Page Patric M, Dastous Sonia A, Richard Patrick O, Pavic Michel, Nishimura Tamiko, Riazalhosseini Yasser, Crapoulet Nicolas, Martin Mykella, Turcotte Sandra
Department of Chemistry and Biochemistry, Université de Moncton, 18 Antonine-Maillet, Moncton, NB, E1A 3E9, Canada.
Atlantic Cancer Research Institute, Moncton, NB, Canada.
Cancer Cell Int. 2025 Feb 27;25(1):71. doi: 10.1186/s12935-025-03711-3.
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.
冯·希佩尔-林道（VHL）肿瘤抑制基因的失活是透明细胞肾细胞癌（ccRCC）肿瘤发生过程中最早的主干事件之一。VHL缺失导致的缺氧诱导因子（HIFα）积累可通过调节微小RNA（miRNA）表达促进ccRCC肿瘤发生。在此，我们进行了miRNA谱分析和高通量分析，以鉴定ccRCC中一组VHL依赖性miRNA。对这些miRNA的验证揭示了miR-2355-5p在ccRCC细胞模型和原发性肿瘤中的过表达。此外，我们发现ccRCC患者血浆中循环miR-2355-5p显著增加。从机制上讲，miR-2355-5p的过表达被证实依赖于HIF-2α。用CRISPR/Cas9系统靶向miR-2355-5p不仅负面破坏了ccRCC细胞刺激血管生成的能力，还降低了细胞增殖，并显著减少了小鼠异种移植模型中的肿瘤生长。最后，一项miR-2355-5p下拉试验确定了五个肿瘤抑制基因ACO1、BTG2、CMTM4、SLIT2和WDFY2为潜在靶点。所有这五个基因在ccRCC肿瘤和小鼠异种移植肿瘤中均显著下调。本研究结果证明了miR-2355-5p的致癌能力，并揭示了这种miRNA控制VHL缺陷型ccRCC血管生成和肿瘤生长的可能机制。
