Prostaglandin F-induced Prostate Transmembrane Protein, Androgen Induced 1 mediates ovarian cancer progression increasing epithelial plasticity
Authors: María-Laura García-Bermejo
Konstantinos Stamatakis
Gema Moreno-Bueno
Pilar Sandoval
Manuel Fresno
Angela Rynne-Vidal
Lukas J A C Hawinkels
Alba Jiménez-Segovia
Alejandro Rojo-Sebastián
Beatriz Barrocal
Manuel López-Cabrera
Raquel Gómez-Bris
Alba Mota
Ramon Garcia-Escudero
Journal: Neoplasia (2019)
Discipline: CLINICAL MEDICINE
Keywords: prostaglandin F2α; ovarian cancer; PMEPA1; cell plasticity; proliferation
Affiliations: Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), c/ Nicolás Cabrera, 1, Campus Cantoblanco, Universidad Autónoma de Madrid, Madrid 28049, Spain., Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), IdiPaz, Madrid, Spain; MD Anderson Cancer Center Madrid & Fundación MD Anderson Internacional, Madrid, Spain., MD Anderson Cancer Center Madrid & Fundación MD Anderson Internacional, Madrid, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain., Biomarkers and Therapeutic Targets Lab, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain., Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands., Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain; Molecular Oncology Unit, CIEMAT, Madrid, Spain; Biomedical Research Institute I+12, University Hospital 12 de Octubre, Madrid 28041, Spain., Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), IdiPaz, Madrid, Spain; MD Anderson Cancer Center Madrid & Fundación MD Anderson Internacional, Madrid, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain., Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), c/ Nicolás Cabrera, 1, Campus Cantoblanco, Universidad Autónoma de Madrid, Madrid 28049, Spain; Instituto de Investigación Sanitaria Hospital Universitario de la Princesa (IIS-P), Madrid, Spain. Electronic address: .

Abstract:  The role of prostaglandin (PG) F2α has been scarcely studied in cancer. We have identified a new function for PGF2α in ovarian cancer, stimulating the production of Prostate Transmembrane Protein, Androgen Induced 1 (PMEPA1). We show that this induction increases cell plasticity and proliferation, enhancing tumor growth through PMEPA1. Thus, PMEPA1 overexpression in ovarian carcinoma cells, significantly increased cell proliferation rates, whereas PMEPA1 silencing decreased proliferation. In addition, PMEPA1 overexpression buffered TGFβ signaling, via reduction of SMAD-dependent signaling. PMEPA1 overexpressing cells acquired an epithelial morphology, associated with higher E-cadherin expression levels while β-catenin nuclear translocation was inhibited. Notwithstanding, high PMEPA1 levels also correlated with epithelial to mesenchymal transition markers, such as vimentin and ZEB1, allowing the cells to take advantage of both epithelial and mesenchymal characteristics, gaining in cell plasticity and adaptability. Interestingly, in mouse xenografts, PMEPA1 overexpressing ovarian cells had a clear survival and proliferative advantage, resulting in higher metastatic capacity, while PMEPA1 silencing had the opposite effect. Furthermore, high PMEPA1 expression in a cohort of advanced ovarian cancer patients was observed, correlating with E-cadherin expression. Most importantly, high PMEPA1 mRNA levels were associated with lower patient survival. 

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