Estrogen regulates Snail and Slug in the down-regulation of E-cadherin and induces metastatic potential of ovarian cancer cells through estrogen receptor alpha.
Tumorigenesis is a multistep process involving dysregulated cell growth and metastasis. Considerable evidence implicates a mitogenic action of estrogen in early ovarian carcinogenesis. In contrast, its influence in the metastatic cascade of ovarian tumor cells remains obscure. In the present study, we showed that 17beta-estradiol (E2) increased the metastatic potential of human epithelial ovarian cancer cell lines. E2 treatment led to clear morphological changes characteristic of epithelial-mesenchymal transition (EMT) and an enhanced cell migratory propensity. These morphological and functional alterations were associated with changes in the abundance of EMT-related genes. Upon E2 stimulation, expression and promoter activity of the epithelial marker E-cadherin were strikingly suppressed, whereas EMT-associated transcription factors, Snail and Slug, were significantly up-regulated. This up-regulation was attributed to the increase in gene transcription activated by E2. Depletion of endogenous Snail or Slug using small interfering RNA (siRNA) attenuated E2-mediated decrease in E-cadherin. In addition, E2-induced cell migration was also neutralized by the siRNAs, suggesting that both transcription factors are indispensable for the prometastatic actions of E2. More importantly, by using selective estrogen receptor (ER) agonists, forced expression, and siRNA approaches, we identified that E2 triggered the metastatic behaviors exclusively through an ERalpha-dependent pathway. We also showed that ERbeta had an opposing action on ERalpha because the presence of ERbeta completely inhibited the EMT and down-regulation of E-cadherin induced by ERalpha. Collectively, this study provides a compelling argument that estrogen can potentiate tumor progression by EMT induction and highlights the crucial role of ERalpha in ovarian tumorigenesis.
Department of Obstetrics and Gynecology, University of British Columbia, 2H-30, 4490 Oak Street, Vancouver, British Columbia, Canada V6H 3V5.
Se-Hyung
SH
Park
Lydia W T
LW
Cheung
Alice S T
AS
Wong
Peter C K
PC
Leung
D001483:Base Sequence; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000378:metabolism; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology / Q000556:secondary; D011401:Promoter Regions, Genetic / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D015820:Cadherins; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D034741:RNA, Small Interfering; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D004958:Estradiol