title: Loss of PAX8 in high-grade serous ovarian cancer reduces cell survival despite unique modes of action in the fallopian tube and ovarian surface epithelium.
abstract: High-grade serous carcinoma (HGSC) is the most common and lethal form of ovarian cancer. PAX8 is a transcription factor expressed in fallopian tube epithelial cells and in 80-96% of HGSC tumors. The ovarian surface epithelium (OSE) only acquires PAX8 expression after malignant transformation. In this study, forced PAX8 expression in OSE cells increased proliferation and migration through upregulation of EMT factors such as N-cadherin and Fibronectin. OSE cells expressing PAX8 also had an increase in the FOXM1 pathway, but PAX8 alone was not sufficient to drive tumorigenesis. PAX8 knockdown in the oviductal epithelium cells did not decrease expression of the FOXM1 pathway and induced only a slight decrease in cell proliferation. No changes in migration, cell cycle, or apoptosis were detected after PAX8 knockdown in oviductal cells. Finally, PAX8 knockdown in HGSC cell lines resulted in increased apoptosis and decreased FOXM1 levels. The results presented here suggest that PAX8 has a cell specific role in governing proliferation and migration in nontransformed ovarian surface epithelium cells compared to the oviductal cells, but its reduction in serous cancer cell lines provides a common mechanism for reducing cell survival.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Laura H
authors.initials: LH
authors.lastname: Rodgers
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Eoghainín
authors.initials: E
authors.lastname: Ó hAinmhire
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Alexandria N
authors.initials: AN
authors.lastname: Young
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Joanna E
authors.initials: JE
authors.lastname: Burdette
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005187:Fallopian Tubes / Q000378:metabolism* / Q000473:pathology; D005260:Female; D000072278:Forkhead Box Protein M1 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008819:Mice, Nude; D060787:Neoplasm Grading; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010053:Ovary / Q000378:metabolism* / Q000473:pathology; D000072636:PAX8 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D000072636:PAX8 Transcription Factor; C083325:PAX8 protein, human; C499496:Pax8 protein, mouse
keywords: FOXM1; PAX8; fallopian tube; high grade serous carcinoma (HGSC); ovary