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

Authors

Geysson Javier Fernandez, Sao Paulo State University
Juarez Henrique Ferreira, Sao Paulo State University
Ivan Jose Vechetti Jr, University of Nebraska-LincolnFollow
Leonardo Nazario de Moraes, Sao Paulo State University
Sarah Santiloni Cury, Sao Paulo State University
Paula Paccielli Freire, Sao Paulo State University
Jayson Gutierrez, Ghent University
Renato Ferretti, Sao Paulo State University
Maeli Dal-Pai-Silva, Sao Paulo State University
Silvia Regina Rogatto, University of South Denmark
Robson Francisco Carvalho, Sao Paulo State University

Date of this Version

5-29-2020

Citation

Fernandez GJ, Ferreira JH, Vechetti IJ Jr, de Moraes LN, Cury SS, Freire PP, Gutiérrez J, Ferretti R, Dal-Pai-Silva M, Rogatto SR and Carvalho RF (2020) MicroRNA-mRNA Co-sequencing Identifies Transcriptional and Post-transcriptional Regulatory Networks Underlying Muscle Wasting in Cancer Cachexia. Front. Genet. 11:541. doi: 10.3389/fgene.2020.00541

Comments

OPEN ACCESS CC-BY

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-κB, 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.