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

Author(s):Show less -

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]

Affiliation

^[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

• Document type: Journal article
• Source: FRONTIERS IN GENETICS; v. 11, MAY 29 2020.
• Web of Science Citations: 0

Abstract

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)

• FAPESP's process: 13/02005-0 - Reconstruction of gene regulation networks involved in cancer cachexia: integrating expression profiles of microRNAs and mRNA
• Grantee: Geysson Javier Fernandez Garcia
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• FAPESP's process: 12/13961-6 - Genomic profiling of messenger RNAs and microRNAs in muscle cells treated in vitro with TNF-alpha and IFN-gamma
• Grantee: Robson Francisco Carvalho
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/50343-1 - Genomic profiling of messenger RNAs and microRNAs in cancer cachexia
• Grantee: Robson Francisco Carvalho
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/08294-1 - Molecular mechanisms underlying TNF-induced and repression gene expression in cachexia
• Grantee: Geysson Javier Fernandez Garcia
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 14/13941-0 - Multilayer-omics analysis of cancer cachexia: integrative approach to identify biomarkers and drug targets
• Grantee: Geysson Javier Fernandez Garcia
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 11/16282-0 - Genomic Profiling of Messenger RNAs and MicroRNAs in muscle cells treated in vitro with TNF-alpha and IFN-gamma
• Grantee: Geysson Javier Fernandez Garcia
• Support Opportunities: Scholarships in Brazil - Master