VHL表达缺失上调NDRG1对肾透明细胞癌的抑制作用及其分子机制研究

VHL-deficiency or mutation is a key molecular event in most renal clear cell carcinomas (ccRCCs). Traditionally, the VHL-deficiency or mutation led to the accumulation of its target protein hypoxia-inducible factor HIF, promoting tumor development. However, the survival period of patients with VHL-deficiency or mutation is often better in clinic, suggesting that VHL-deficiency or mutation may also be detrimental to tumor. Breaking this mechanism may be the key to the poor prognosis of some ccRCCs. Recently, we used quantitative proteomics to analyze VHL and hypoxia-regulated proteins in ccRCC cells, and found that the most significant change of hypoxia-responsive protein NDRG1. Furthermore, we found that the high expression of NDRG1 in ccRCC was negatively correlated with tumor staging. There was a positive correlation between the expression of NDRG1 and survival in ccRCC. Silencing the expression of NDRG1 in VHL-deficient renal cell carcinoma cell line significantly promoted cell proliferation and tumorigenicity. It suggested that the upregulation of NDRG1 in VHL-deficiency ccRCC was not a promotion but a brake to renal clear cell carcinoma. Based on these work, this project intends to study the effect of NDRG1 on the biological function of VHL and its molecular mechanism in ccRCC. To further elucidate the role of VHL-deficiency in the pathogenesis of ccRCC. It is expected to provide potential targets and markers for clinical treatment of ccRCC and clues for understanding the role of NDRG1 in other tumors under hypoxia.

泛素连接酶VHL突变或缺失是大部分肾透明细胞癌（ccRCC）的关键分子事件，导致其靶蛋白低氧诱导因子的累积，促进肿瘤发生发展。然而，临床上VHL突变或缺失的患者生存期往往更好，提示有不利于肿瘤的机制，打破该机制，可能是部分ccRCC预后不好的关键。最近我们利用定量蛋白质组学系统分析ccRCC细胞中被VHL和低氧调控的蛋白质，发现低氧反应蛋白NDRG1变化最显著；并进一步发现，ccRCC中NDRG1的高表达与肿瘤分级分期负相关，与患者生存期正相关；在VHL缺失的ccRCC中沉默NDRG1的表达，会显著促进其细胞增殖和成瘤能力。提示VHL表达缺失上调NDRG1不利于ccRCC，是对自身的制衡和刹车。本项目拟以这些工作为基础，在ccRCC中深入研究NDRG1对VHL生物学功能的影响及其分子机制，深入解析VHL缺失在ccRCC的发病学中的作用，可望为ccRCC的临床治疗提供潜在的治疗靶标和标志物。

泛素连接酶VHL突变或缺失是大部分肾透明细胞癌（ccRCC）的关键分子事件，导致其靶蛋白低氧诱导因子的累积，促进肿瘤发生发展。然而，临床上VHL突变或缺失的患者生存期往往更好，提示有不利于肿瘤的机制，打破该机制，可能是部分ccRCC预后不好的关键。项目利用定量蛋白质组学系统分析ccRCC细胞中被VHL和低氧调控的蛋白质，发现低氧反应蛋白NDRG1变化最显著；而沉默及过表达VHL 表达的细胞中NDRG1 的表达显著增加和减少，沉默HIF-1/2的细胞NDRG1 的表达显著减少，提示VHL和HIF都可以调控NDRG1的表达；项目进一步发现ccRCC中NDRG1的高表达与肿瘤分级分期负相关，与患者生存期正相关；而矫正NDRG1表达水平后的患者预后与HIF的表达明显负相关；与此相呼应，VHL缺失的ccRCC中沉默NDRG1的表达，会显著促进其细胞体外增殖和迁移能力，以及体内皮下成瘤和肺转移的能力；项目的这些研究结果提示VHL表达缺失上调NDRG1不利于ccRCC，是对自身的制衡和刹车，而NDRG1可望为ccRCC的临床治疗提供潜在的治疗靶标和标志物。