Cancer-derived exosome miRNAs induce skeletal muscle wasting by Bcl-2-mediated apoptosis in colon cancer cachexia

Abstract

Cancer cachexia is a kind of whole-body metabolic disorder syndrome accompanied by severe wasting of muscle tissue in which cancer exosomes may be involved. Analysis of clinical samples showed that the serum exosome concentrations were correlated with the development of cancer cachexia. Exosomes secreted by C26 cells could decrease the diameter of C2C12 myotubes in vitro and decrease mouse muscle strength and tibialis anterior (TA) muscle weight in vivo . GW4869, an inhibitor of exosome excretion, ameliorated muscle wasting in C26 tumor-bearing mice. MicroRNA (miRNA) sequencing (miRNA-seq) analysis suggested that miR-195a-5p and miR-125b-1-3p were richer in C26 exosomes than in exosomes secreted from MC38 cells (non-cachexic). Both miR-195a-5p and miR-125b-1-3p mimics could induce atrophy of C2C12 myoblasts. Downregulation of Bcl-2 and activation of the apoptotic signaling pathway were observed in C2C12 myoblasts transfected with miR-195a-5p and miR-125b-1-3p mimics, in the gastrocnemius muscle of C26 tumor-bearing mice and in the TA muscle injected with C26 exosomes. Results of dual-luciferase assay confirmed the targeting of miR-195a-5p/miR-125b-1-3p to Bcl-2. Overexpression of Bcl-2 successfully reversed atrophy of C2C12 myoblasts induced by the two miRNA mimics. These results suggested that cancer exosome enriched miRNAs might induce muscle atrophy by targeting Bcl-2-mediated apoptosis.

The Overexpression of TOB1 Induces Autophagy in Gastric Cancer Cells by Secreting Exosomes

“…Exosome-derived miR-452-5p can be used for noninvasive diagnosis and treatment monitoring of esophageal adenocarcinoma [ 64 ]. miR-125b-1-3p plays an antitumor role in lung cancer [ 65 ], while exosome-derived miR-125b-1-3p is an active component that mediates skeletal muscle atrophy during cancer cachexia [ 66 ]. In addition, miR-125b-1-3p [ 67 ], miR-146a-5p [ 68 ], miR-3615 [ 69 ], and miR-12136 [ 70 ] can also be used as noninvasive biomarkers of cancer.…”

Cancer-Associated Fibroblasts Influence the Biological Properties of Malignant Tumours via Paracrine Secretion and Exosome Production

“…However, non-coding RNAs seem to be critically important in the regulation of the metabolic changes leading to cachexia [163]. Mechanistically, skeletal muscle wasting as part of tumour-related cachexia in an animal model is associated with the presence of miR-125b-1-3P in the exosomes [164]. Similarly, structural and functional changes of white adipose tissue were observed in cachectic patients.…”

GDF-15 in tumor-derived exosomes promotes muscle atrophy via Bcl-2/caspase-3 pathway

“…Exosomes had been reported to be involved in the progression of cancer cachexia [ 6 , 7 ]. Exosomes are now considered as an integral part of the intercellular microenvironment and may act as regulators of cell-to-cell communication [ 8 ].…”

“…Cargos in exosomes contain functional nucleic acids as well as proteins which can be absorbed and influence the biological functions of recipient cells [ 9 – 12 ]. Previous studies showed that IL-6, HSP70/90 and miRNAs in cancer exosomes could participate in triggering muscle degradation [ 6 , 13 – 16 ], emphasizing the important roles of cancer exosomes in the development of cancer cachexia. In our previous study, we also found that miR-195a-5p and miR-125b-1-3p in exosomes of C26 colon tumor cells could induce muscle atrophy by apoptosis [ 6 ].…”

“…Previous studies showed that IL-6, HSP70/90 and miRNAs in cancer exosomes could participate in triggering muscle degradation [ 6 , 13 – 16 ], emphasizing the important roles of cancer exosomes in the development of cancer cachexia. In our previous study, we also found that miR-195a-5p and miR-125b-1-3p in exosomes of C26 colon tumor cells could induce muscle atrophy by apoptosis [ 6 ]. However, the roles of proteins in tumor-derived exosomes in the development of muscle atrophy in cancer cachexia have not been fully clarified.…”