Small RNAome profiling from human skeletal muscle: novel miRNAs and their targets associated with cancer cachexia

Abstract

BackgroundMicroRNAs (miRs) are small non‐coding RNAs that regulate gene (mRNA) expression. Although the pathological role of miRs have been studied in muscle wasting conditions such as myotonic and muscular dystrophy, their roles in cancer cachexia (CC) are still emerging.ObjectivesThe objectives are (i) to profile human skeletal muscle expressed miRs; (ii) to identify differentially expressed (DE) miRs between cachectic and non‐cachectic cancer patients; (iii) to identify mRNA targets for the DE miRs to gain mechanistic insights; and (iv) to investigate if miRs show potential prognostic and predictive value.MethodsStudy subjects were classified based on the international consensus diagnostic criteria for CC. Forty‐two cancer patients were included, of which 22 were cachectic cases and 20 were non‐cachectic cancer controls. Total RNA isolated from muscle biopsies were subjected to next‐generation sequencing.ResultsA total of 777 miRs were profiled, and 82 miRs with read counts of ≥5 in 80% of samples were retained for analysis. We identified eight DE miRs (up‐regulated, fold change of ≥1.4 at P < 0.05). A total of 191 potential mRNA targets were identified for the DE miRs using previously described human skeletal muscle mRNA expression data (n = 90), and a majority of them were also confirmed in an independent mRNA transcriptome dataset. Ingenuity pathway analysis identified pathways related to myogenesis and inflammation. qRT‐PCR analysis of representative miRs showed similar direction of effect (P < 0.05), as observed in next‐generation sequencing. The identified miRs also showed prognostic and predictive value.ConclusionsIn all, we identified eight novel miRs associated with CC.

Retracted: Exosomal circRNA derived from gastric tumor promotes white adipose browning by targeting the miR‐133/PRDM16 pathway

“…It has been reported that tumors cause muscle wasting by releasing Hsp70 and Hsp90, but the complex molecular mechanism involved in cancer‐associated cachexia is far from fully understood . microRNAs have been found to be involved in each stage of cancer, including cancer cachexia . A recent article published in Nature demonstrated that adipose‐derived exosomes regulate gene expression in other tissues, implying that exosomes are important carriers that mediate signaling transduction between adipocytes and target organs …”

MicroRNAs in muscle wasting

“…4 MyomiRs comprise a group of miRs, who display an enriched expression in skeletal muscle including miR-1, miR-133a, miR-133b, miR-206, miR-208, miR-208b, miR-486, and miR-499. 9 In a rat model of paralysed muscle by spinal cord injury, a down-regulation of miRs 23a, 23b, 27b, 145, and 206 was observed 56 days after injury, 10 while injection of 30 μg of mir-206 attenuated muscle loss in a rat denervation model. 5 The expression of MyomiRs is modulated in skeletal muscle growth, its development and maintenance, and during atrophy.…”

“…8 In contrast to healthy adaptation, not only myomiRs are regulated in cancer cachexia, a recent publication showed an up-regulation of hsa-miR-3184-3p, hsa-miR-423-5p, hsa-let-7d-3p, hsa-miR-1296-5p, hsa-miR-345-5p, hsa-miR-532-5p, hsa-miR-423-3p, and hsa-miR-199a-3p, but no down-regulation of miRs in skeletal muscle biopsies of patients with pancreatic and colorectal cancer ( Table 1). 9 In a rat model of paralysed muscle by spinal cord injury, a down-regulation of miRs 23a, 23b, 27b, 145, and 206 was observed 56 days after injury, 10 while injection of 30 μg of mir-206 attenuated muscle loss in a rat denervation model. 11 In patients with chronic obstructive pulmonary disease (COPD), an up-regulation of miR-542-3p/5p in quadricep muscle has been described, which caused muscle wasting and reduced mitochondrial function when overexpressed in mice possibly due to a suppression of the mitochondrial ribosomal protein MRPS10, reduced 12S ribosomal RNA expression, and increased TGF-b signalling.…”

Non-coding RNAs as Putative Biomarkers of Cancer-Associated Cachexia

“…Interestingly, Narasimhan et al (2017) analyzed miRNAs expression of human skeletal muscle in cachectic and noncachectic pancreatic and colorectal cancer patients and identified 8 novel deregulated miRNAs: miR-3184-3p, miR-423-5p, let-7d-3p, miR-1296-5p, miR-345-5p, miR-532-5p, miR-423-3p, and miR-199a-3p. These miRNAs resulted to be up-regulated in skeletal muscle of cachectic patients, and pathway analysis of their potential mRNA targets identified pathways related to myogenesis and inflammation (Narasimhan et al, 2017).…”