Exosomal transfer of miR-223-3p from carcinoma-associated fibroblasts promotes the malignant properties and chemoresistance of colon cancer cells by targeting NF2/Hippo signaling.

Cancer-associated fibroblasts (CAFs) play a key role in malignant progression and chemoresistance of cancer. Accumulating studies indicate that exosomal transfer of microRNAs from CAFs to cancer cells is responsible for the effects of CAFs in cancer (Wang et al. in Cancers, 2021, https://doi.org/10.3390/cancers13133160 ). In the present study, we explored the impact of CAFs-derived exosomes on tumorigenesis and chemoresistance of colon cancer, and potential microRNAs involved in this process. CAFs were isolated form colon cancer samples. CAFs-derived exosomes were separated by ultracentrifugation. Differentially expressed microRNAs were identified by microRNA expression array. The function of CAFs-derived exsomes and exosomal microRNAs were evaluated by cell viability assay, soft agar assay, transwell invasion assay, sphere formation assay, qRT-PCR, tumor xenograft model, flow cytometry, western blot, luciferase reporter assay, biotin microRNA pull-down assay. In our study, CAFs-derived exosomes promoted proliferation, anchorage-independent growth, invasion, stemness, tumor xenograft growth and 5-FU resistance of colon cancer cells. MiR-223-3p was significantly upregulated in CAFs-derived exosomes and serum or tissue samples of colon cancer patients. Exosomal transfer of miR-223-3p facilitated malignant properties and 5-FU resistance of colon cancer cells. Moreover, NF2 was identified as a downstream target for miR-223-3p. Restored NF2 expression partially abrogated the effects caused by exosomal transfer of miR-223-3p in colon cancer cells. In addition, exosomal miR-223-3 regulated Hippo pathway in colon cancer cells by targeting NF2. Our results indicated that exosomal transfer of miR-223-3p from CAFs to colon cancer cells promoted malignant properties and chemoresistance through NF2/Hippo pathway.