/STAT3 pathway, antagonized the tumour‐suppressive effect of OCA on colon cancer cells. Dual‐luciferase reporter and quantitative chromatin immunoprecipitation (qChIP) assays further confirmed that OCA promoted SOCS3 transcription by enhancing the binding of FXR to the FXRE/IR9 of the SOCS3 promoter. In conclusion, our study demonstrates that targeting FXR and improving its function might be a promising strategy for CRC treatment.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Agonists / Animals / Antibodies / Apoptosis / Apoptosis - genetics / Cancer therapies / Caspase / Cell adhesion & migration / Cell cycle / Cell Cycle - genetics / Cell growth / Cell Line, Tumor / Cell Proliferation / Chemotherapy / Chromatin / Colon cancer / Colorectal cancer / Colorectal carcinoma / Cyclin D1 / Deoxyribonucleic acid / DNA / Drug dosages / Epithelial-Mesenchymal Transition - genetics / Experiments / Farnesoid X receptor / FDA approval / Flow cytometry / Fluorescent Antibody Technique / Gelatinase B / Gene Expression Regulation, Neoplastic / Genes, Reporter / Humans / Immunohistochemistry / Immunoprecipitation / JAK2/STAT3 signalling / Janus kinase 2 / Janus Kinase 2 - metabolism / Laboratory animals / Liver cancer / Medical prognosis / Mice / Myc protein / obeticholic acid / Original / Phase transitions / Receptor mechanisms / Receptors, Cytoplasmic and Nuclear - agonists / Receptors, Cytoplasmic and Nuclear - metabolism / S phase / Signal Transduction / SOCS3 / Stat3 protein / STAT3 Transcription Factor - metabolism / Suppressor of Cytokine Signaling 3 Protein - genetics / Transcription / Tumor suppressor genes / Tumorigenesis / Tumors / Vimentin