miR-30a inhibits endothelin A receptor and chemoresistance in ovarian carcinoma

Autor: Gabriella Ferrandina, Andrea Sacconi, Giovanni Blandino, Rosanna Sestito, Roberta Cianfrocca, Elisa Semprucci, Laura Rosanò, Anna Bagnato, Valeriana Di Castro, Piera Tocci, Valentina Caprara
Jazyk: angličtina
Rok vydání: 2015
Předmět:
0301 basic medicine
endocrine system diseases
Blotting
Western
Mice
Nude
Apoptosis
Enzyme-Linked Immunosorbent Assay
Biology
Real-Time Polymerase Chain Reaction
Immunoenzyme Techniques
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Cell Movement
microRNA
Tumor Cells
Cultured
Animals
Humans
RNA
Messenger
Receptor
Protein kinase B
endothelin A receptor
Cell Proliferation
Ovarian Neoplasms
Cell growth
Reverse Transcriptase Polymerase Chain Reaction
chemoresistance
Receptor
Endothelin A
Xenograft Model Antitumor Assays
Vascular endothelial growth factor
ovarian carcinoma
MicroRNAs
030104 developmental biology
Oncology
chemistry
Drug Resistance
Neoplasm
030220 oncology & carcinogenesis
Mitogen-activated protein kinase
Immunology
endothelin-1
Cancer research
biology.protein
Ectopic expression
Female
miR-30a
Signal transduction
Research Paper
Zdroj: Oncotarget
ResearcherID
ISSN: 1949-2553
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: