YAP Activates STAT3 Signalling to Promote Colonic Epithelial Cell Proliferation in DSS-Induced Colitis and Colitis Associated Cancer

Feihong Deng; Zengrong Wu; Mengmeng Xu; Pianpian Xia

doi:10.2147/JIR.S377077

YAP Activates STAT3 Signalling to Promote Colonic Epithelial Cell Proliferation in DSS-Induced Colitis and Colitis Associated Cancer

J Inflamm Res. 2022 Sep 19:15:5471-5482. doi: 10.2147/JIR.S377077. eCollection 2022.

Authors

Feihong Deng^{1

2}, Zengrong Wu^{1

2}, Mengmeng Xu^{1

2}, Pianpian Xia^{1

2}

Affiliations

¹ Department of Gastroenterology, the Second Xiangya Hospital of Central South University, Changsha, 410011, People's Republic of China.
² Research Center of Digestive Disease, Central South University, Changsha, 410011, People's Republic of China.

Abstract

Background and aims: Yes-associated protein (YAP) is a key transcriptional coactivator of cell proliferation and differentiation. In this study, we sought to identify the roles of YAP in colonic epithelial regeneration and tumourigenesis.

Methods: Murine DSS-induced colitis and YAP overexpression models were constructed via lentiviral intraperitoneal injection. Stable YAP-overexpressing cells, protein immunoprecipitation, and ChIP were used to deeply explore the molecular mechanism.

Results: We found that the expression of YAP was dramatically diminished in the colonic crypts during the acute colitis phase, while YAP was strikingly enhanced to initiate tissue repair after DSS withdrawal. Overexpressing YAP in mice drastically accelerated epithelial regeneration, presenting with more intact structural integrity and reduced inflammatory cell infiltration in the mucosa. Further mechanistic studies showed that the expression of YAP in the nucleus was significantly increased by 2 h post-DSS removal, accompanied by upregulated protein levels of activated STAT3. Overexpression of YAP (YAP^WT) elevated the expression of activated STAT3 and its transcriptional targets and strengthened the proliferation and "wound healing" ability of colonic cells. However, these effects were reversed when STAT3 was silenced in YAP^WT cells. Moreover, YAP could directly interact with STAT3 in the nucleus, and c-Myc and CyclinD1 were the transcriptional targets. Finally, during colitis-associated cancer (CAC), YAP^WT promoted the progression of CAC, while the phosphomimetic YAP downregulated the expression of STAT3 and inhibited the development and progression of CAC.

Conclusion: YAP activates STAT3 signalling to facilitate mucosal regeneration after DSS-induced colitis. However, excessive YAP activation in the colonic epithelium promotes CAC development.

Keywords: DSS induced colitis; STAT3; YAP; colitis-associated cancer; dextran sodium sulfate; mucosal repair.

Grants and funding

The study was sponsored by the National Natural Science Foundation of China (No. 81900478) and the Natural Science Foundation of Hunan Province (No. 2020JJ5801), China.