The potential roles of vesicle-enclosed miRNAs in communication between macrophages and cancer cells in tumor microenvironment
Abstract:
Functional microRNA (miRNA) molecules are transported in extracellular vesicles among tumor cells and cells of the immune system. Macrophages as integral components of tumor microenvironment are known as potential contributors to tumor growth and progression. We searched for studies which could provide a direct link between the particular miRNAs transported between cancer cells and macrophages and experimental evidence of subsequent alterations in biological functions of target cells. The validated targets of such microRNAs were found using miRWalk database. These targets were further subjected to analysis by DAVID (Database for Annotation, Visualization and Integrated Discovery) to find the most prominent cellular events that could be potentially regulated in macrophages by miRNAs originated from cancer cells and vice versa. We found that the 5 miRNAs (let-7b, miR-21, miR-29a, miR-222-3p, miR-451) derived from cancer cells may together regulate 2304 target genes in macrophages. The genes involved in regulation of apoptosis, regulation of gene expression and protein transport were significantly overrepresented in this set. Four of the five sets of target genes for these individual miRNAs overlap in MYC oncogene. MYC dependent transcriptional program is responsible for cell cycle entry and regulates the inflammatory response in macrophages.Both miRNAs for which the functional transports from macrophages to cancer cells were experimental proven (miR-223, miR-142-3p) target total 684 genes including some well-known tumor suppressors like TP53 or APC. Suppression of tumor suppressor genes by miRNAs derived from macrophages may eventually contribute to cancer cell proliferation.Due to the complexity of tumor microenvironment, the altered expression profiles of its components affected by miRNA uptake from extracellular vesicles could contribute to the outcome of carcinogenesis therefore the vesicular transport of miRNAs should be studied more extensively in this context.