TLRs as miRNA receptors.

MicroRNAs (miRNA) are small noncoding RNAs with gene regulatory functions. Their expression is frequently dysregulated in almost all human tumors and they can be found circulating within exosomes secreted by cancer cells. In addition to being promising cancer biomarkers with diagnostic, prognostic, and theranostic implications, circulating miRNAs have also important biologic functions: they can be engulfed by immune cells surrounding cancer cells within the tumor microenvironment and bind to toll-like receptors (TLR7 in mice and TLR8 in human) expressed by the immune cells. As a result, the binding miRNAs function as agonists of these single-stranded RNA-binding TLRs, leading to NF-κB signaling activation and secretion of interleukin (IL)-6 and TNF-α, which promote cancer cell growth and metastasization. This novel miRNA mechanism of action suggests that these small noncoding RNAs can act as hormones (we call these miRNAs hormone miRNAs or H-miRNAs). The discovery that miRNAs released by cancer cells can bind to a receptor in a surrounding immune cell is completely novel. Other receptors (in addition to TLR7 and TLR8) are likely to be found, but this is the first identified miRNA receptor and it is relevant to cancer. This review discusses the meaning of this discovery and comments on the exciting future implications of these findings in the context of tumor microenvironment biology as well as of other human diseases.