Non-Genomic Estrogen/Estrogen Receptor α Promotes Cellular Malignancy of Immature Ovarian Teratoma In Vitro

Malignant immature ovarian teratomas (IOTs) most often occur in women of reproductive age. It is unclear, however, what roles estrogenic signaling plays in the development of IOT. In this study, we examined whether estrogen receptors (ER and ) promote the cellular malignancy of IOT. Estradiol (E2), PPT (propylpyrazole), and DPN (diarylpropionitrile) (ER- and -specific agonists, respectively), as well as ER- or ER-specific short hairpin (sh)RNA were applied to PA-1 cells, a well-characterized IOT cell line. Cellular tumorigenic characteristics, for example, cell migration/invasion, expression of the cancer stem/progenitor cell marker CD133, and evidence for epithelial-mesenchymal transition (EMT) were examined. In PA-1 cells that expressed ER and ER, we found that ER promoted cell migration and invasion. We also found that E2/ER signaling altered cell behavior through non-classical transactivation function. Our data show non-genomic E2/ER activations of focal adhesion kinase-Ras homolog gene family member A (FAK-RhoA) and ERK governed cell mobility capacity. Moreover, E2/ER signaling induces EMT and overexpression of CD133 through upregulation micro-RNA 21 (miR21; IOT stem/progenitor promoter), and ERK phosphorylations. Furthermore, E2/ER signaling triggers a positive feedback regulatory loop within miR21 and ERK. At last, expression levels of ER, CD133, and EMT markers in IOT tissue samples were examined by immunohistochemistry. We found that cytosolic ER was co-expressed with CD133 and mesenchymal cell markers but not epithelial cell markers. In conclusion, estrogenic signals exert malignant transformation capacity of cancer cells, exclusively through non-genomic regulation in female germ cell tumors. J. Cell. Physiol. 229: 752-761, 2014. (c) 2013 Wiley Periodicals, Inc.