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

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

  • Mol Cell Endocrinol. 2025 Apr 1:599:112470. doi: 10.1016/j.mce.2025.112470.
Tao Wang 1,  Mei Ji 1,  Pusheng Yang 1,  Jiaxin Zhang 1,  Xiaotong Peng 1,  Yaxin Miao 1,  Wenwen Liu 1,  Jing Sun 2
Affiliations

Affiliations

  • 1 The Gynecology Department, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
  • 2 The Gynecology Department, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China. Electronic address: sunjing61867@tongji.edu.cn.
PMID: 39864487 DOI: 10.1016/j.mce.2025.112470
Abstract

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.

Keywords

COX-2; ERK1/2; Endometriosis; Proliferation; Smad3; TGFβ1.

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