Department of Urology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, People's Republic of China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Clinical Laboratory, Peking University Cancer Hospital and Institute, Beijing, 100142, People's Republic of China.
Cancer Immunol Immunother. 2021 Jun;70(6):1619-1634. doi: 10.1007/s00262-020-02791-6. Epub 2020 Nov 25.
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.
miRNA let-7d 已被报道为肾细胞癌（RCC）中的肿瘤抑制因子。肿瘤相关巨噬细胞（TAM）是 M2 极化的巨噬细胞，可在许多人类癌症中促进肿瘤生长和血管生成。然而，let-7d 在 TAM 相关 RCC 进展中的作用仍不清楚。首先，我们观察到 let-7d 表达与 RCC 组织中微血管密度之间存在强烈的负相关。此外，佛波醇肉豆蔻酸乙酸酯预处理的人 THP-1 巨噬细胞和 let-7d 过表达 RCC 细胞共培养体系的条件培养基显著抑制了 HUVEC 的增殖、迁移和管形成。此外，与共培养 let-7d 过表达 RCC 细胞的组相比，M2 巨噬细胞的比例显著降低。与注射对照 RCC 细胞与 THP-1 细胞相比，注射 let-7d 过表达 RCC 细胞与 THP-1 细胞形成的皮下异种移植物中 M2 巨噬细胞比例和微血管密度显著降低。计算机分析和实验分析表明白细胞介素-10（IL-10）和白细胞介素-13（IL-13）是 let-7d 的靶基因。重要的是，添加 IL-10 和 IL-13 可抵消体外共培养体系中 let-7d 对 RCC 细胞的抑制作用。此外，IL-10 和 IL-13 的过表达逆转了 let-7d 对体内巨噬细胞 M2 极化和肿瘤血管生成的作用。最后，IL-10 和 IL-13 的表达与 RCC 临床标本中 let-7d 的表达呈负相关。这些结果表明，let-7d 可能通过靶向 IL-10 和 IL-13 抑制肿瘤内巨噬细胞 M2 极化和随后的肿瘤血管生成。
