Exosome-derived hsa-miR-21-5p stimulates malignant progression of colorectal cancer by regulating HRK

Exosome-mediated microRNAs (miRNA) delivery is increasingly recognized as a central mechanism in tumor microenvironment (TME) remodeling. While the pro-tumorigenic role of tumor cell-derived exosomal miRNAs in colorectal cancer (CRC) is established, their specific regulatory mechanisms require further elucidation. In this study, we demonstrate that exosomes originating from CRC cells not only markedly enhance the proliferation, migration, and invasion capacities of recipient CRC cells but also lead to the suppression of apoptosis in the recipient cells. By means of integrated public database analysis and RT-qPCR validation in clinical tissue samples, researchers confirmed that miR-21-5p is a key oncogenic regulator. Subsequent RT-qPCR analysis of clinical serum exosomes and CRC cells incubated with CRC-derived exosomes revealed significant enrichment of miR-21-5p within these exosomes. HARAKIRI (HRK) was found to serve as a putative downstream target for miR-21-5p. Bioinformatics analysis and examination of clinical CRC tissues demonstrated significant downregulation of HRK in tumors, which correlated negatively with miR-21-5p expression. The direct targeting and repression of HRK expression by miR-21-5p were ascertained through luciferase reporter assays and functional validation experiments. Mechanistically, CRC-derived exosomes deliver miR-21-5p into CRC cells, leading to HRK suppression. This downregulation relieves inhibition of Bcl-2, thereby promoting the malignant progression of CRC cells. Notably, in vivo HRK overexpression partially rescued the tumor growth-promoting effect of CRC-derived exosomes. Collectively, our findings elucidate a novel exosomal miR-21-5p/HRK/Bcl-2 signaling axis in CRC progression, while supplying putative diagnostic and therapeutic targets for this malignancy.