A new role for microRNAs, as ligands of Toll-like receptors

Abstract

Tumor microenvironment plays a central role in the development and dissemination of cancer cells. In addition to study each specific cellular component of the microenvironment, it has become clear that it is the type and amount of information that cells exchange that ultimately affects cancer phenotype. Recently, it has been discovered that intercellular communication occurs through the release of microvesicles and exosomes, whose cargo represents the information released by one cell to a recipient cell. A key component of this cargo is represented by microRNAs (miRNAs), small non-coding RNAs with gene regulatory functions. We discovered that miRNAs released by cancer cells within microvesicles can reach and bind to Toll-like receptors (TLRs) in surrounding immune cells, and activate them in a paracrine loop. As a result, immune cells produce cytokines that increase cell proliferation and metastatic potential. This discovery provides the rationale for the development of new drugs that might be used in the treatment of cancer as well as other inflammation-related diseases.

Keywords: IL-6; TNF-α; Toll-like receptors; exosomes; metastasis; microRNAs; tumor microenvironment.

Figure 1. Different mechanisms of action of mature microRNAs. (A) The “classical” mechanism of action of mature miRNAs consists in their binding to a partially (upper panel) or completely (lower panel) complementary sequence in a target mRNA leading to translational repression or mRNA cleavage, respectively. (B) MiRNAs can also bind to proteins and affect their function. The case of miR-328 is here described. By directly binding to hRNP E2, miR-328 functions as a decoy and subtracts hRNP E2 from binding to and inhibiting CEBPA. As a result of miR-328-hRNP E2 interaction, CEBPA is able to bind to target mRNAs exerting its transcription factor function leading to increased granulocytic differentiation. (C) MiRNAs can also bind to proteic receptors and activate them. Here we describe the mechanism of action of miR-21 and -29a, released by cancer cells within MVs, and able to bind to TLR8 (in humans) or TLR7 (in mice) in surrounding immune cells. As a result of this interaction, immune cells release IL-6 and TNF-α which promote cancer growth.