|Impact of the integrin signaling adaptor protein NEDD9 on prognosis and metastatic behavior of human lung cancer.|
|PMID: 23037767 Owner: NLM Status: MEDLINE|
|PURPOSE: 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.
EXPERIMENTAL DESIGN: 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.
CONCLUSION: Our data thus suggest that NEDD9 is a promising biomarker for the prognosis of NSCLCs and its expression can promote NSCLC metastasis.
|Shunsuke Kondo; Satoshi Iwata; Taketo Yamada; Yusuke Inoue; Hiromi Ichihara; Yoshiko Kichikawa; Tomoki Katayose; Akiko Souta-Kuribara; Hiroto Yamazaki; Osamu Hosono; Hiroshi Kawasaki; Hirotoshi Tanaka; Yuichiro Hayashi; Michiie Sakamoto; Kazunori Kamiya; Nam H Dang; Chikao Morimoto|
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|Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2012-10-04|
|Title: Clinical cancer research : an official journal of the American Association for Cancer Research Volume: 18 ISSN: 1078-0432 ISO Abbreviation: Clin. Cancer Res. Publication Date: 2012 Nov|
|Created Date: 2012-11-16 Completed Date: 2013-04-26 Revised Date: 2013-06-03|
Medline Journal Info:
|Nlm Unique ID: 9502500 Medline TA: Clin Cancer Res Country: United States|
|Languages: eng Pagination: 6326-38 Citation Subset: IM|
|Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Tokyo, Japan.|
|APA/MLA Format Download EndNote Download BibTex|
Adaptor Proteins, Signal Transducing
Carcinoma, Non-Small-Cell Lung / metabolism*, mortality, secondary
Cell Line, Tumor
Crk-Associated Substrate Protein / genetics, metabolism
Epidermal Growth Factor / physiology
Gene Knockdown Techniques
Integrins / metabolism
Lung Neoplasms / metabolism*, mortality, pathology
Mice, Inbred NOD
Phosphoproteins / genetics, metabolism*
Proportional Hazards Models
Protein Processing, Post-Translational
Quinazolines / pharmacology
RNA, Small Interfering / genetics
Receptor, Epidermal Growth Factor / antagonists & inhibitors, metabolism
Tumor Markers, Biological / genetics, metabolism*
|0/Adaptor Proteins, Signal Transducing; 0/BCAR1 protein, human; 0/Crk-Associated Substrate Protein; 0/Integrins; 0/NEDD9 protein, human; 0/Phosphoproteins; 0/Quinazolines; 0/RNA, Small Interfering; 0/Tumor Markers, Biological; 62229-50-9/Epidermal Growth Factor; EC 18.104.22.168/Receptor, Epidermal Growth Factor; S65743JHBS/gefitinib|
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