Deregulation of E2-EPF Ubiquitin Carrier Protein in Papillary Renal Cell Carcinoma
| Autor: | Jeffery Klomp, Christian Hampel, Bill Wondergem, Michael Ohh, Bin Tean Teh, Walburgis Brenner, Heiko Schimmel, Andrew Evans, Christian Thomas, Kyle A. Furge, Olga Roche, Frederik C. Roos, Joachim W. Thüroff, Pardeep Heir |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Pathology medicine.medical_specialty Molecular Sequence Data Biology Response Elements Pathology and Forensic Medicine Renal cell carcinoma Gene expression medicine Carcinoma Humans Carcinoma Renal Cell Tissue microarray Base Sequence Papillary renal cell carcinomas Regular Article Hypoxia-Inducible Factor 1 alpha Subunit Prognosis medicine.disease Primary tumor Cell Hypoxia HEK293 Cells Von Hippel-Lindau Tumor Suppressor Protein Sporadic Papillary Renal Cell Carcinoma Mutation Ubiquitin-Conjugating Enzymes Disease Progression Female Kidney cancer |
| Zdroj: | The American Journal of Pathology. 178:853-860 |
| ISSN: | 0002-9440 |
| DOI: | 10.1016/j.ajpath.2010.10.033 |
| Popis: | Molecular pathways associated with pathogenesis of sporadic papillary renal cell carcinoma (PRCC), the second most common form of kidney cancer, are poorly understood. We analyzed primary tumor specimens from 35 PRCC patients treated by nephrectomy via gene expression analysis and tissue microarrays constructed from an additional 57 paraffin-embedded PRCC samples via immunohistochemistry. Gene products were validated and further studied by Western blot analyses using primary PRCC tumor samples and established renal cell carcinoma cell lines, and potential associations with pathologic variables and survival in 27 patients with follow-up information were determined. We show that the expression of E2-EPF ubiquitin carrier protein, which targets the principal negative regulator of hypoxia-inducible factor (HIF), von Hippel-Lindau protein, for proteasome-dependent degradation, is markedly elevated in the majority of PRCC tumors exhibiting increased HIF1α expression, and is associated with poor prognosis. In addition, we identified multiple hypoxia-responsive elements within the E2-EPF promoter, and for the first time we demonstrated that E2-EPF is a hypoxia-inducible gene directly regulated via HIF1. These findings reveal deregulation of the oxygen-sensing pathway impinging on the positive feedback mechanism of HIF1-mediated regulation of E2-EPF in PRCC. |
| Databáze: | OpenAIRE |
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