SMURF1-mediated ubiquitylation of SHP-1 promotes cell proliferation and invasion of endometrial stromal cells in endometriosis

Yunmeng Bian; Li Yuan; Xiaoqian Yang; Lichun Weng; Yanli Zhang; He Bai; Jinhong Chen

doi:10.21037/atm-20-2897

SMURF1-mediated ubiquitylation of SHP-1 promotes cell proliferation and invasion of endometrial stromal cells in endometriosis

Ann Transl Med. 2021 Mar;9(5):362. doi: 10.21037/atm-20-2897.

Authors

Yunmeng Bian¹, Li Yuan², Xiaoqian Yang¹, Lichun Weng¹, Yanli Zhang¹, He Bai³, Jinhong Chen¹

Affiliations

¹ Department of Gynaecology and Obstetrics, Shanghai First Maternity and Infant Hospital, Tongji University, Shanghai, China.
² International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai, China.
³ Department of Gynaecology and Obstetrics, Kaiyuan People's Hospital, Kaiyuan, China.

Abstract

Background: Endometriosis is a widespread benign gynecological disorder. The signal transducer and activator of transcription 3 (STAT3) signaling pathway plays an important role in the pathogenesis of endometriosis through regulating proliferation and invasion of endometrial stromal cells. Furthermore, the protein tyrosine phosphatase (PTP), SH2 domain-containing phosphatase 1 (SHP-1), negatively regulates STAT3 activation. However, regulation of the SHP-1-STAT3 pathway in the pathogenesis of endometriosis remains unclear.

Methods: Cell proliferation and invasion were assessed by Cell Counting Kit-8 (CCK-8) assay and Transwell analysis, respectively, to investigate the role and regulation of the SHP-1-STAT3 pathway in the proliferation and invasion of endometrial stromal cells. Expression of Smad ubiquitin regulatory factor 1 (SMURF1), SHP-1, matrix metalloproteinase 2 (MMP2), MMP9, STAT3, and phospho-STAT3 (p-STAT3) level in patients with endometriosis were measured by Western blotting and/or immunohistochemical staining. The interaction between SMURF1 and SHP-1 was investigated by co-immunoprecipitation and ubiquitylation analysis.

Results: The present study demonstrated that downregulation of SHP-1 expression in patients with endometriosis was negatively correlated with SMURF1 expression. SMURF1, an E3 ubiquitin ligase, activated the STAT3 pathway via ubiquitylation and degradation of SHP-1. Furthermore, SMURF1 promoted cell proliferation and invasion of endometrial stromal cells by activating STAT3 signaling and expression of its downstream targets, MMP2 and MMP9, whereas SHP-1 demonstrated an inverse effect. Additionally, SHP-1 inhibited SMURF1-mediated cell invasion and proliferation of endometrial stromal cells.

Conclusions: Our findings indicate that SMURF1-mediated ubiquitylation of SHP-1 regulates endometrial stromal cell proliferation and invasion during endometriosis.

Keywords: Endometriosis; SH2 domain-containing phosphatase 1 (SHP-1); Smad ubiquitin regulatory factor 1 (SMURF1); invasion; ubiquitylation.