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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Basic Helix-Loop-Helix Transcription Factors / biosynthesis
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / physiology*
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Biopsy
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Cadherins / biosynthesis*
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Cadherins / genetics
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Carcinoma, Renal Cell / genetics
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Carcinoma, Renal Cell / metabolism*
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Carcinoma, Renal Cell / pathology
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Cell Adhesion / physiology
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Down-Regulation
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Epithelial Cells / pathology
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Gene Expression Regulation, Neoplastic
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Homeodomain Proteins / biosynthesis
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Homeodomain Proteins / genetics
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Homeodomain Proteins / physiology*
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Humans
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Hypoxia-Inducible Factor 1 / biosynthesis
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Hypoxia-Inducible Factor 1 / genetics
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Hypoxia-Inducible Factor 1 / physiology*
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Immunohistochemistry
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Kidney Neoplasms / genetics
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Kidney Neoplasms / metabolism*
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Kidney Neoplasms / pathology
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Mesoderm / pathology
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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RNA, Small Interfering / genetics
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Repressor Proteins / biosynthesis
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Repressor Proteins / genetics
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Repressor Proteins / physiology*
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Transcription Factors / biosynthesis
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Transcription, Genetic
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Von Hippel-Lindau Tumor Suppressor Protein / biosynthesis
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Von Hippel-Lindau Tumor Suppressor Protein / genetics
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Von Hippel-Lindau Tumor Suppressor Protein / physiology*
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Zinc Finger E-box Binding Homeobox 2
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Zinc Finger E-box-Binding Homeobox 1
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Cadherins
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Homeodomain Proteins
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Hypoxia-Inducible Factor 1
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RNA, Messenger
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RNA, Small Interfering
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Repressor Proteins
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TCF3 protein, human
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Transcription Factors
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ZEB1 protein, human
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ZEB2 protein, human
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Zinc Finger E-box Binding Homeobox 2
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Zinc Finger E-box-Binding Homeobox 1
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Von Hippel-Lindau Tumor Suppressor Protein