title: Non-genomic estrogen/estrogen receptor α promotes cellular malignancy of immature ovarian teratoma in vitro.
abstract: 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 (ERα and β) promote the cellular malignancy of IOT. Estradiol (E2), PPT (propylpyrazole), and DPN (diarylpropionitrile) (ERα- and β-specific agonists, respectively), as well as ERα- or ERβ-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 ERα and ERβ, we found that ERα promoted cell migration and invasion. We also found that E2/ERα signaling altered cell behavior through non-classical transactivation function. Our data show non-genomic E2/ERα activations of focal adhesion kinase-Ras homolog gene family member A (FAK-RhoA) and ERK governed cell mobility capacity. Moreover, E2/ERα signaling induces EMT and overexpression of CD133 through upregulation micro-RNA 21 (miR21; IOT stem/progenitor promoter), and ERK phosphorylations. Furthermore, E2/ERα signaling triggers a positive feedback regulatory loop within miR21 and ERK. At last, expression levels of ERα, CD133, and EMT markers in IOT tissue samples were examined by immunohistochemistry. We found that cytosolic ERα 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.
authors.affiliation: Sex Hormone Research Center, Department of Obstetric and Gynecology, China Medical University Hospital, Taichung, Taiwan; Department of Pathology, China Medical University Hospital, Taichung, Taiwan; Graduate Institution of Clinical Medical Science, School of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Yao-Ching
authors.initials: YC
authors.lastname: Hung
authors.forename: Wei-Chun
authors.initials: WC
authors.lastname: Chang
authors.forename: Lu-Min
authors.initials: LM
authors.lastname: Chen
authors.forename: Ying-Yi
authors.initials: YY
authors.lastname: Chang
authors.forename: Ling-Yu
authors.initials: LY
authors.lastname: Wu
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Chung
authors.forename: Tze-Yi
authors.initials: TY
authors.lastname: Lin
authors.forename: Liang-Chi
authors.initials: LC
authors.lastname: Chen
authors.forename: Wen-Lung
authors.initials: WL
authors.lastname: Ma
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D013724:Teratoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D046509:Tissue Culture Techniques; D014410:Tumor Stem Cell Assay
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D000077267:Fulvestrant; D004958:Estradiol; D048049:Extracellular Signal-Regulated MAP Kinases