AUTHOR=Fernandez Geysson Javier , Ferreira Juarez Henrique , Vechetti Ivan José , de Moraes Leonardo Nazario , Cury Sarah Santiloni , Freire Paula Paccielli , Gutiérrez Jayson , Ferretti Renato , Dal-Pai-Silva Maeli , Rogatto Silvia Regina , Carvalho Robson Francisco 

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

JOURNAL=Frontiers in Genetics

VOLUME=Volume 11 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2020.00541

DOI=10.3389/fgene.2020.00541

ISSN=1664-8021

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 tibialis anterior (TA) muscles of the Lewis lung carcinoma model of cancer cachexia. We found 1,008 mRNAs and 18 microRNAs differentially expressed in cachectic mice compared with controls. Although our transcriptomic analysis has demonstrated a high heterogeneity on mRNA profiles of cachectic mice, we identified a minimum number of differentially expressed genes that were uniformly regulated across cachectic muscles. This set of uniformly regulated genes is associated with the extracellular matrix (ECM), proteolysis, and inflammatory response. We also used the transcriptomic data to perform enrichment analysis of transcriptional factor binding sites in promoter sequences, which revealed activation of the atrophy-related transcriptional 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 FoxO signaling pathway. Our integrative analysis of microRNA-mRNA co-profiles comprehensive characterized regulatory relationships of molecular pathways and revealed microRNAs targeting ECM-associated genes in cancer cachexia.