Abstract
Macrophage polarization is a highly plastic physiological process that responds to a variety of environmental factors by changing macrophage phenotype and function. Tumor-associated macrophages (TAMs) are generally recognized as promoting tumor progression. As universal regulators, microRNAs (miRNAs) are functionally involved in numerous critical cellular processes including macrophage polarization. Let-7b, a miRNA, has differential expression patterns in inflamed tissues compared with healthy controls. However, whether and how miRNA let-7b regulates macrophage phenotype and function is unclear. In this report, we find that up-regulation of let-7b is characteristic of prostatic TAMs, and down-regulation of let-7b in TAMs leads to changes in expression profiles of inflammatory cytokines, such as IL-12, IL-23, IL-10 and TNF-α. As a result, TAMs treated with let-7b inhibitors reduce angiogenesis and prostate carcinoma (PCa) cell mobility. Let-7b may play a vital role in regulating macrophage polarization, thus modulating the prognosis of prostate cancer.
Highlights
IL-13, and characterized by an IL-10high and IL-12low phenotype
We measured the expression of IL-10, IL-12 and IL-1β which have been used for phenotyping macrophages
We demonstrate the importance of let-7b, confirming that its decreased expression inhibits the pro-angiogenic effect of tumor-associated macrophages (TAMs) and their capacity to enhance PC-3 cell motility
Summary
IL-13, and characterized by an IL-10high and IL-12low phenotype. M1 macrophages are generally considered potent effector cells that kill microorganisms and tumor cells and produce copious amounts of pro-inflammatory cytokines, whereas M2 macrophages fine-tune inflammatory responses and adaptive Th2 immunity, scavenge debris, and promote angiogenesis, tissue remodeling and repair[6,7]. Recent studies have shown that let-7f, another member of the let-7 family, was over-expressed in tuberculosis-infected macrophages that induce tumor necrosis factor (TNF), and IL-1β secretion. This process is regulated by A20, which is the target of let-7 and an inhibitor of the NF-κ B pathway[17]. We identified that let-7 modulates cytokine profiles in PCa-conditioned TAMs, allowing the setup of a pro-inflammatory or pro-tumor microenvironment. These inflammatory cytokines actively affected motility and angiogenesis of PCa cells, fostering cancer cells’ escape from primary tumors and favoring metastatic spread
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