title: Oncogenic Ras/ERK signaling activates CDCP1 to promote tumor invasion and metastasis.
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.
  
  
  CONCLUSIONS
  CDCP1 protein induced by oncogenic Ras/Erk signaling is essential for Ras-mediated metastatic potential of cancer cells.
authors.affiliation: Division of Metastasis and Invasion Signaling, National Cancer Center Research Institute, Tokyo, Japan. Department of Applied Chemistry, National Defense Academy, Yokosuka, Kanagawa, Japan.
authors.forename: Takamasa
authors.initials: T
authors.lastname: Uekita
authors.affiliation: Division of Metastasis and Invasion Signaling, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Fujii
authors.affiliation: Division of Metastasis and Invasion Signaling, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Miyazawa
authors.affiliation: Division of Multistep Carcinogenesis, National Cancer Research Institute, Tokyo, Japan.
authors.forename: Reika
authors.initials: R
authors.lastname: Iwakawa
authors.affiliation: Division of Virology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Mako
authors.initials: M
authors.lastname: Narisawa-Saito
authors.affiliation: Division of Metastasis and Invasion Signaling, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nakashima
authors.affiliation: Department of Pathology and Clinical Laboratory, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Tsuta
authors.affiliation: Department of Pathology and Clinical Laboratory, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Tsuda
authors.affiliation: Division of Virology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Kiyono
authors.affiliation: Division of Multistep Carcinogenesis, National Cancer Research Institute, Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Yokota
authors.affiliation: Division of Metastasis and Invasion Signaling, National Cancer Center Research Institute, Tokyo, Japan. rsakai@ncc.go.jp.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Sakai
mesh_terms: D023102:Anoikis; D015703:Antigens, CD / Q000378:metabolism*; D000951:Antigens, Neoplasm; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; C432044:CDCP1 protein, human; D015815:Cell Adhesion Molecules; D009363:Neoplasm Proteins; D019061:src-Family Kinases; D020782:Matrix Metalloproteinases