title: Activin A stimulates migration of the fallopian tube epithelium, an origin of high-grade serous ovarian cancer, through non-canonical signaling.
abstract: Factors that stimulate the migration of fallopian tube epithelial (FTE)-derived high-grade serous ovarian cancer (HGSOC) to the ovary are poorly elucidated. This study characterized the effect of the ovarian hormone, activin A, on normal FTE and HGSOC. Activin A and TGFβ1 induced an epithelial-to-mesenchymal transition in murine oviductal epithelial (MOE) cells, but only activin A increased migration. The migratory effect of activin A was independent of Smad2/3 and required phospho-AKT, phospho-ERK, and Rac1. Exogenous activin A stimulated migration of the HGSOC cell line OVCAR3 through a similar mechanism. Activin A signaling inhibitors, SB431542 and follistatin, reduced migration in OVCAR4 cells, which expressed activin A subunits (encoded by INHBA). Murine superovulation increased phospho-Smad2/3 immunostaining in the FTE. In Oncomine, transcripts for the activin A receptors (ACVR1B and ACVR2A) were higher in serous tumors relative to the normal ovary, while inhibitors of activin A signaling (INHA and TGFB3) were lower. High expression of both INHBA and ACVR2A, but not TGFβ receptors or co-receptors, was associated with shorter disease-free survival in serous cancer patients. These results suggest activin A stimulates migration of FTE-derived tumors to the ovary.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, Center for Biomolecular Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, 60607, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Dean
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, Center for Biomolecular Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, 60607, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Davis
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, Center for Biomolecular Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, 60607, USA. Electronic address: joannab@uic.edu.
authors.forename: Joanna E
authors.initials: JE
authors.lastname: Burdette
mesh_terms: D028341:Activins / Q000378:metabolism*; D000818:Animals; D002465:Cell Movement; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000473:pathology; D005185:Fallopian Tube Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction; D014162:Transfection
chemical_list: C422405:activin A; D028341:Activins
keywords: Activin; Fallopian tube; Ovarian cancer; Oviduct; Serous cancer