Cancer-derived exosome miRNAs induce skeletal muscle wasting by Bcl-2-mediated apoptosis in colon cancer cachexia
| Autor: | Xianling Guo, Xiaofan Gu, Qiang Shen, Meng Fan, Xiongwen Zhang, Chunxiao Miao, Shanshan Lu, Wanli Zhang, Hui Wang, Yu-Shui Ma, Lixing Feng, Xuan Liu, Yiwei Li |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
RM1-950 Exosome Cachexia 03 medical and health sciences 0302 clinical medicine Drug Discovery medicine Myocyte exosome miRNA Chemistry Myogenesis apoptosis Skeletal muscle medicine.disease musculoskeletal system Muscle atrophy 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer research Molecular Medicine Apoptotic signaling pathway Original Article skeletal muscle wasting Therapeutics. Pharmacology medicine.symptom C2C12 cancer cachexia |
| Zdroj: | Molecular Therapy. Nucleic Acids Molecular Therapy: Nucleic Acids, Vol 24, Iss, Pp 923-938 (2021) |
| ISSN: | 2162-2531 |
| Popis: | 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. Graphical abstract Zhang and colleagues report that C26 exosome/miR-125b-1-3p/miR-195a-5p mediates skeletal muscle wasting via inhibition of the target gene bcl2 and the apoptosis pathway during cancer cachexia. Their work implies that inhibition of C26 exosomes/miRNA and the apoptosis pathway is a novel approach to counteract muscle wasting induced by colon cancer cachexia. |
| Databáze: | OpenAIRE |
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