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

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

  • Mol Ther Nucleic Acids. 2021 Apr 24;24:923-938. doi: 10.1016/j.omtn.2021.04.015.
Chunxiao Miao 1 2 Wanli Zhang 1 Lixing Feng 1 Xiaofan Gu 1 Qiang Shen 1 3 Shanshan Lu 1 Meng Fan 1 Yiwei Li 1 Xianling Guo 4 Yushui Ma 1 Xuan Liu 3 Hui Wang 4 Xiongwen Zhang 1
Affiliations

Affiliations

  • 1 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
  • 2 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 3 Institute of Interdisciplinary Integrative Biomedical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 4 Department of Oncology, The Tenth People's Hospital, Tongji University, Shanghai, China.
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.

Keywords

apoptosis; cancer cachexia; exosome; miRNA; skeletal muscle wasting.

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