title: miR-30a inhibits endothelin A receptor and chemoresistance in ovarian carcinoma.
abstract: Drug resistance remains the major clinical barrier to successful treatment in epithelial ovarian carcinoma (EOC) patients, and the evidence of microRNA involvement in drug resistance has been recently emerging. Endothelin-1 (ET-1)/ETA receptor (ETAR) axis is aberrantly activated in chemoresistant EOC cells and elicits pleiotropic effects promoting epithelial-to-mesenchymal transition (EMT) and the acquisition of chemoresistance. However, the relationship between ETAR and miRNA is still unknown. Hence, in this study we evaluated whether dysregulation of miRNA might enhance ETAR expression in sensitive and resistant EOC cells. Based on bioinformatic tools, we selected putative miRNA able to recognize the 3'UTR of ETAR. An inverse correlation was observed between the expression levels of miR-30a and ETAR in both EOC cell lines and tumor samples. miR-30a was found to specifically bind to the 3'UTR of ETAR mRNA, indicating that ETAR is a direct target of miR-30a. Overexpression of miR-30a decreased Akt and mitogen activated protein kinase signaling pathway activation, cell proliferation, invasion, plasticity, EMT marker levels, and vascular endothelial growth factor release. Interestingly, ectopic expression of miR-30a re-sensitized platinum-resistant EOC cells to cisplatinum-induced apoptosis. Consistently, resistant EOC xenografts overexpressing miR-30a resulted in significantly less tumor growth than controls. Together our study provides a new perspective on the regulatory mechanism of ETAR gene. Interestingly, our findings highlight that blockade of ETAR regulatory axis is the mechanism underlying the tumor suppressor function of miR-30a in chemoresistant EOC cells.
authors.affiliation: Translational Research Functional Departmental Area, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Sestito
authors.affiliation: Translational Research Functional Departmental Area, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Cianfrocca
authors.affiliation: Translational Research Functional Departmental Area, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Rosanò
authors.affiliation: Translational Research Functional Departmental Area, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Piera
authors.initials: P
authors.lastname: Tocci
authors.affiliation: Translational Research Functional Departmental Area, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Semprucci
authors.affiliation: Translational Research Functional Departmental Area, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Valeriana
authors.initials: V
authors.lastname: Di Castro
authors.affiliation: Translational Research Functional Departmental Area, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Caprara
authors.affiliation: Gynecologic Oncology Unit, Catholic University of Rome, Rome, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Ferrandina
authors.affiliation: Translational Oncogenomic Unit, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sacconi
authors.affiliation: Translational Oncogenomic Unit, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Blandino
authors.affiliation: Translational Research Functional Departmental Area, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Bagnato
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D044022:Receptor, Endothelin A / Q000737:chemistry* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C546086:MIRN30b microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D044022:Receptor, Endothelin A
keywords: chemoresistance; endothelin A receptor; endothelin-1; miR-30a; ovarian carcinoma