Leptin receptor is induced in endometriosis and leptin stimulates the growth of endometriotic epithelial cells through the JAK2/STAT3 and ERK pathways

Mol Hum Reprod. 2013 Mar;19(3):160-8. doi: 10.1093/molehr/gas055. Epub 2012 Nov 25.

Abstract

Leptin acts as a potential growth stimulator in several normal and neoplastic cells. Recent studies have shown the presence of increased levels of leptin in the peritoneal fluid of patients with endometriosis, implicating leptin in the pathogenesis of endometriosis. However, the specific function of leptin in the induction of mitogenesis in endometriosis is not known. This study investigated the expression of the leptin receptor (ObR) in endometrioma tissues and immortalized endometriotic cells, and the effect of leptin on cell growth. ObR expression was higher in endometriomas than in the normal endometrium, and it was detected in 74% of epithelial and 30% of stromal endometrioma tissues. In addition, human endometriotic epithelial cells (11Z and 12Z) showed a high level of ObR when compared with endometrial cells and endometriotic stromal cells (22B). Furthermore, leptin treatment stimulated the growth of 11Z and 12Z cells, but not that of 22B cells. Knockdown of the ObR in 11Z and 12Z cells impaired the ability of leptin to induce cell growth. Leptin induced the activation of Janus Kinases 2 (JAK2), signal transducers and activators of transcription 3 (STAT3) and extracellular signal-regulated kinase (ERK) in endometriotic epithelial cells. Moreover, pretreatment with the JAK2/STAT3 inhibitor AG490 and the ERK inhibitor PD98059 significantly inhibited leptin-induced cell growth. The present results show that the ObR is induced in endometriosis, and that leptin stimulates the growth of endometriotic epithelial cells through the JAK2/STAT3 and ERK pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Endometriosis / metabolism*
  • Endometriosis / pathology
  • Endometrium / drug effects
  • Endometrium / metabolism
  • Endometrium / pathology
  • Enzyme Inhibitors / pharmacology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Female
  • Flavonoids / pharmacology
  • Gene Expression Regulation / drug effects
  • Humans
  • Janus Kinase 2 / genetics*
  • Janus Kinase 2 / metabolism
  • Leptin / metabolism
  • Leptin / pharmacology
  • MAP Kinase Signaling System / drug effects
  • Middle Aged
  • RNA, Small Interfering / genetics
  • Receptors, Leptin / agonists
  • Receptors, Leptin / genetics*
  • Receptors, Leptin / metabolism
  • STAT3 Transcription Factor / genetics*
  • STAT3 Transcription Factor / metabolism
  • Stromal Cells / drug effects
  • Stromal Cells / metabolism
  • Stromal Cells / pathology
  • Tyrphostins / pharmacology

Substances

  • Enzyme Inhibitors
  • Flavonoids
  • Leptin
  • RNA, Small Interfering
  • Receptors, Leptin
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Tyrphostins
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • JAK2 protein, human
  • Janus Kinase 2
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one