miR-410-3P inhibits adipocyte differentiation by targeting IRS-1 in cancer-associated cachexia patients

Abstract

Backgrounds: Cancer-associated cachexia (CAC) is a metabolic syndrome characterized by progressive depletion of adipose and muscle tissue that cannot be corrected by conventional nutritional therapy. Adipose tissue, an important form of energy storage, exhibits marked loss in the early stages of CAC, which affects quality of life and efficacy of chemotherapy. MicroRNAs (miRNAs) are a class of noncoding RNAs that widely exist in all kinds of eukaryotic cells and play regulatory roles in various biological processes. However, the role of miRNAs in adipose metabolism in CAC has rarely been reported. This study attempted to identify important miRNAs in adipose metabolism in CAC and explore their mechanism to identify a new predictive marker or therapeutic target for CAC-related adipose tissue loss (CAL). Methods: In this study, miRNA sequencing was firstly used to identify differentially expressed miRNAs related to CAL and the reliability of the conclusions was verified in large population samples. Furthermore, functional experiments were performed by up and down regulating miR-410-3p in adipocytes. The binding of miR-410-3p to Insulin Receptor Substrate 1 (IRS-1) was verified by Luciferase reporter assay and functional experiments of IRS-1 were performed in adipocytes. Finally, the expression of miR-410-3p in serum exosomes was detected. Results: miR-410-3p was selected as differentially expressed miRNA through screening and validation. Adipogenesis was suppressed in miR-410-3p upregulation experiment and increased in downregulation experiment. Luciferase reporter assay showed that miR-410-3p binds to 3′ non-coding region of IRS-1 and represses its expression and ultimately inhibits adipogenesis. miR-410-3p was highly expressed in serum exosomes of CAC patients, which was consistent with results in adipose tissue. Conclusions: The expression of miR-410-3p was higher in subcutaneous adipose tissues and serum exosomes of CAC patients, which significantly inhibits adipogenesis and lipid accumulation. The study shows that miR-410-3p could downregulate IRS-1 and downstream adipose differentiation factors including C/EBP-a and PPAR-γ by targeting 3′ noncoding region.