MicroRNA profiling identifies VHL/HIF-2α dependent miR-2355-5p as a key modulator of clear cell Renal cell carcinoma tumor growth
Abstract Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is one of the first truncal events in clear cell Renal Cell Carcinoma (ccRCC) tumorigenesis. The accumulation of Hypoxia Induced Factor (HIFα) resulting from VHL loss can promote ccRCC tumorigenesis by regulating microRNA (mi...
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2025-02-01
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| Online Access: | https://doi.org/10.1186/s12935-025-03711-3 |
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| author | Patric M. Page Sonia A. Dastous Patrick O. Richard Michel Pavic Tamiko Nishimura Yasser Riazalhosseini Nicolas Crapoulet Mykella Martin Sandra Turcotte |
| author_facet | Patric M. Page Sonia A. Dastous Patrick O. Richard Michel Pavic Tamiko Nishimura Yasser Riazalhosseini Nicolas Crapoulet Mykella Martin Sandra Turcotte |
| author_sort | Patric M. Page |
| collection | DOAJ |
| description | Abstract Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is one of the first truncal events in clear cell Renal Cell Carcinoma (ccRCC) tumorigenesis. The accumulation of Hypoxia Induced Factor (HIFα) resulting from VHL loss can promote ccRCC tumorigenesis by regulating microRNA (miRNA) expression. Here, we performed miRNA profiling and high-throughput analysis to identify a panel of VHL-dependent miRNAs in ccRCC. Validation of these miRNAs revealed the overexpression of miR-2355-5p in ccRCC cell models and primary tumors. Moreover, we showed a significant increase in circulating miR-2355-5p in plasma from patients with ccRCC. Mechanistically, miR-2355-5p overexpression was confirmed to be HIF-2α dependent. Targeting miR-2355-5p with the CRISPR/Cas9 system not only negatively disrupted the ability of ccRCC cells to stimulate angiogenesis but also decreased cell proliferation and drastically reduced tumor growth in mouse xenograft models. Finally, a miR-2355-5p pulldown assay identified five tumor suppressor genes, ACO1, BTG2, CMTM4, SLIT2, and WDFY2, as potential targets. All five genes were significantly downregulated in ccRCC tumors and mouse xenograft tumors. The results from this research demonstrate the oncogenic ability of miR-2355-5p and shed light on the possible mechanism by which this miRNA controls angiogenesis and tumor growth in VHL-deficient ccRCC. |
| format | Article |
| id | doaj-art-626f7dfdb65a4b53bc457879aaffdccb |
| institution | DOAJ |
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| language | English |
| publishDate | 2025-02-01 |
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| series | Cancer Cell International |
| spelling | doaj-art-626f7dfdb65a4b53bc457879aaffdccb2025-08-20T03:03:24ZengBMCCancer Cell International1475-28672025-02-0125111810.1186/s12935-025-03711-3MicroRNA profiling identifies VHL/HIF-2α dependent miR-2355-5p as a key modulator of clear cell Renal cell carcinoma tumor growthPatric M. Page0Sonia A. Dastous1Patrick O. Richard2Michel Pavic3Tamiko Nishimura4Yasser Riazalhosseini5Nicolas Crapoulet6Mykella Martin7Sandra Turcotte8Department of Chemistry and Biochemistry, Université de MonctonDepartment of Chemistry and Biochemistry, Université de MonctonDepartment of Urology, Centre Hospitalier Universitaire de SherbrookeInstitut de recherche sur le cancer de l’Université de SherbrookeDepartment of Human Genetics, McGill UniversityDepartment of Human Genetics, McGill UniversityLaboratoire de Génétique Moléculaire, Vitalité Health NetworkCentre de formation médicale du Nouveau-BrunswickDepartment of Chemistry and Biochemistry, Université de MonctonAbstract Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is one of the first truncal events in clear cell Renal Cell Carcinoma (ccRCC) tumorigenesis. The accumulation of Hypoxia Induced Factor (HIFα) resulting from VHL loss can promote ccRCC tumorigenesis by regulating microRNA (miRNA) expression. Here, we performed miRNA profiling and high-throughput analysis to identify a panel of VHL-dependent miRNAs in ccRCC. Validation of these miRNAs revealed the overexpression of miR-2355-5p in ccRCC cell models and primary tumors. Moreover, we showed a significant increase in circulating miR-2355-5p in plasma from patients with ccRCC. Mechanistically, miR-2355-5p overexpression was confirmed to be HIF-2α dependent. Targeting miR-2355-5p with the CRISPR/Cas9 system not only negatively disrupted the ability of ccRCC cells to stimulate angiogenesis but also decreased cell proliferation and drastically reduced tumor growth in mouse xenograft models. Finally, a miR-2355-5p pulldown assay identified five tumor suppressor genes, ACO1, BTG2, CMTM4, SLIT2, and WDFY2, as potential targets. All five genes were significantly downregulated in ccRCC tumors and mouse xenograft tumors. The results from this research demonstrate the oncogenic ability of miR-2355-5p and shed light on the possible mechanism by which this miRNA controls angiogenesis and tumor growth in VHL-deficient ccRCC.https://doi.org/10.1186/s12935-025-03711-3ccRCCVHLHIFmiRNAsmiR-2355-5pTumor growth |
| spellingShingle | Patric M. Page Sonia A. Dastous Patrick O. Richard Michel Pavic Tamiko Nishimura Yasser Riazalhosseini Nicolas Crapoulet Mykella Martin Sandra Turcotte MicroRNA profiling identifies VHL/HIF-2α dependent miR-2355-5p as a key modulator of clear cell Renal cell carcinoma tumor growth Cancer Cell International ccRCC VHL HIF miRNAs miR-2355-5p Tumor growth |
| title | MicroRNA profiling identifies VHL/HIF-2α dependent miR-2355-5p as a key modulator of clear cell Renal cell carcinoma tumor growth |
| title_full | MicroRNA profiling identifies VHL/HIF-2α dependent miR-2355-5p as a key modulator of clear cell Renal cell carcinoma tumor growth |
| title_fullStr | MicroRNA profiling identifies VHL/HIF-2α dependent miR-2355-5p as a key modulator of clear cell Renal cell carcinoma tumor growth |
| title_full_unstemmed | MicroRNA profiling identifies VHL/HIF-2α dependent miR-2355-5p as a key modulator of clear cell Renal cell carcinoma tumor growth |
| title_short | MicroRNA profiling identifies VHL/HIF-2α dependent miR-2355-5p as a key modulator of clear cell Renal cell carcinoma tumor growth |
| title_sort | microrna profiling identifies vhl hif 2α dependent mir 2355 5p as a key modulator of clear cell renal cell carcinoma tumor growth |
| topic | ccRCC VHL HIF miRNAs miR-2355-5p Tumor growth |
| url | https://doi.org/10.1186/s12935-025-03711-3 |
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