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Regulation of E-cadherin Expression by VHL and Hypoxia-Inducible Factor
Open accessAbstract
Mutations in von Hippel-Lindau tumor suppressor gene (VHL) underlie the VHL hereditary cancer syndrome and also occur in most sporadic clear cell renal cell cancers (CCRCC). Currently, the mechanism(s) by which VHL loss of function promotes tumor development in the kidney are not fully elucidated. Here, we show that VHL inactivation in precancerous lesions in kidneys from patients with VHL disease correlates with marked down-regulation of the intercellular adhesion molecule E-cadherin. Moreover, in VHL-defective cell lines (RCC4 and RCC10) derived from sporadic CCRCC, reexpression of VHL was found to restore E-cadherin expression. The product of the VHL gene has multiple reported functions, the best characterized of which is its role as the recognition component of an ubiquitin E3 ligase complex responsible for mediating oxygen-dependent destruction of hypoxia-inducible factor-α (HIF-α) subunits. We show that HIF activation is necessary and sufficient to suppress E-cadherin in renal cancer cells. Given the fundamental role of E-cadherin in controlling epithelial behavior, our findings give insight into how VHL inactivation/HIF activation may lead to kidney cancer and also indicate a mechanism by which reduced oxygenation could alter E-cadherin expression in other cancers and influence normal homeostasis in other epithelia. (Cancer Res 2006; 66(7): 3567-75)
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“Loss of VHL in ccRCC also downregulates E-cadherin in a HIF-dependent manner (Esteban et al., 2006).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Esteban et al., 2006
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Metadata
- Authors
- Esteban, M. A., Tran, M. G. B., Harten, S. K., Hill, P., Castellanos, M. C., Chandra, A., Raval, R., O'Brien, T. S., & Maxwell, P. H.
- Affiliations
- Imperial College London (GB)
- 3Servicio de Immunología, Hospital de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain; and
- Guy's Hospital (GB)
- 4Henry Wellcome Building of Genomic Medicine, Oxford, United Kingdom
- 2Department of Urology, Guy's Hospital, London Bridge, London, United Kingdom;
- Venue
- Cancer Research
- Published
- 2006-04-01
- Volume
- 66
- Issue
- 7
- Pages
- 3567-3575
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2039412091
- Cited by
- 262
- References
- 37
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 7 · 2023: 6 · 2022: 6 · 2021: 6 · 2020: 7 · 2019: 7 · 2018: 10 · 2017: 5 · 2016: 14 · 2015: 14 · 2014: 18 · 2013: 17 · 2012: 19
- FWCI
- 10.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust
- European Commission
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Renal cell carcinoma treatment
- Health Sciences › Medicine › Oncology › Ear and Head Tumors
- Keywords
- E-cadherin, von Hippel-Lindau tumor suppressor, hypoxia-inducible factor alpha, clear cell renal cell carcinoma, von Hippel-Lindau disease, cell-cell adhesion, epithelial cell adhesion, E3 ubiquitin ligase, tumor suppressor inactivation, oxygenation
- MeSH terms
- Adult, Carcinoma, Renal Cell, Cell Transformation, Neoplastic, Female, von Hippel-Lindau Disease, Humans, Kidney Neoplasms, Kidney Tubules, Male, Middle Aged, Precancerous Conditions, RNA, Messenger, Down-Regulation, Cadherins, Hypoxia-Inducible Factor 1, Von Hippel-Lindau Tumor Suppressor Protein
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