Deregulation of E2-EPF Ubiquitin Carrier Protein in Papillary Renal Cell Carcinoma
Deregulation of E2-EPF Ubiquitin Carrier Protein in Papillary Renal Cell Carcinoma
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DOI：
10.1016/j.ajpath.2010.10.033
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发表时间：
2011-02-01
影响因子：
6
通讯作者：
Ohh, Michael
中科院分区：
文献类型：
--
作者：
Roos, Frederik C.;Evans, Andrew J.;Ohh, Michael
散发性乳头状肾细胞癌（PRCC）是第二种最常见的肾癌，其发病机制相关的分子途径尚不清楚。我们通过基因表达分析分析了 35 名接受肾切除术治疗的 PRCC 患者的原发肿瘤标本，并通过免疫组织化学分析了由另外 57 份石蜡包埋的 PRCC 样本构建的组织微阵列。使用原发性 PRCC 肿瘤样本和建立的肾细胞癌细胞系，通过蛋白质印迹分析对基因产物进行了验证和进一步研究，并确定了 27 名具有随访信息的患者与病理变量和生存的潜在关联。 蛋白酶体依赖性降解的蛋白质在大多数 PRCC 肿瘤中显着升高，表现出 HIF1 α 表达增加，并且与不良预后相关。此外，我们在E2-EPF启动子内鉴定了多个缺氧反应元件，并首次证明E2-EPF是通过HIF1直接调控的缺氧诱导基因。这些发现揭示了 PRCC 中氧传感通路的失调影响了 HIF1 介导的 E2-EPF 调节的正反馈机制。 (Am J Pathol 2011, 178:853-860; 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)