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

Autor(es):Mostrar menos -

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]}

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: Cancer Research; v. 79, n. 13, p. 3294-3305, JUL 1 2019.
• Citações Web of Science: 0

Resumo

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)

• Processo FAPESP: 13/25326-6 - Estudo funcional dos microRNAs miR-450a e miR-450b-5p na tumorigênese
• Beneficiário: Bruna Rodrigues Muys
• Linha de fomento: Bolsas no Brasil - Doutorado
• Processo FAPESP: 13/25119-0 - Estudo do metabolismo energético na progressão do melanoma com base na instabilidade do genoma mitocondrial
• Beneficiário: Luíza Ferreira de Araújo
• Linha de fomento: Bolsas no Brasil - Doutorado
• Processo FAPESP: 09/53853-5 - Aquisição de uma plataforma de alta performance para análises computacionais aplicadas à medicina
• Beneficiário: Wilson Araújo da Silva Junior
• Linha de fomento: Auxílio à Pesquisa - Programa Equipamentos Multiusuários
• Processo FAPESP: 16/22307-9 - Busca de alvos dos microRNAs miR-450a e miR-450b, pelo método PAR-CLIP, nas linhagens de carcinoma de ovário A2780 e SKOV-3
• Beneficiário: Bruna Rodrigues Muys
• Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
• Processo FAPESP: 13/08135-2 - CTC - Centro de Terapia Celular
• Beneficiário: Dimas Tadeu Covas
• Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs