Human mesenchymal stem cell-derived miR-3614-5p exosomes suppress progression of colorectal cancer by targeting IL7Rα.

BACKGROUND

Colorectal cancer (CRC) represents a growing global health burden, particularly in developing countries. Mesenchymal stem cells (MSCs) have been reported to suppress tumor progression partly through the release of exosomes that deliver therapeutic molecules. However, the therapeutic potential of engineered MSC-derived exosomal microRNAs (Exo-miRNAs) in CRC remains largely unexplored.

METHODS

Plasma exosome miRNA sequencing was performed to identify dysregulated miRNAs in CRC. Gain- and loss-of-function assays were conducted to evaluate the biological effects of candidate miRNAs in CRC cells. Human mesenchymal stem cells (hMSCs) were engineered to overexpress miR-3614-5p via Lipofectamine-mediated transfection, and exosomes enriched with miR-3614-5p were isolated and characterized. The effects of engineered hMSC-derived exosomal miR-3614-5p (Exo-miR-3614-5p) on CRC progression were assessed both in vitro and in vivo. Mechanistic studies were performed to identify downstream targets and signaling pathways.

RESULTS

miR-3614-5p was identified as a therapeutic miRNA that was significantly downregulated in CRC. Engineered hMSCs efficiently loaded miR-3614-5p into secreted exosomes. Treatment with Exo-miR-3614-5p markedly suppressed CRC cell proliferation in vitro and inhibited tumor growth in vivo. Mechanistically, miR-3614-5p directly bound to the 3' untranslated region (3'UTR) of IL7Rα, resulting in translational repression and subsequent inactivation of the JAK2/STAT3 signaling pathway. In addition, miR-3614-5p exhibited potential diagnostic value for CRC.

CONCLUSIONS

This study demonstrates that engineered hMSC-derived exosomal miR-3614-5p effectively inhibits CRC progression primarily through downregulation of IL7Rα and suppression of the JAK2/STAT3 signaling pathway. These findings suggest that Exo-miR-3614-5p represents a promising therapeutic and diagnostic candidate for CRC.