Let-7d inhibits intratumoral macrophage M2 polarization and subsequent tumor angiogenesis by targeting IL-13 and IL-10
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ORIGINAL ARTICLE
Let‑7d inhibits intratumoral macrophage M2 polarization and subsequent tumor angiogenesis by targeting IL‑13 and IL‑10 Boxing Su1 · Haibo Han2 · Yanqing Gong3,4 · Xuesong Li3,4 · Chaoyue Ji1 · Jingjing Yao5 · Jianghui Yang5 · Weiguo Hu1 · Wei Zhao6 · Jianxing Li1 · Gang Zhang1 · Liqun Zhou3,4 Received: 22 June 2020 / Accepted: 7 November 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
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. Keywords microRNA · Let-7d · Macrophage · Angiogenesis · IL-10 · IL-13
Boxing Su, Haibo Han, and Yanqing Gong contribute equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00262-020-02791-6) contains supplementary material, which is available to authorized users.
Abbreviations ccRCC Clear cell renal cell carcinoma EGF Epidermal growth factor FGF Fibroblast growth factor HUVEC Human umbilical vein endothelial cell 3
* Gang Zhang [email protected]
Department of Urology, Peking University First Hospital and the Institute of Urology, Peking University, Beijing 100034, People’s Republic of China
4
* Liqun Zhou [email protected]
National Urological Cancer Center, Beijing 100034, People’s Republic of China
5
Department of Pathology, Beijing Tsi
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