Krishnamachary Balaji, Zagzag David, Nagasawa Hideko, Rainey Karin, Okuyama Hiroaki, Baek Jin H, Semenza Gregg L
Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Cancer Res. 2006 Mar 1;66(5):2725-31. doi: 10.1158/0008-5472.CAN-05-3719.
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-1alpha mutant, or a short hairpin RNA directed against HIF-1alpha. In human RCC biopsies, expression of E-cadherin and HIF-1alpha 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.
侵袭性和转移性癌症发病机制中的一个关键事件是E-钙黏蛋白功能丧失。肾透明细胞癌（RCC）的特征是冯·希佩尔-林道肿瘤抑制因子（VHL）功能丧失，VHL对缺氧诱导因子-1（HIF-1）起负调控作用。通过强制表达VHL、显性负性HIF-1α突变体或针对HIF-1α的短发夹RNA，可纠正VHL缺失的RCC4细胞中E-钙黏蛋白表达的丧失和细胞间黏附的减少。在人类RCC活检中，E-钙黏蛋白和HIF-1α的表达相互排斥。编码抑制E-钙黏蛋白基因转录的TCF3、ZFHX1A和ZFHX1B的mRNA表达在VHL缺失的RCC4细胞中以HIF-1依赖的方式增加。因此，HIF-1通过间接抑制E-钙黏蛋白促进VHL缺失的RCC中的上皮-间质转化。
