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EGF-like growth factors induce COX-2-derived PGE2 production through ERK1/2 in human granulosa cells

Lanlan Fang1, Jung-Chien Cheng, Hsun-Ming Chang

  • 1PhD, FCAHS, FRSC, Department of Obstetrics and Gynaecology, Child and Family Research Institute, University of British Columbia, Room 317, 950 West 28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4. peter.leung@ubc.ca.

The Journal of Clinical Endocrinology and Metabolism
|October 5, 2013
PubMed
Abstract

Insights

Three growth factors, amphiregulin (AREG), betacellulin (BTC), and epiregulin (EREG), stimulate prostaglandin E2 (PGE2) production in human granulosa cells. This occurs by upregulating cyclooxygenase-2 (COX-2) expression via ERK1/2 signaling, offering insights into ovulation regulation.

Area of Science:

  • Reproductive Biology
  • Cell Signaling
  • Molecular Endocrinology

Background:

  • Aberrant ovulation regulation is a primary cause of infertility.
  • Epidermal growth factor (EGF)-like growth factors (AREG, BTC, EREG) influence ovulation in animal models by affecting cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2).
  • The role of AREG, BTC, and EREG in human ovulation remains largely uncharacterized.

Purpose of the Study:

  • To investigate the effects of AREG, BTC, and EREG on COX-2 expression and PGE2 production in human granulosa cells.
  • To elucidate the signaling pathways involved in these processes.

Main Methods:

  • Utilized immortalized human granulosa (SVOG) cells.
  • Assessed mRNA and protein levels using quantitative RT-PCR and Western blotting.
  • Measured PGE2 protein levels via ELISA.
  • Investigated the role of EGF receptor (EGFR) and ERK1/2 signaling.

Main Results:

  • Luteinizing hormone (LH) upregulated AREG, BTC, EREG, and COX-2 expression.
  • Knockdown of EGFR diminished LH-induced COX-2 and PGE2 production.
  • AREG, BTC, and EREG treatment increased COX-2 expression and PGE2 production.
  • EGFR inhibition blocked the stimulatory effects of AREG, BTC, and EREG.
  • ERK1/2 signaling, but not Akt signaling, was essential for AREG-, BTC-, and EREG-induced COX-2 expression and PGE2 production.

Conclusions:

  • AREG, BTC, and EREG stimulate prostaglandin E2 (PGE2) production in human granulosa cells.
  • This stimulation is mediated by the upregulation of cyclooxygenase-2 (COX-2) expression.
  • The process involves activation of the ERK1/2 signaling pathway, highlighting its role in human ovulation.

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