Tumor-associated macrophage-derived exosomes transmitting miR-193a-5p promote the progression of renal cell carcinoma via TIMP2-dependent vasculogenic mimicry

  • Cell Death Dis. 2022 Apr 20;13(4):382. doi: 10.1038/s41419-022-04814-9.
Qing Liu   #  1  2 ,  Enyang Zhao   #  3 ,  Bo Geng   #  3 ,  Shan Gao  4 ,  Hongyang Yu  1 ,  Xinyang He  1 ,  Xuedong Li  5 ,  Guanglu Dong  6 ,  Bosen You  7  8
Affiliations
  • 1. Department of Radiation Oncology, The Second Affiliated Hospital of Harbin Medical University, 150001, Harbin, China.
  • 2. Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, 150001, Harbin, China.
  • 3. Department of Urology, The Second Affiliated Hospital of Harbin Medical University, 150001, Harbin, China.
  • 4. Department of Pathology, The Second Affiliated Hospital of Harbin Medical University, 150001, Harbin, China.
  • 5. Department of Urology, The Second Affiliated Hospital of Harbin Medical University, 150001, Harbin, China. [email protected].
  • 6. Department of Radiation Oncology, The Second Affiliated Hospital of Harbin Medical University, 150001, Harbin, China. [email protected].
  • 7. Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, 150001, Harbin, China. [email protected].
  • 8. Department of Urology, The Second Affiliated Hospital of Harbin Medical University, 150001, Harbin, China. [email protected].
  • # Contributed equally.
PMID: 35443741 DOI: 10.1038/s41419-022-04814-9
Abstract

Previous studies have investigated whether tumor-associated macrophages (TAMs) play tumorigenic and immunosuppressive roles to encourage Cancer development, but the role of TAMs in regulating vasculogenic mimicry (VM) in clear-cell renal cell carcinoma (ccRCC) cells has not been completely clarified. We conducted immunostaining of the tumor-associated macrophage biomarkers CD68/CD163 and double staining for PAS/CD31 in ccRCC human specimens to find that higher TAM infiltration was positively correlated with VM formation. Then we demonstrated that TAM-derived exosomes downregulate TIMP2 expression in RCC cells to promote VM and invasion by shuttling miR-193a-5p. Mechanistic analysis indicated that HIF-1α upregulation in macrophages could transcriptionally increase miR-193a-5p expression. Exosome-shuttled miR-193a-5p then targeted the 3' untranslated region (UTR) of TIMP2 mRNA to suppress its translation. A preclinical study using an in vivo orthotopic xenograft model of ccRCC in mice substantiated that TAM-derived exosomes enhance VM and enable tumor progression, which confirmed our in vitro data. Suppressing TAM-derived exosomal miR-193a-5p successfully inhibited tumor progression and metastasis. Overall, miR-193a-5p from TAM-derived exosomes downregulates the TIMP2 gene to facilitate the development of RCC, which provides a novel perspective for developing therapeutic strategies for RCC.

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