The identification and application of the Von Hippel-Lindau (VHL) gene is a seminal breakthrough in kidney cancer research. VHL and its protein pVHL are the root cause of most kidney cancers, and the cascading pathway below them is crucial for understanding hypoxia, in addition to the aforementioned tumorigenesis routes and treatments. We reviewed the history and functions of VHL/pVHL and Hypoxia-inducible factor (HIF), their well-known activities under low-oxygen environments as an E3 ubiquitin ligase and as a transcription factor, respectively, as well as their non-canonical functions revealed recently. Additionally, we discussed how their dysregulation promotes tumorigenesis: beginning with chromosome 3 p-arm (3p) loss/epigenetic methylation, followed by two-allele knockout, before the loss of complimentary tumor suppressor genes leads cells down predictable oncological paths. These different pathways can ultimately determine the grade, outcome, and severity of the deadliest genitourinary cancer. We finished by investigating current and proposed schemes to therapeutically treat clear cell renal cell carcinoma (ccRCC) by manipulating the hypoxic pathway utilizing Vascular Endothelial Growth Factor (VEGF) inhibitors, mammalian target of rapamycin complex 1 (mTORC1) inhibitors, small molecule HIF inhibitors, immune checkpoint blockade therapy, and synthetic lethality.

Von Hippel-Lindau ( VHL ) 基因的鉴定和应用是肾癌研究的重大突破。 VHL及其蛋白pVHL是大多数肾癌的根本原因，除了上述的肿瘤发生途径和治疗之外，它们下面的级联通路对于理解缺氧至关重要。我们回顾了VHL /pVHL 和缺氧诱导因子 (HIF) 的历史和功能，它们在低氧环境下分别作为 E3 泛素连接酶和转录因子的众所周知的活性，以及​​它们的非规范功能最近透露。此外，我们讨论了它们的失调如何促进肿瘤发生：从 3 号染色体 p 臂 (3p) 丢失/表观遗传甲基化开始，然后是两个等位基因敲除，然后互补肿瘤抑制基因的丢失导致细胞沿着可预测的肿瘤路径发展。这些不同的途径最终可以决定最致命的泌尿生殖系统癌症的级别、结果和严重程度。最后，我们研究了当前和拟议的透明细胞肾细胞癌 (ccRCC) 治疗方案，通过利用血管内皮生长因子 (VEGF) 抑制剂、哺乳动物雷帕霉素靶点复合物 1 (mTORC1) 抑制剂、小分子 HIF 抑制剂、免疫检查点阻断疗法和综合致死率。