Impact of the integrin signaling adaptor protein NEDD9 on prognosis and metastatic behavior of human lung cancer

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

研究成果: Article査読

36 被引用数 (Scopus)

抄録

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-2Rγnull 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.

本文言語English
ページ(範囲)6326-6338
ページ数13
ジャーナルClinical Cancer Research
18
22
DOI
出版ステータスPublished - 2012 11月 15

ASJC Scopus subject areas

  • 腫瘍学
  • 癌研究

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