MicroRNA-mRNA Co-sequencing Identifies Transcriptional and Post-transcriptional Regulatory Networks Underlying Muscle Wasting in Cancer Cachexia

Autor(es):Mostrar menos -

Fernandez, Geysson Javier ^{[1, 2]} ; Ferreira, Juarez Henrique ^[2] ; Vechetti Jr, Ivan Jose ; de Moraes, Leonardo Nazario ^[3] ; Cury, Sarah Santiloni ^[3] ; Freire, Paula Paccielli ^[3] ; Gutierrez, Jayson ^[4] ; Ferretti, Renato ^[3] ; Dal-Pai-Silva, Maeli ^[3] ; Rogatto, Silvia Regina ^[5] ; Carvalho, Robson Francisco ^[3]

Afiliação do(s) autor(es)

^[1] Univ Antioquia, Fac Med, Medellin - Colombia

^[2] Sao Paulo State Univ, Inst Biosci, Dept Struct & Funct Biol, Botucatu, SP - Brazil

^[3] Vechetti Jr, Jr., Ivan Jose, Sao Paulo State Univ, Inst Biosci, Dept Struct & Funct Biol, Botucatu, SP - Brazil

^[4] Univ Ghent, Dept Plant Biotechnol & Bioinformat, Ghent - Belgium

^[5] Univ Southern Denmark, Dept Clin Genet, Univ Hosp Southern Denmark, Inst Reg Hlth Res, Odense - Denmark

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN GENETICS; v. 11, MAY 29 2020.
• Citações Web of Science: 0

Resumo

Cancer cachexia is a metabolic syndrome with alterations in gene regulatory networks that consequently lead to skeletal muscle wasting. Integrating microRNAs-mRNAs omics profiles offers an opportunity to understand transcriptional and post-transcriptional regulatory networks underlying muscle wasting. Here, we used RNA sequencing to simultaneously integrate and explore microRNAs and mRNAs expression profiles in the tibialis anterior (TA) muscles of the Lewis Lung Carcinoma (LLC) model of cancer cachexia. We found 1,008 mRNAs and 18 microRNAs differentially expressed in cachectic mice compared with controls. Although our transcriptomic analysis demonstrated a high heterogeneity in mRNA profiles of cachectic mice, we identified a reduced number of differentially expressed genes that were uniformly regulated within cachectic muscles. This set of uniformly regulated genes is associated with the extracellular matrix (ECM), proteolysis, and inflammatory response. We also used transcriptomic data to perform enrichment analysis of transcriptional factor binding sites in promoter sequences, which revealed activation of the atrophy-related transcription factors NF-kappa B, Stat3, AP-1, and FoxO. Furthermore, the integration of mRNA and microRNA expression profiles identified post-transcriptional regulation by microRNAs of genes involved in ECM organization, cell migration, transcription factors binding, ion transport, and the FoxO signaling pathway. Our integrative analysis of microRNA-mRNA co-profiles comprehensively characterized regulatory relationships of molecular pathways and revealed microRNAs targeting ECM-associated genes in cancer cachexia. (AU)

• Processo FAPESP: 13/02005-0 - Integração do perfil de expressão de microRNAs e mRNAs para reconstrução de redes de regulação gênica envolvidas na caquexia
• Beneficiário: Geysson Javier Fernandez Garcia
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Mestrado
• Processo FAPESP: 12/13961-6 - Perfil genômico de RNAs mensageiros e microRNAs em células musculares esqueléticas tratadas in vitro com TNF-alfa e IFN-gama
• Beneficiário: Robson Francisco Carvalho
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/50343-1 - Genomic profiling of messenger RNAs and microRNAs in cancer cachexia
• Beneficiário: Robson Francisco Carvalho
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/08294-1 - Mecanismos moleculares subjacentes à indução e repressão da expressão gênica mediada pelo TNF na caquexia
• Beneficiário: Geysson Javier Fernandez Garcia
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
• Processo FAPESP: 14/13941-0 - Análises "omics" na caquexia associada ao câncer: uma abordagem integrativa para identificação de biomarcadores e alvos de drogas
• Beneficiário: Geysson Javier Fernandez Garcia
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 11/16282-0 - Perfil genômico de RNAs mensageiros e microRNAs em células musculares esqueléticas tratadas in vitro com TNF-aplha e IFN-gamma
• Beneficiário: Geysson Javier Fernandez Garcia
• Modalidade de apoio: Bolsas no Brasil - Mestrado