title: Impact of the integrin signaling adaptor protein NEDD9 on prognosis and metastatic behavior of human lung cancer.
abstract: OBJECTIVE
  In a substantial population of non-small cell lung cancer (NSCLC), expression and activation of EGF receptor (EGFR) have been reported and is regarded as a novel molecular target. A growing body of evidence has shown the signaling crosstalk between EGFR and integrins in cellular migration and invasion. NEDD9 is an integrin signaling adaptor protein composed of multiple domains serving as substrate for a variety of tyrosine kinases. In the present study, we aimed at elucidating a role of NEDD9 in the signaling crosstalk between EGFR and integrins.
  
  
  METHODS
  Using NSCLC cell lines, we conducted immunoblotting and cellular migration/invasion assay in vitro. Next, we analyzed metastasis assays in vivo by the use of xenograft transplantation model. Finally, we retrospectively evaluated clinical samples and records of patients with NSCLCs.
  
  
  RESULTS
  We showed that tyrosine phosphorylation of NEDD9 was reduced by the inhibition of EGFR in NSCLC cell lines. Overexpression of constitutively active EGFR caused tyrosine phosphorylation of NEDD9 in the absence of integrin stimulation. By gene transfer and gene knockdown, we showed that NEDD9 plays a pivotal role in cell migration and invasion of those cells in vitro. Furthermore, overexpression of NEDD9 promoted lung metastasis of an NSCLC cell line in NOD/Shi-scid, IL-2Rγ(null) mice (NOG) mice. Finally, univariate and multivariate Cox model analysis of NSCLC clinical specimens revealed a strong correlation between NEDD9 expression and recurrence-free survival as well as overall survival.
  
  
  CONCLUSIONS
  Our data thus suggest that NEDD9 is a promising biomarker for the prognosis of NSCLCs and its expression can promote NSCLC metastasis.
authors.affiliation: Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kondo
authors.forename: Satoshi
authors.initials: S
authors.lastname: Iwata
authors.forename: Taketo
authors.initials: T
authors.lastname: Yamada
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Inoue
authors.forename: Hiromi
authors.initials: H
authors.lastname: Ichihara
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Kichikawa
authors.forename: Tomoki
authors.initials: T
authors.lastname: Katayose
authors.forename: Akiko
authors.initials: A
authors.lastname: Souta-Kuribara
authors.forename: Hiroto
authors.initials: H
authors.lastname: Yamazaki
authors.forename: Osamu
authors.initials: O
authors.lastname: Hosono
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawasaki
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Tanaka
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Michiie
authors.initials: M
authors.lastname: Sakamoto
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kamiya
authors.forename: Nam H
authors.initials: NH
authors.lastname: Dang
authors.forename: Chikao
authors.initials: C
authors.lastname: Morimoto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement; D050719:Crk-Associated Substrate Protein / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D004815:Epidermal Growth Factor / Q000502:physiology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D055785:Gene Knockdown Techniques; D006801:Humans; D016023:Integrins / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015999:Multivariate Analysis; D009368:Neoplasm Transplantation; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D016016:Proportional Hazards Models; D011499:Protein Processing, Post-Translational; D011799:Quinazolines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D020239:Receptor Cross-Talk; D012189:Retrospective Studies; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C493841:BCAR1 protein, human; D014408:Biomarkers, Tumor; D050719:Crk-Associated Substrate Protein; D016023:Integrins; C099942:NEDD9 protein, human; D010750:Phosphoproteins; D011799:Quinazolines; D034741:RNA, Small Interfering; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D000077156:Gefitinib