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Let-7d inhibits intratumoral macrophage M2 polarization and subsequent tumor angiogenesis by targeting IL-13 and IL-10

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A Correction to this article was published on 14 February 2023

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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.

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All data supporting the conclusions of this article are included in the article.

Change history

Abbreviations

ccRCC:

Clear cell renal cell carcinoma

EGF:

Epidermal growth factor

FGF:

Fibroblast growth factor

HUVEC:

Human umbilical vein endothelial cell

KICH:

Kidney chromophobe

KIRC:

Kidney renal clear cell carcinoma

KIRP:

Kidney renal papillary cell carcinoma

MVD:

Microvessel density

PDGF:

Platelet-derived growth factor

PMA:

Phorbol myristate acetate

PIGF:

Placental growth factor

qRT–PCR:

Quantitative reverse transcription–polymerase chain reaction

RCC:

Renal cell carcinoma

TAM:

Tumor-associated macrophage

TCGA:

The cancer genome atlas

TGF-β:

Transforming growth factor-β

TNF-α:

Tumor necrosis factor α

3′-UTR:

3′-Untranslated regions

VEGF:

Vascular endothelial growth factor

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Acknowledgements

The authors thank Yunfei Fan for the support and help for technical assistance.

Funding

This study was supported by Grants from the National Natural Science Foundation (Grant No.8170101445), the Beijing Natural Science Foundation (No.7182191) and the Capital Health Research and Development of Special (code: 2016-1-2241).

Author information

Author notes

  1. Boxing Su, Haibo Han, and Yanqing Gong contribute equally to this work.

Authors and Affiliations

  1. Department of Urology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, People’s Republic of China

    Boxing Su, Chaoyue Ji, Weiguo Hu, Jianxing Li & Gang Zhang

  2. 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

    Haibo Han

  3. Department of Urology, Peking University First Hospital and the Institute of Urology, Peking University, Beijing, 100034, People’s Republic of China

    Yanqing Gong, Xuesong Li & Liqun Zhou

  4. National Urological Cancer Center, Beijing, 100034, People’s Republic of China

    Yanqing Gong, Xuesong Li & Liqun Zhou

  5. Department of Pathology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, People’s Republic of China

    Jingjing Yao & Jianghui Yang

  6. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital and Institute, Beijing, 100142, People’s Republic of China

    Wei Zhao

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  1. Boxing Su
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Contributions

Design: BS, HH, YG, WZ, GZ and LZ Experimental operation: BSu, HH, WH, XL, JY and JY. Acquisition of data and Analysis (acquired and managed patients’ information and statistical analysis): BS, HH, YG, XL and GZ. Writing, review, and/or revision of the manuscript: BS, HH, GZ and LZ. All authors read and approved the submitted manuscript.

Corresponding authors

Correspondence to Boxing Su, Gang Zhang or Liqun Zhou.

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The authors declare no conflict of interest.

Ethics approval and consent to participate

All Procedures performed in studies involving human participants or animals were reviewed and granted by the Ethics Committee of Peking University First Hospital and the Ethics Committee of Tsinghua Changgung Hospital, Beijing, China. Informed consent was obtained from all the patients.

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Su, B., Han, H., Gong, Y. et al. Let-7d inhibits intratumoral macrophage M2 polarization and subsequent tumor angiogenesis by targeting IL-13 and IL-10. Cancer Immunol Immunother 70, 1619–1634 (2021). https://doi.org/10.1007/s00262-020-02791-6

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