Exosomal miR-155 from gastric cancer induces cancer-associated cachexia by suppressing adipogenesis and promoting brown adipose differentiation via C/EPBβ

Objective: The aim of this research was to identify whether exosomes were involved in impairing adipogenesis in cancer-associated cachexia(CAC) by detecting the adipodifferentiation capacity and the expressions of adipogenic proteins in gastric cancer(GC)-associated adipocytes.Methods: Western blotting and RT-PCR were used to investigate the expressions of C/EPBβ, C/EPBα, PPARγ, and UCP1 in adipose mesenchymal stem cells(A-MSCs) to evaluate the function of exosomal mi R-155. BALB/c nude mice were intravenously injected in vivo with GC exosomes with different levels of mi R-155 to determine changes in adipodifferentiation of A-MSCs.Results: Exosomes derived from GC cells suppressed adipogenesis in A-MSCs as characterized by decreased lipid droplets. Similarly, A-MSCs co-cultured with GC exosomes exhibited increased ATP production through brown adipose differentiation characterized by highly dense mitochondria and enhanced UCP1 expression(P < 0.05). Mechanistically, exosomal mi R-155 secreted from GC cells suppressed adipogenesis and promoted brown adipose differentiation by targeting C/EPBβ, accompanied by downregulated C/EPBα and PPARγ and upregulated UCP1(P < 0.05). Moreover, overexpression of mi R-155 in GC exosomes improved CAC in vivo, which was characterized by fat loss, suppressed expressions of C/EPBβ, C/EPBα, and PPARγ in A-MSCs, and high expression of UCP1(P < 0.05). Decreasing the level of mi R-155 in injected GC exosomes abrogated the improved CAC effects.Conclusions: GC exosomal mi R-155 suppressed adipogenesis and enhanced brown adipose differentiation in A-MSCs by targeting C/EPBβ of A-MSCs, which played a crucial role in CAC.