Oncogenic Ras/ERK signaling activates CDCP1 to promote tumor invasion and metastasis

Mol Cancer Res. 2014 Oct;12(10):1449-59. doi: 10.1158/1541-7786.MCR-13-0587. Epub 2014 Jun 17.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anoikis
  • Antigens, CD / metabolism*
  • Antigens, Neoplasm
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Adhesion Molecules / metabolism*
  • Cell Line, Tumor
  • Cell Movement
  • Genes, ras*
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • MAP Kinase Signaling System*
  • Male
  • Matrix Metalloproteinases / metabolism
  • Mutation / genetics
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasm Proteins / metabolism*
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • src-Family Kinases / metabolism

Substances

  • Antigens, CD
  • Antigens, Neoplasm
  • CDCP1 protein, human
  • Cell Adhesion Molecules
  • Neoplasm Proteins
  • src-Family Kinases
  • Matrix Metalloproteinases