Cancer-associated fibroblasts regulate gene expression of breast cancer cells via exosomal microRNAs

Abstract

Cell-derived vesicles known as exosomes facilitate communication between cancer cells and cancer-associated fibroblasts (CAFs). CAF-derived molecules, including microRNAs (miRNAs), were recently found to be transferred to cancer cells via exosomes. However, little is known about the role of CAF-derived exosomal miRNAs in tumor progression. To investigate the relationship between miRNA levels in fibroblast-derived exosomes and breast cancer progression, we analyzed exosomal miRNAs of normal breast fibroblasts (NBFs) and CAFs using microarray, examined the delivery of exosomal miRNAs from fibroblasts to cancer cells by direct exosome treatment, and confirmed the function of exosomal miRNA in gene regulation through overexpression. Several miRNAs were downregulated more than two-fold in CAF-derived exosomes, compared to NBF-derived exosomes. Endogenous miR-4516, a miRNA downregulated five-fold in CAF-derived exosomes, was also downregulated in CAF cells. In MCF7 cells, NBF-derived exosomes delivered four-fold more miR-4516 than CAF-derived exosomes. Overexpression of miR-4516 in MCF7 and MDA-MB-231 cells induced downregulation of several tumor progression-associated genes (PHF8 and STAT3). Thus, CAFs may regulate gene expression in breast cancer cells via exosomal miR-4516. By modulating the expression level of miR-4516 in CAF and NBF-derived exosomes, breast cancer cells could circumvent the inhibitory effect of exosomal miR-4516, promoting tumor progression.