Induction of the LRP16 gene by estrogen promotes the invasive growth of Ishikawa human endometrial cancer cells through the downregulation of E-cadherin.
LRP16 was previously identified as an estrogen-induced gene in breast cancer cells. The responsiveness of LRP16 to estrogen and its functional effects in endometrial cancer (EC) cells are still unclear. Here, we show that the mRNA level and promoter activity of the LRP16 gene were significantly increased by 17beta-estradiol (E2) in estrogen receptor alpha (ER alpha)-positive Ishikawa human EC cells. Although the growth rate of Ishikawa cells was not obviously affected by ectopic expression of LRP16, the results of a Transwell assay showed an approximate one-third increase of the invasive capacity of LRP16-overexpressing cells. As a result of molecular screening, we observed that the expression of E-cadherin, an essential adhesion molecule associated with tumor metastasis, was repressed by LRP16. Further promoter analyses demonstrated that LRP16 inhibited E-cadherin transactivation in a dose-dependent manner. However, the inhibition was abolished by estrogen deprivation, indicating that the downregulation of E-cadherin transcription by LRP16 requires ER alpha mediation. Chromatin immunoprecipitation analyses revealed that the binding of ER alpha to the E-cadherin promoter was antagonized by LRP16, suggesting that LRP16 could interfere with ER alpha-mediated transcription. These results suggest that the upregulation of LRP16 by estrogen could be involved in invasive growth by downregulating E-cadherin in human ECs.
Meng
Yuan Guang
YG
Department of Obstetrics and Gynecology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, China.
Han
Wei Dong
WD
Zhao
Ya Li
YL
Huang
Ke
K
Si
Yi Ling
YL
Wu
Zhi Qiang
ZQ
Mu
Yi Ming
YM
D015152:Blotting, Northern; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding
D015820:Cadherins; D047628:Estrogen Receptor alpha; D004967:Estrogens; D009363:Neoplasm Proteins; D004958:Estradiol; D002265:Carboxylic Ester Hydrolases; C476832:MACROD1 protein, human