Balamurugan K, Luu V-D, Kaufmann M R, Hofmann V S, Boysen G, Barth S, Bordoli M R, Stiehl D P, Moch H, Schraml P, Wenger R H, Camenisch G
Institute of Physiology and Zürich Center for Integrative Human Physiology ZIHP, University of Zürich UZH, Zürich, Switzerland.
Oncogene. 2009 Sep 17;28(37):3274-85. doi: 10.1038/onc.2009.186. Epub 2009 Jul 6.
The onconeuronal cerebellar degeneration-related antigen Cdr2 is associated with paraneoplastic syndromes. Neoplastic expression of Cdr2 in ovary and breast tumors triggers an autoimmune response that suppresses tumor growth by developing tumor immunity, but culminates in cerebellar degeneration when Cdr2-specific immune cells recognize neuronal Cdr2. We identified Cdr2 as a novel interactor of the hypoxia-inducible factor (HIF) prolyl-4-hydroxylase PHD1 and provide evidence that Cdr2 might represent a novel important tumor antigen in renal cancer. Strong Cdr2 protein expression was observed in 54.2% of papillary renal cell carcinoma (pRCC) compared with 7.8% of clear-cell RCC and no staining was observed in chromophobe RCC or oncocytoma. High Cdr2 protein levels correlated with attenuated HIF target gene expression in these solid tumors, and Cdr2 overexpression in tumor cell lines reduced HIF-dependent transcriptional regulation. This effect was because of both attenuation of hypoxic protein accumulation and suppression of the transactivation activity of HIF-1alpha. pRCC is known for its tendency to avascularity, usually associated with a lower pathological stage and higher survival rates. We provide evidence that Cdr2 protein strongly accumulates in pRCC, attenuates the HIF response to tumor hypoxia and may become of diagnostic importance as novel renal tumor marker.
癌性神经元小脑变性相关抗原Cdr2与副肿瘤综合征有关。Cdr2在卵巢和乳腺肿瘤中的肿瘤性表达引发自身免疫反应，通过产生肿瘤免疫来抑制肿瘤生长，但当Cdr2特异性免疫细胞识别神经元Cdr2时，最终会导致小脑变性。我们鉴定出Cdr2是缺氧诱导因子（HIF）脯氨酰-4-羟化酶PHD1的一种新型相互作用蛋白，并提供证据表明Cdr2可能是肾癌中一种新型重要的肿瘤抗原。在54.2%的乳头状肾细胞癌（pRCC）中观察到强烈的Cdr2蛋白表达，相比之下，透明细胞肾细胞癌中的表达率为7.8%，而在嫌色细胞肾细胞癌或嗜酸性细胞瘤中未观察到染色。在这些实体瘤中，高Cdr2蛋白水平与HIF靶基因表达减弱相关，并且肿瘤细胞系中Cdr2的过表达降低了HIF依赖性转录调控。这种效应是由于缺氧蛋白积累的减弱和HIF-1α反式激活活性的抑制。pRCC以其无血管倾向而闻名，通常与较低的病理分期和较高的生存率相关。我们提供证据表明Cdr2蛋白在pRCC中强烈积累，减弱了HIF对肿瘤缺氧的反应，并且可能作为一种新型肾肿瘤标志物具有诊断重要性。
