The up-regulation of NDRG1 by HIF counteracts the cancer-promoting effect of HIF in VHL-deficient clear cell renal cell carcinoma
The up-regulation of NDRG1 by HIF counteracts the cancer-promoting effect of HIF in VHL-deficient clear cell renal cell carcinoma
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HIF 上调 NDRG1 抵消了 VHL 缺陷型透明细胞肾细胞癌中 HIF 的促癌作用
DOI：
10.1111/cpr.12853
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发表时间：
2020-07-01
影响因子：
8.5
通讯作者：
Wang, Li-Shun
中科院分区：
文献类型：
--
作者：
Zhang, Zheng-Yan;Zhang, Shi-Long;Wang, Li-Shun
背景低氧诱导因子（HIF）在VHL缺陷型肾透明细胞癌（ccRCC）的发生、发展中起重要作用。方法应用生物信息学分析、免疫组化染色和Kaplan-Meier生存分析等方法，探讨HIF-1/2 α在VHL缺陷型肾透明细胞癌中的作用。通过无偏蛋白质组学分析抵消HIF促癌作用的下游基因，并通过体外和体内测定进行验证。结果在我们的大量临床数据中，高HIF-1/2 α蛋白水平与ccRCC患者的不良预后无关。此外，发现NDRG 1在细胞水平和ccRCC组织中被HIF-1 α和HIF-2 α上调。有趣的是，与NDRG 1低表达相比，NDRG 1高表达与ccRCC患者的Furman分级、TNM分期和更长的生存期相关。NDRG 1在体外和体内均能抑制VHL缺陷的ccRCC细胞的增殖、转移和侵袭，并抑制一系列癌基因的表达。结论NDRG 1基因下游的HIF基因可能对HIF的促癌作用有拮抗作用。这些结果提供了NDRG 1可能是ccRCC中潜在的预后生物标志物以及治疗靶点的证据。
Background Hypoxia-inducible factors (HIFs) are thought to play important roles in the carcinogenesis and progression of VHL-deficient clear cell renal cell carcinoma (ccRCC). Methods The roles of HIF-1/2 alpha in VHL-deficient clear cell renal cell carcinoma were evaluated by bioinformatics analysis, immunohistochemistry staining and Kaplan-Meier survival analysis. The downstream genes that counteract the cancer-promoting effect of HIF were analysed by unbiased proteomics and verified by in vitro and in vivo assays. Results There was no correlation between the high protein level of HIF-1/2 alpha and the poor prognosis of ccRCC patients in our large set of clinical data. Furthermore, NDRG1 was found to be up-regulated by both HIF-1 alpha and -2 alpha at the cellular level and in ccRCC tissues. Intriguingly, the high NDRG1 expression was correlated with lower Furman grade, TNM stage and longer survival for ccRCC patients compared with the low NDRG1 expression. In addition, NDRG1 suppressed the expression of series oncogenes as well as the proliferation, metastasis and invasion of VHL-deficient ccRCC cells in vitro and vivo. Conclusions Our study demonstrated that HIF downstream gene of NDRG1 may counteract the cancer-promoting effect of HIF. These results provided evidence that NDRG1 may be a potential prognostic biomarker as well as a therapeutic target in ccRCC.