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

Author(s):Show less -

Muys, Bruna Rodrigues ^{[1, 2, 3, 4, 5]} ; Sousa, Josane F. ^{[1, 2, 3, 6]} ; Placa, Jessica Rodrigues ^{[1, 2, 3]} ; de Araujo, Luiza Ferreira ^{[1, 2, 3, 7]} ; Sarshad, Aishe A. ^[4] ; Anastasakis, Dimitrios G. ^[4] ; Wang, Xiantao ^[4] ; Li, Xiao Ling ^[5] ; de Molfetta, Greice Andreotti ^{[1, 2, 3]} ; Ramao, Anelisa ^{[2, 3]} ; Lal, Ashish ^[5] ; Vidal, Daniel Onofre ^[8] ; Hafner, Markus ^[4] ; Silva, Wilson A. ^{[1, 2, 3]}

Affiliation

^[1] Ctr Integrat Syst Biol CISBi NAP USP, Ctr Med Genom HCFMRP USP, Ribeirao Preto - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Genet, Ave Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP - Brazil

^[3] Nat Inst Sci & Technol Stem Cell & Cell Therapy I, Reg Blood Ctr Ribeirao Preto, Ctr Cell Based Therapy CEPID FAPESP, Ribeirao Preto - Brazil

^[4] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, Bethesda, MD 20892 - USA

^[5] NCI, Regulatory RNAs & Canc Sect, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 - USA

^[6] Fed Univ Para UFPA, Inst Biol Sci, Genet & Mol Biol Program, Belem, Para - Brazil

^[7] AC Camargo Canc Ctr, Med Genom Lab, Sao Paulo - Brazil

^[8] Barretos Canc Hosp, Mol Oncol Res Ctr, Barretos - Brazil

• Document type: Journal article
• Source: Cancer Research; v. 79, n. 13, p. 3294-3305, JUL 1 2019.
• Web of Science Citations: 3

Abstract

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. (AU)

• FAPESP's process: 16/22307-9 - Screening miR-450a and miR-450b targets in ovarian carcinoma cell lines A2780 and SKOV-3 by PAR-CLIP
• Grantee: Bruna Rodrigues Muys
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 13/08135-2 - CTC - Center for Cell-Based Therapy
• Grantee: Dimas Tadeu Covas
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 09/53853-5 - Acquisition of a high-performance platform for computational analyses applied to the field of medicine
• Grantee: Wilson Araújo da Silva Junior
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 13/25119-0 - Energetic metabolism study on melanoma progression based on mitochondrial genome instability
• Grantee: Luíza Ferreira de Araújo
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 13/25326-6 - Functional study of microRNAs miR-450a and miR-450b-5p in tumorigenesis
• Grantee: Bruna Rodrigues Muys
• Support Opportunities: Scholarships in Brazil - Doctorate