Tumor-associated macrophage-derived exosomes transmitting miR-193a-5p promote the progression of renal cell carcinoma via TIMP2-dependent vasculogenic mimicry
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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-04-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-04814-9 |
| _version_ | 1818047269723701248 |
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| author | Qing Liu Enyang Zhao Bo Geng Shan Gao Hongyang Yu Xinyang He Xuedong Li Guanglu Dong Bosen You |
| author_facet | Qing Liu Enyang Zhao Bo Geng Shan Gao Hongyang Yu Xinyang He Xuedong Li Guanglu Dong Bosen You |
| author_sort | Qing Liu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T10:03:07Z |
| format | Article |
| id | doaj.art-07f16b25859b47288be40bfb83b53e6d |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-10T10:03:07Z |
| publishDate | 2022-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-07f16b25859b47288be40bfb83b53e6d2022-12-22T01:53:19ZengNature Publishing GroupCell Death and Disease2041-48892022-04-0113411410.1038/s41419-022-04814-9Tumor-associated macrophage-derived exosomes transmitting miR-193a-5p promote the progression of renal cell carcinoma via TIMP2-dependent vasculogenic mimicryQing Liu0Enyang Zhao1Bo Geng2Shan Gao3Hongyang Yu4Xinyang He5Xuedong Li6Guanglu Dong7Bosen You8Department of Radiation Oncology, The Second Affiliated Hospital of Harbin Medical UniversityDepartment of Urology, The Second Affiliated Hospital of Harbin Medical UniversityDepartment of Urology, The Second Affiliated Hospital of Harbin Medical UniversityDepartment of Pathology, The Second Affiliated Hospital of Harbin Medical UniversityDepartment of Radiation Oncology, The Second Affiliated Hospital of Harbin Medical UniversityDepartment of Radiation Oncology, The Second Affiliated Hospital of Harbin Medical UniversityDepartment of Urology, The Second Affiliated Hospital of Harbin Medical UniversityDepartment of Radiation Oncology, The Second Affiliated Hospital of Harbin Medical UniversityFuture Medical Laboratory, The Second Affiliated Hospital of Harbin Medical UniversityAbstract 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.https://doi.org/10.1038/s41419-022-04814-9 |
| spellingShingle | Qing Liu Enyang Zhao Bo Geng Shan Gao Hongyang Yu Xinyang He Xuedong Li Guanglu Dong Bosen You Tumor-associated macrophage-derived exosomes transmitting miR-193a-5p promote the progression of renal cell carcinoma via TIMP2-dependent vasculogenic mimicry Cell Death and Disease |
| title | Tumor-associated macrophage-derived exosomes transmitting miR-193a-5p promote the progression of renal cell carcinoma via TIMP2-dependent vasculogenic mimicry |
| title_full | Tumor-associated macrophage-derived exosomes transmitting miR-193a-5p promote the progression of renal cell carcinoma via TIMP2-dependent vasculogenic mimicry |
| title_fullStr | Tumor-associated macrophage-derived exosomes transmitting miR-193a-5p promote the progression of renal cell carcinoma via TIMP2-dependent vasculogenic mimicry |
| title_full_unstemmed | Tumor-associated macrophage-derived exosomes transmitting miR-193a-5p promote the progression of renal cell carcinoma via TIMP2-dependent vasculogenic mimicry |
| title_short | Tumor-associated macrophage-derived exosomes transmitting miR-193a-5p promote the progression of renal cell carcinoma via TIMP2-dependent vasculogenic mimicry |
| title_sort | tumor associated macrophage derived exosomes transmitting mir 193a 5p promote the progression of renal cell carcinoma via timp2 dependent vasculogenic mimicry |
| url | https://doi.org/10.1038/s41419-022-04814-9 |
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