Oncogenic Ras/ERK Signaling Activates CDCP1 to Promote Tumor Invasion and Metastasis
Oncogenic Ras/ERK Signaling Activates CDCP1 to Promote Tumor Invasion and Metastasis
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DOI：
10.1158/1541-7786.mcr-13-0587
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发表时间：
2014-06
影响因子：
5.2
通讯作者：
T. Uekita;S. Fujii;Yuri Miyazawa;Reika Iwakawa;M. Narisawa‐Saito;K. Nakashima;K. Tsuta;H. Tsuda;T. Kiyono;J. Yokota;R. Sakai
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文献类型：
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作者：
T. Uekita;S. Fujii;Yuri Miyazawa;Reika Iwakawa;M. Narisawa‐Saito;K. Nakashima;K. Tsuta;H. Tsuda;T. Kiyono;J. Yokota;R. Sakai
RAS参与肿瘤的发生已为人所知，但最近的证据表明RAS在肿瘤的进展中发挥作用，包括转移和侵袭；然而，其机制仍不清楚。在这项研究中，研究确定，在其他常见的突变中，具有RAS突变的人肺癌细胞显示出显著高于没有突变的人肺癌细胞的CUB结构域包含蛋白1(CDCP1)的表达。此外，激活RAS可明显诱导CDCP1，而通过Src定向治疗抑制CDCP1的表达或抑制CDCP1的磷酸化，则可消除激活的RAS诱导的失巢抵抗、迁移和侵袭。在RAS诱导的侵袭模型中，MMP2的激活和MMP9的分泌被发现通过诱导磷酸化的CDCP1来调节。因此，在人类恶性肿瘤的多阶段发展过程中，CDCP1在RAS和Src信号之间的功能联系中是必需的，这突显了CDCP1是与这些癌基因相关的广泛人类癌症的有效治疗靶点。研究提示：癌基因RAS/ERK信号通路诱导的CDCP1蛋白对RAS介导的癌细胞转移潜能具有重要作用。摩尔癌症资源；12(10)；1449-59。©2014 AACR。
Involvement of Ras in cancer initiation is known, but recent evidence indicates a role in cancer progression, including metastasis and invasion; however, the mechanism is still unknown. In this study, it was determined that human lung cancer cells with Ras mutations, among other popular mutations, showed significantly higher expression of CUB domain–containing protein 1 (CDCP1) than those without. Furthermore, activated Ras clearly induced CDCP1, whereas CDCP1 knockdown or inhibition of CDCP1 phosphorylation by Src-directed therapy abrogated anoikis resistance, migration, and invasion induced by activated-Ras. Activation of MMP2 and secretion of MMP9, in a model of Ras-induced invasion, was found to be regulated through induction of phosphorylated CDCP1. Thus, CDCP1 is required for the functional link between Ras and Src signaling during the multistage development of human malignant tumors, highlighting CDCP1 as a potent target for treatment in the broad spectrum of human cancers associated with these oncogenes. Implications: CDCP1 protein induced by oncogenic Ras/Erk signaling is essential for Ras-mediated metastatic potential of cancer cells. Mol Cancer Res; 12(10); 1449–59. ©2014 AACR.