Division of Metastasis and Invasion Signaling, National Cancer Center Research Institute, Tokyo, Japan. Department of Applied Chemistry, National Defense Academy, Yokosuka, Kanagawa, Japan.
Division of Metastasis and Invasion Signaling, National Cancer Center Research Institute, Tokyo, Japan.
Mol Cancer Res. 2014 Oct;12(10):1449-59. doi: 10.1158/1541-7786.MCR-13-0587. Epub 2014 Jun 17.
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.
CDCP1 protein induced by oncogenic Ras/Erk signaling is essential for Ras-mediated metastatic potential of cancer cells.
已知 Ras 参与癌症的起始，但最近的证据表明它在癌症的进展中起作用，包括转移和侵袭；然而，其机制尚不清楚。在这项研究中，确定具有 Ras 突变的人类肺癌细胞（除了其他常见的突变外）比没有突变的细胞表现出更高水平的 CUB 结构域蛋白 1（CDCP1）表达。此外，激活的 Ras 明显诱导了 CDCP1，而 CDCP1 的敲低或 Src 定向治疗抑制 CDCP1 磷酸化则消除了由激活的 Ras 诱导的抗凋亡、迁移和侵袭。在 Ras 诱导的侵袭模型中发现，MMP2 的激活和 MMP9 的分泌是通过诱导磷酸化的 CDCP1 来调节的。因此，在人类恶性肿瘤的多阶段发展过程中，CDCP1 是 Ras 和 Src 信号之间功能性联系所必需的，这突出了 CDCP1 作为与这些致癌基因相关的广泛人类癌症治疗的有效靶点。
由致癌性 Ras/Erk 信号诱导的 CDCP1 蛋白对于 Ras 介导的癌细胞转移潜能是必需的。
