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

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)...

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Published in:	Journal of cellular and molecular medicine 2020-12, Vol.24 (24), p.14549-14560
Main Authors:	Li, Shan, Xu, Zhengshui, Guo, Jing, Zheng, Jianbao, Sun, Xuejun, Yu, Junhui
Format:	Article
Language:	eng
Subjects:	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 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 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 Tumorigenesis Tumors Vimentin
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Summary:	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.
ISSN:	1582-1838 1582-4934