Cyclooxygenase 2 overexpression suppresses Smad3 and augments ERK1/2 signaling activated by TGFβ1 in endometrial stromal cells: A novel insight into endometriosis pathogenesis.

RESEARCH QUESTION

To investigate the underlying mechanisms driving the opposing effects of transforming growth factor-beta 1 (TGFβ1) on the proliferation of control (CESCs) and ectopic (EESCs) endometrial stromal cells.

DESIGN

Cell proliferation assays (CCK-8 and colony formation) were employed to assess the effects of TGFβ1 on CESC and EESC proliferation. An immortalized human endometrial stromal cell line (HESC) was used to elucidate the mechanisms behind cytostatic effect of TGFβ1 and the potential role of cyclooxygenase (COX)-2 in mediating the modulation of TGFβ1 signaling.

RESULTS

This study demonstrated that TGFβ1 inhibited the proliferation of CESCs and HESCs while significantly promoting the proliferation of EESCs. In both CESCs and HESCs, TGFβ1-induced growth arrest was primarily mediated by cell cycle arrest rather than apoptosis. Mechanistically, TGFβ1 activated both Smad3 and ERK1/2 signaling pathways, with Smad3 acting to inhibit proliferation and ERK1/2 to promote it. Notably, overexpression of COX-2 in HESCs abolished the cytostatic effect of TGFβ1 by enhancing ERK1/2 signaling and decreasing Smad3 protein levels and its nuclear translocation. Similar effects were observed following prostaglandin E2 (PGE2) treatment. In contrast, inhibition of COX-2 activity in EESCs resulted in increased Smad3 expression, reduced ERK1/2 activation, and a restoration of the cytostatic effect of TGFβ1.

CONCLUSION

COX-2 modulates the effects of TGFβ1 on endometrial stromal cells by altering the balance between the Smad3 and ERK1/2 signaling pathways, thereby converting TGFβ1 from a growth inhibitor to a proliferation stimulator.