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VHL基因具有调节转录、稳定细胞生长相关基因和调节细胞周期的功能,其突变、缺失、重排和超甲基化与肾细胞癌(RCC)的发生密切相关。VHL基因产物VHL肿瘤抑制蛋白(p VHL)是泛素连接酶的成分,具有调节低氧诱导因子(HIF)稳定性的作用。HIF家族主要包含三种HIFα因子(HIF1α、HIF2α、HIF3α)和两种HIFβ因子(HIF1β、HIF2β)。HIF1α位于14q染色体上,在肾透明细胞癌中该染色体经常缺失,且这种14q的缺失常伴有预后不良。HIF2α的表达异常促进了p VHL缺陷型肾透明细胞癌中的发生。目前,抑制HIF2α及其下游的血管内皮生长因子(VEGF)的药物都处于临床试验的不同阶段,已有四种VEGF抑制剂获准用于肾透明细胞癌的治疗。选择抑制HIF或具有HIF靶基因抑制选择性的药物进行研究,可能为肾透明细胞癌的治疗提供新的方法。本文就HIF在VHL蛋白缺陷型肾透明细胞癌中作用的研究进展进行了综述。
VHL gene has functions of regulating transcription, stabilizing cell growth related genes and regulating cell cycle. Mutations, deletions, rearrangements and hypermethylation of VHL gene are closely related to the occurrence of renal cell carcinoma (RCC). VHL Gene Product VHL tumor suppressor protein (p VHL) is a component of ubiquitin ligase and has the effect of regulating the stability of hypoxia-inducible factor (HIF). The HIF family mainly contains three HIFα factors (HIF1α, HIF2α, HIF3α) and two HIFβ (HIF1β, HIF2β). HIF1α is located on chromosome 14q, which is often absent in clear cell renal cell carcinoma. This deletion of 14q is often associated with poor prognosis. Abnormal expression of HIF2α promotes the occurrence of p VHL-deficient renal clear cell carcinoma. Currently, drugs that inhibit HIF2α and its downstream vascular endothelial growth factor (VEGF) are at various stages of clinical trials and four VEGF inhibitors have been approved for the treatment of renal clear cell carcinoma. The choice of drugs that inhibit HIF or have selectivity for inhibition of HIF target genes may provide a new approach to the treatment of renal clear cell carcinoma. This review summarizes the research progress on the role of HIF in VHL-deficient renal clear cell carcinoma.