Identification of CDCP1 as a hypoxia-inducible factor 2α (HIF-2α) target gene that is associated with survival in clear cell renal cell carcinoma patients
Identification of CDCP1 as a hypoxia-inducible factor 2α (HIF-2α) target gene that is associated with survival in clear cell renal cell carcinoma patients
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DOI：
10.1073/pnas.1222435110
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发表时间：
2013-02-26
影响因子：
11.1
通讯作者：
Cantley, Lewis C.
中科院分区：
文献类型：
--
作者：
Emerling, Brooke M.;Benes, Cyril H.;Cantley, Lewis C.
CUB结构域包含蛋白1(CDCP1)是一种跨膜蛋白，在干细胞中高表达，在肿瘤中经常过表达，并被酪氨酸磷酸化。CDCP1促进癌细胞转移。然而，调控CDCP1的机制还不是很明确。在这里，我们发现低氧诱导CDCP1的表达和酪氨酸磷酸化是以低氧诱导因子-2α依赖的方式进行的，而不是低氧诱导因子-Lα依赖的。在低氧条件下，CDCP1的shRNA敲除会削弱癌细胞的迁移，而HIF-2α的过表达则通过增强CDCP1的表达和酪氨酸磷酸化来促进肿瘤移植瘤的生长。对肾透明细胞癌患者肿瘤组织微阵列样本的免疫组织化学分析表明，CDCP1表达增加与总体生存率下降相关。综上所述，这些数据支持CDCP1作为一个独特的HIF-2α靶基因在肿瘤转移调控中的关键作用，并提示CDCP1是转移癌的生物标志物和潜在的治疗靶点。
CUB domain-containing protein 1 (CDCP1) is a transmembrane protein that is highly expressed in stem cells and frequently overexpressed,and tyrosine-phosphorylated in cancer. CDCP1 promotes cancer cell metastasis. However, the mechanisms that regulate CDCP1 are not well-defined. Here we show that hypoxia induces CDCP1 expression and tyrosine phosphorylation in hypoxia-inducible factor (HIF)-2 alpha-, but not HIF-l alpha-, dependent fashion. shRNA knockdown of CDCP1 impairs cancer cell migration under hypoxic conditions, whereas overexpression of HIF-2 alpha promotes the growth of tumor xenografts in association with enhanced CDCP1 expression and tyrosine phosphorylation. Immunohistochemistry analysis of tissue microarray samples from tumors of patients with clear cell renal cell carcinoma shows that increased CDCP1 expression correlates with decreased overall survival. Together, these data support a critical role for CDCP1 as a unique HIF-2 alpha target gene involved in the regulation of cancer metastasis, and suggest that CDCP1 is a biomarker and potential therapeutic target for metastatic cancers.