Abstract
BACKGROUND: miRNAs have recently been implicated in tumor's microenvironment remodeling and tumor-stromal cells interactions. We have previously reported a signaling role for miR-21, as a secretory molecule released by cancer associated fibroblasts (CAF) adjacent to esophagus tumor cells. OBJECTIVE: To discover other potential signaling miRNAs, we employed a co-culture system of esophageal cancer cell line and normal fibroblasts to mimic the tumor microenvironment. METHODS: We measured the expression profile of secretory miRNAs in the conditioned media (CM) of our co-culture system using a panel PCR array. We used pathway enrichment analysis to define potential pathways regulated by these miRNAs. Then using ultracentrifugation, we purified exosomes secreted to the CM of co-cultured cell lines and evaluated exosomal secretion of these miRNAs. RESULTS: We found 18 miRNAs which were significantly up/down-regulated in the CM of co-culture system. Pathways related to cell adhesion, endocytosis and cell junctions were among the enriched pathways that might be related to CAF phenotype and tumor progression. Moreover, we detected higher exosomal levels of miR-33a and miR-326 in the purified exosomes both in co-cultured and untreated CM. So, these miRNAs are mainly secreted into the CM by means of exosomes. CONCLUSIONS: Briefly, our data shed more light on the role of CAFs through secretion of miRNAs within tumor microenvironment and propose novel therapeutic targets for esophageal and probably other cancer types.