Deregulation of E2-EPF Ubiquitin Carrier Protein in Papillary Renal Cell Carcinoma

作者：Roos Frederik C; Evans Andrew J; Brenner Walburgis; Wondergem Bill; Klomp Jeffery; Heir Pardeep; Roche Olga; Thomas Christian; Schimmel Heiko; Furge Kyle A; Teh Bin T; Thueroff Joachim W; Hampel Christian; Ohh Michael^*

来源：American Journal Of Pathology, 2011, 178(2): 853-860.

DOI：10.1016/j.ajpath.2010.10.033

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 HIF1 alpha 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 path-way impinging on the positive feedback mechanism of HIF1-mediated regulation of E2-EPF in PRCC. (Am J Pathol 2011, 178:853-860; DOI: 10.1016/j.ajpath.2010.10.033)

• 出版日期2011-2