Estrogenic G protein-coupled receptor 30 signaling is involved in regulation of endometrial carcinoma by promoting proliferation, invasion potential, and interleukin-6 secretion via the MEK/ERK mitogen-activated protein kinase pathway

Cancer Sci. 2009 Jun;100(6):1051-61. doi: 10.1111/j.1349-7006.2009.01148.x. Epub 2009 Mar 9.


The regulatory mechanism of endometrial carcinoma and the signal transduction pathways involved in hormone action are poorly defined. It has become apparent that the G protein-coupled receptor (GPR) 30 mediates the non-genomic signaling of 17beta-estradiol (E2). Here we show that GPR30 is highly expressed in endometrial cancer tissues and cancer cell lines and positively regulates cell proliferation and invasion. GPR30 expression was detected in 50 human endometrial carcinomas. The transcription level of GPR30 was significantly higher in the tissue of endometrial carcinoma than in normal endometrium (P < 0.05). Immunohistochemical assays revealed that the positive expression rate of GPR30 protein in endometrial carcinoma tissue (35/50, 70%) was statistically higher than in normal endometrium tissue (8/30, 26.67%) (chi2 = 14.16, P = 0.0002). GPR30 overexpression was correlated with high-grade endometrial carcinoma. GPR30 expression was also found in two human endometrial cancer cell lines: RL95-2 (estrogen receptor positive) and KLE (estrogen receptor negative). The roles of GPR30 in proliferative and invasive responses to E2 and G1, a non-steroidal GPR30-specific agonist, in RL95-2 and KLE cell lines were then explored. We showed that E2 and G1 could initiate the MAPK/ERK mitogen-activated protein kinase pathway in both cell lines. What's more, E2 and G1 promoted KLE and RL95-2 proliferation and stimulated matrix metalloproteinase production and activity via the GPR30-mediated MEK/ERK mitogen-activated protein kinase pathway, as well as increased interleukin-6 secretion. These findings suggest that GPR30-mediated non-genomic signaling could play an important role in endometrial cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Division
  • Cell Line, Tumor
  • DNA Primers
  • Endometrial Neoplasms / enzymology
  • Endometrial Neoplasms / pathology*
  • Endometrium / pathology
  • Endometrium / physiology
  • Endometrium / physiopathology
  • Enzyme Activation
  • Enzyme-Linked Immunosorbent Assay
  • Estrogens / physiology*
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Female
  • Humans
  • Interleukin-6 / metabolism*
  • MAP Kinase Kinase 1 / metabolism*
  • Matrix Metalloproteinases / metabolism
  • Middle Aged
  • Neoplasm Invasiveness
  • Receptors, Estrogen / physiology*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction


  • DNA Primers
  • Estrogens
  • GPER1 protein, human
  • Interleukin-6
  • Receptors, Estrogen
  • Receptors, G-Protein-Coupled
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase 1
  • Matrix Metalloproteinases