VHL loss in renal cell carcinoma leads to up-regulation of CUB domain-containing protein 1 to stimulate PKCδ-driven migration
VHL loss in renal cell carcinoma leads to up-regulation of CUB domain-containing protein 1 to stimulate PKCδ-driven migration
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DOI：
10.1073/pnas.1011777108
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发表时间：
2011-02-01
影响因子：
11.1
通讯作者：
Giaccia, Amato J.
中科院分区：
文献类型：
--
作者：
Razorenova, Olga V.;Finger, Elizabeth C.;Giaccia, Amato J.
透明细胞肾细胞癌 (CC-RCC) 中常见的基因突变是 von Hippel-Lindau (VHL) 基因缺失，该基因导致缺氧诱导因子 (HIF) 稳定，并有助于癌症进展和转移。含 CUB 结构域的蛋白 1 (CDCP1) 显示可促进硬腺癌、肺腺癌以及前列腺癌的转移。在这项研究中，我们建立了肾癌中 VHL 丢失与通过 HIF-1/2 途径诱导 CDCP1 基因联系起来的分子机制。此外，我们报告 Fyn 是 HIF-1 靶基因，它与 CDCP1 形成复合物并介导其向 PKC delta 的信号传导。从机制上讲，我们发现CDCP1特异性调节PKC delta的磷酸化，但不调节粘着斑激酶或Crk相关底物的磷酸化。从 CDCP1 到 PKC delta 的信号转导导致其激活，从而增加 CC-RCC 的迁移。此外，患者的生存率可以通过肿瘤细胞表面的CDCP1表达进行分层。综上所述，我们的数据表明 CDCP1 蛋白可能作为 CC-RCC 的治疗靶点。
A common genetic mutation found in clear cell renal cell carcinoma (CC-RCC) is the loss of the von Hippel-Lindau (VHL) gene, which results in stabilization of hypoxia-inducible factors (HIFs), and contributes to cancer progression and metastasis. CUB-domain-containing protein 1 (CDCP1) was shown to promote metastasis in scirrhous and lung adenocarcinomas as well as in prostate cancer. In this study, we established a molecular mechanism linking VHL loss to induction of the CDCP1 gene through the HIF-1/2 pathway in renal cancer. Also, we report that Fyn, which forms a complex with CDCP1 and mediates its signaling to PKC delta, is a HIF-1 target gene. Mechanistically, we found that CDCP1 specifically regulates phosphorylation of PKC delta, but not of focal adhesion kinase or Crk-associated substrate. Signal transduction from CDCP1 to PKC delta leads to its activation, increasing migration of CC-RCC. Furthermore, patient survival can be stratified by CDCP1 expression at the cell surface of the tumor. Taken together, our data indicates that CDCP1 protein might serve as a therapeutic target for CC-RCC.