Abstract
The microRNA let-7d has been reported to be a tumor suppressor in renal cell carcinoma (RCC). Tumor-associated macrophages (TAM) are M2-polarized macrophages that can enhance tumor growth and angiogenesis in many human cancers. However, the role of let-7d in TAM-associated RCC progression remains elusive. First, we observed a strongly inverse correlation between let-7d expression and microvessel density in RCC tissues. Furthermore, the proliferation, migration, and tube formation of HUVECs were significantly inhibited by conditioned medium from a coculture system of the phorbol myristate acetate pretreated human THP-1 macrophages and let-7d-overexpressing RCC cells. Moreover, the proportion of M2 macrophages was significantly lower in the group that was cocultured with let-7d-overexpressing RCC cells. Subcutaneous xenografts formed by the injection of let-7d-overexpressing RCC cells together with THP-1 cells resulted in a significant decrease in the M2 macrophage ratio and microvessel density compared with those formed by the injection of control RCC cells with THP-1 cells. In silico and experimental analysis revealed interleukin-10 (IL-10) and IL-13 as let-7d target genes. Importantly, the addition of IL-10 and IL-13 counteracted the inhibitory effects of the conditioned medium from the coculture system with let-7d-overexpressing RCC cells in vitro. Additionally, overexpression of IL-10 and IL-13 reversed the effects of let-7d on macrophage M2 polarization and tumor angiogenesis in vivo. Finally, the expression of IL-10 and IL-13 were inversely correlated with the expression of let-7d in RCC clinical specimens. These results suggest that let-7d may inhibit intratumoral macrophage M2 polarization and subsequent tumor angiogenesis by targeting IL-10 and IL-13.
Highlights
The microRNA let-7d has been reported to be a tumor suppressor in many types of cancer, including renal cell carcinoma (RCC)
These results suggest that let-7d may inhibit intratumoral macrophage M2 polarization and subsequent tumor angiogenesis at least in part by targeting IL-10 and IL-13
To investigate the role of let-7d expression in RCC cells on tumor angiogenesis, we evaluated the association between let-7d expression and microvessel density (MVD) in 80 RCC tissues
Summary
The microRNA let-7d has been reported to be a tumor suppressor in many types of cancer, including renal cell carcinoma (RCC). The role of let-7d in TAM-associated RCC tumor progression remains elusive. Renal cell carcinoma (RCC) has been described as the most common malignant tumor of the adult kidney and is responsible for approximately 90% to 95% of neoplasms that arise from the kidney [1]. Tumor angiogenesis has been indicated as a promising therapeutic target for advanced RCC. Angiogenesis is a complex process that involves multiple steps, including endothelial cell proliferation and migration, matrix degradation and capillary sprouting, all of which are regulated by countervailing factors that either induce or oppose angiogenesis. The well-known inducers of angiogenesis include factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), placental growth factor (PIGF) and platelet-derived growth factor (PDGF) [4]
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