Abstract
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.
Highlights
Epithelial cell-cell adhesion in humans and other mammals is mediated by intercellular junctional complexes consisting of tight junctions, adherens junctions, and desmosomes
RCC4 cells expressed high levels of HIF-1a and HIF2a protein under nonhypoxic conditions, as previously described [32], showing loss of physiologic regulation in the absence of von Hippel-Lindau tumor suppressor (VHL), which was corrected by restoration of VHL expression (Fig. 1A)
E-cadherin protein was not detected in lysates of VHL-null RCC4 cells using antibodies directed against either the extracellular domain, which is the site of homophilic interactions, or the intracellular domain, which interacts with catenins that link E-cadherin to the cytoskeleton
Summary
Epithelial cell-cell adhesion in humans and other mammals is mediated by intercellular junctional complexes consisting of tight junctions, adherens junctions, and desmosomes. We investigated whether dysregulated HIF1 activity contributes to down-regulation of E-cadherin expression, loss of cell-cell adhesion, and the epithelial-mesenchymal transition in RCC.
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