Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B
Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B
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DOI：
10.1158/0008-5472.can-05-3719
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发表时间：
2006-03-01
期刊：
影响因子：
11.2
通讯作者：
Semenza, GL
中科院分区：
文献类型：
--
作者：
Krishnamachary, B;Zagzag, D;Semenza, GL
侵袭性和转移性癌症发病机制中的一个关键事件是E-钙粘附素功能丧失。肾透明细胞癌(RCC)以von Hippel-Lindau肿瘤抑制因子(VHL)功能丧失为特征，VHL负性调节缺氧诱导因子-1(HIF-1)。在VHL缺失的RCC4细胞中，E-钙粘蛋白表达的缺失和细胞间黏附能力的降低可以通过强制表达VHL(显性阴性HIF-1α突变体)或针对HIF-1α的短发夹RNA来纠正。在肾细胞癌活检组织中，E-钙粘蛋白和HIF-1α的表达是相互排斥的。在VHL缺失的RCC4细胞中，抑制E-cadherin基因转录的TCF3、ZFHX1A和ZFHX1B的mRNAs的表达以HIF-1依赖的方式增加。因此，HIF-1通过间接抑制E-钙粘蛋白参与VHL缺失型肾细胞癌上皮细胞向间充质细胞的转化。
A critical event in the pathogenesis of invasive and metastatic cancer is E-cadherin loss of function. Renal clear cell carcinoma (RCC) is characterized by loss of function of the von Hippel-Lindau tumor suppressor (VHL), which negatively regulates hypoxia-inducible factor-1 (HIF-1). Loss of E-cadherin expression and decreased cell-cell adhesion in VHL-null RCC4 cells were corrected by enforced expression of VHL, a dominant-negative HIF-1 alpha mutant, or a short hairpin RNA directed against HIF-1 alpha. In human RCC biopsies, expression of E-cadherin and HIF-1 alpha was mutually exclusive. The expression of mRNAs encoding TCF3, ZFHX1A, and ZFHX1B, which repress E-cadherin gene transcription, was increased in VHL-null RCC4 cells in a HIF-1-dependent manner. Thus, HIF-1 contributes to the epithelial-mesenchymal transition in VHL-null RCC by indirect repression of E-cadherin.