title: Ligand-independent androgen receptors promote ovarian teratocarcinoma cell growth by stimulating self-renewal of cancer stem/progenitor cells.
abstract: BACKGROUND
  Ovarian teratocarcinoma (OVTC) arises from germ cells and contains a high percentage of cancer stem/progenitor cells (CSPCs), which promote cancer development through their ability to self-renew. Androgen and androgen receptor (androgen/AR) signaling has been reported to participate in cancer stemness in some types of cancer; however, this phenomenon has never been studied in OVTC.
  
  
  METHODS
  Ovarian teratocarcinoma cell line PA1 was manipulated to overexpress or knockdown AR by lentiviral deliver system. After analyzing of AR expression in PA1 cells, cell growth assay was assessed at every given time point. In order to determine ligand effect on AR actions, luciferase assay was performed to evaluate endogenous and exogenous AR function in PA1 cells. CD133 stem cell marker antibody was used to identify CSPCs in PA1 cells, and AR expression level in enriched CSPCs was determined. To assess AR effects on CD133+ population progression, stem cell functional assays (side population, sphere formation assay, CD133 expression) were used to analyze role of AR in PA1 CSPCs. In tissue specimen, immunohistochemistry staining was used to carry out AR and CD133 staining in normal and tumor tissue.
  
  
  RESULTS
  We examined androgen/AR signaling in OVTC PA1 cells, a CSPCs-rich cell line, and found that AR, but not androgen, promoted cell growth. We also examined the effects of AR on CSPCs characteristics and found that AR expression was more abundant in CD133+ cells, a well-defined ovarian cancer stem/progenitor marker, than in CD133- populations. Moreover, results of the sphere formation assay revealed that AR expression was required to maintain CSPCs populations. Interestingly, this AR-governed self-renewal capacity of CSPCs was only observed in CD133+ cells. In addition, we found that AR-mediated CSPCs enrichment was accompanied by down-regulation of p53 and p16. Finally, co-expression of AR and CD133 was more abundant in OVTC lesions than in normal ovarian tissue.
  
  
  CONCLUSIONS
  The results of this study suggest that AR itself might play a ligand-independent role in the development of OVTC.
authors.affiliation: Sex Hormone Research Center, Graduate Institution of Clinical Medical Science, School of Medicine, China Medical University, Taichung 404, Taiwan; Sex Hormone Research Center, Department of Obstetrics and Gynecology, and Department of Pathology, China Medical University Hospital, Taichung 404, Taiwan.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Chung
authors.affiliation: Sex Hormone Research Center, Department of Obstetrics and Gynecology, and Department of Pathology, China Medical University Hospital, Taichung 404, Taiwan.
authors.forename: Wei-Chun
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Sex Hormone Research Center, Graduate Institution of Clinical Medical Science, School of Medicine, China Medical University, Taichung 404, Taiwan; Sex Hormone Research Center, Department of Obstetrics and Gynecology, and Department of Pathology, China Medical University Hospital, Taichung 404, Taiwan.
authors.forename: Lumin
authors.initials: L
authors.lastname: Chen
authors.affiliation: Sex Hormone Research Center, Department of Obstetrics and Gynecology, and Department of Pathology, China Medical University Hospital, Taichung 404, Taiwan.
authors.forename: Tze-Yi
authors.initials: TY
authors.lastname: Lin
authors.affiliation: Sex Hormone Research Center, Department of Obstetrics and Gynecology, and Department of Pathology, China Medical University Hospital, Taichung 404, Taiwan.
authors.forename: Liang-Chi
authors.initials: LC
authors.lastname: Chen
authors.affiliation: Sex Hormone Research Center, Graduate Institution of Clinical Medical Science, School of Medicine, China Medical University, Taichung 404, Taiwan; Sex Hormone Research Center, Department of Obstetrics and Gynecology, and Department of Pathology, China Medical University Hospital, Taichung 404, Taiwan. Electronic address: ych6375@gmail.com.
authors.forename: Yao-Ching
authors.initials: YC
authors.lastname: Hung
authors.affiliation: Sex Hormone Research Center, Graduate Institution of Clinical Medical Science, School of Medicine, China Medical University, Taichung 404, Taiwan; Sex Hormone Research Center, Department of Obstetrics and Gynecology, and Department of Pathology, China Medical University Hospital, Taichung 404, Taiwan. Electronic address: maverick@mail.cmu.edu.tw.
authors.forename: Wen-Lung
authors.initials: WL
authors.lastname: Ma
mesh_terms: D048708:Cell Growth Processes / Q000502:physiology; D015331:Cohort Studies; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008297:Male; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction; D018243:Teratocarcinoma / Q000378:metabolism* / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: C410798:AR protein, human; D008024:Ligands; D011944:Receptors, Androgen