miRNA-223 at the crossroads of inflammation and cancer

Abstract

miR-223 is an evolutionarily conserved anti-inflammatory microRNA primarily expressed in myeloid cells. miR-223 post-transcriptionally regulates many genes essential in inflammation, cell proliferation, and invasion. Recent studies show that miR-223 is either endogenously expressed or transferred in exosomes or extracellular vesicles to non-phagocytic cells including cancer cells, where it exerts biological functions. In cancerous cells, miR-223 acts either as an oncomiR promoting tumors or as a tumor suppressor in a context-dependent manner. Taken together, miR-223 can regulate tumorigenesis at multiple levels, including by suppressing the inflammatory tumor microenvironment and modulating malignancy of cancer cells.

Keywords: Macrophages; NF-κB; Neutrophils; OncomiR; Tumor suppressor; microRNA.

Figure 1.

miR-223 regulates the canonical NF-κB pathway and other pathways related to cancer. miR-223 is released from neutrophils and macrophages as a cargo of macrovesicles, exosomes, and possibly high-density lipoproteins (HDL), that can be delivered to phagocytes or nonphagocytic cells. Macrophages, in addition, deliver miR-223 into recipient cells through gap junctions. miR-223 is transcribed under the control of PU.1 and C\EBP family transcriptional factors and others, which also contributes to the cytosolic pool of miR-223. miR-223 suppresses the canonical NF-κB pathway by downregulating the expression of components in the signaling transduction pathway. In addition, miR-223 directly targets STAT1 and STAT3 and NLRP3 to suppress the inflammasome activation and production of inflammatory cytokines. In various cancer cells, miR-223 regulates genes involved in cell proliferation, survival, differentiation, immune evasion, cell adhesion and migration. Note, only selected direct miR-223 targets are included, and the target genes are different depending on the cell type investigated.