NADPH oxidase NOX4 supports renal tumorigenesis by promoting the expression and nuclear accumulation of HIF2α.
NADPH oxidase NOX4 supports renal tumorigenesis by promoting the expression and nuclear accumulation of HIF2α.
复制标题
NADPH 氧化酶 NOX4 通过促进 HIF2α 的表达和核积累来支持肾肿瘤发生。
DOI：
10.1158/0008-5472.can-13-2979
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发表时间：
2014-07-01
期刊：
影响因子：
11.2
通讯作者：
Maranchie JK
中科院分区：
文献类型：
--
作者：
Gregg JL;Turner RM 2nd;Chang G;Joshi D;Zhan Y;Chen L;Maranchie JK
大多数偶发性肾肿瘤包括肿瘤抑制因子VHL的功能丧失。VHL缺陷型肾细胞癌（RCC）的发生依赖于缺氧诱导因子HIF-2α的激活，HIF-2α是驱动血管生成、增殖和无氧代谢等多种过程的基因的主要转录调节因子。在确定RCC细胞中HIF-2α表达的关键功能时，已经鉴定了NADPH氧化酶NOX 4，但尚未直接评估NOX 4对RCC的致病作用。在这里，我们报告说，在VHL-缺陷RCC细胞中的NOX 4沉默废除细胞分支，侵袭，集落形成和生长在小鼠异种移植模型RCC。这些变化的超氧化物清除剂，TEMPOL，或锰超氧化物歧化酶或过氧化氢酶的过度表达的治疗phenocopied。值得注意的是，NOX 4沉默或超氧化物清除足以阻断RCC细胞中HIF-2α的核积累。我们的研究结果提供了直接的证据，表明NOX 4对肾肿瘤的发生至关重要，并且它们显示了NOX 4抑制和VHL缺陷RCC细胞中VHL的再表达在遗传上是同义的，支持了针对NOX 4阻断的治疗方案的开发。
Most sporadically occurring renal tumors include a functional loss of the tumor suppressor VHL. Development of VHL-deficient renal cell carcinoma (RCC) relies upon activation of the hypoxia-inducible factor HIF-2α, a master transcriptional regulator of genes that drive diverse processes including angiogenesis, proliferation and anaerobic metabolism. In determining the critical functions for HIF-2α expression in RCC cells, the NADPH oxidase NOX4 has been identified, but the pathogenic contributions of NOX4 to RCC have not been evaluated directly. Here we report that NOX4 silencing in VHL-deficient RCC cells abrogates cell branching, invasion, colony formation and growth in a murine xenograft model RCC. These alterations were phenocopied by treatment of the superoxide scavenger, TEMPOL, or by overexpression of manganese superoxide dismutase or catalase. Notably, NOX4 silencing or superoxide scavenging was sufficient to block nuclear accumulation of HIF-2α in RCC cells. Our results offer direct evidence that NOX4 is critical for renal tumorigenesis and they show how NOX4 suppression and VHL re-expression in VHL-deficient RCC cells are genetically synonymous, supporting development of therapeutic regimens aimed at NOX4 blockade.