miR-450a Acts as a Tumor Suppressor in Ovarian Cancer by Regulating Energy Metabolism

• Published in: Cancer research (Chicago, Ill.) Vol. 79; no. 13; pp. 3294 - 3305
• Main Authors: Muys, Bruna Rodrigues, Sousa, Josane F, Plaça, Jessica Rodrigues, de Araújo, Luíza Ferreira, Sarshad, Aishe A, Anastasakis, Dimitrios G, Wang, Xiantao, Li, Xiao Ling, de Molfetta, Greice Andreotti, Ramão, Anelisa, Lal, Ashish, Vidal, Daniel Onofre, Hafner, Markus, Silva, Wilson A
• Format: Journal Article
• Language: English
• Published: United States 01.07.2019
• Subjects: Aconitate Hydratase - genetics; Aconitate Hydratase - metabolism; Animals; Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cell Cycle; Cell Movement; Cell Proliferation; Energy Metabolism; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Humans; Membrane Potential, Mitochondrial; Mice; Mice, Inbred NOD; Mice, SCID; MicroRNAs - genetics; Mitochondrial Membrane Transport Proteins - genetics; Mitochondrial Membrane Transport Proteins - metabolism; Mitochondrial Proton-Translocating ATPases - genetics; Mitochondrial Proton-Translocating ATPases - metabolism; NADH Dehydrogenase - genetics; NADH Dehydrogenase - metabolism; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Prognosis; Survival Rate; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-19-0490

Dysregulation of miRNA expression is associated with multiple diseases, including cancers, in which small RNAs can have either oncogenic or tumor suppressive functions. Here we investigated the potential tumor suppressive function of miR-450a, one of the most significantly downregulated miRNAs in ovarian cancer. RNA-seq analysis of the ovarian cancer cell line A2780 revealed that overexpression of miR-450a suppressed multiple genes involved in the epithelial-to-mesenchymal transition (EMT). Overexpression of miR-450a reduced tumor migration and invasion and increased anoikis in A2780 and SKOV-3 cell lines and reduced tumor growth in an ovarian tumor xenographic model. Combined AGO-PAR-CLIP and RNA-seq analysis identified a panel of potential miR-450a targets, of which many, including TIMMDC1, MT-ND2, ACO2, and ATP5B, regulate energetic metabolism. Following glutamine withdrawal, miR-450a overexpression decreased mitochondrial membrane potential but increased glucose uptake and viability, characteristics of less invasive ovarian cancer cell lines. In summary, we propose that miR-450a acts as a tumor suppressor in ovarian cancer cells by modulating targets associated with glutaminolysis, which leads to decreased production of lipids, amino acids, and nucleic acids, as well as inhibition of signaling pathways associated with EMT. SIGNIFICANCE: miR-450a limits the metastatic potential of ovarian cancer cells by targeting a set of mitochondrial mRNAs to reduce glycolysis and glutaminolysis. http://cancerres.aacrjournals.org/content/canres/79/13/3294/F1.large.jpg.