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Oncogene (2013) 32, 40344042 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13
http://www.nature.com/ONC
Web End =www.nature.com/onc
ORIGINAL ARTICLE
Oncogenic KRAS-induced epiregulin overexpression contributes to aggressive phenotype and is a promising therapeutic targetin non-small-cell lung cancer
N Sunaga1, K Kaira1, H Imai1, K Shimizu2, T Nakano2, DS Shames3,4, L Girard4,5, J Soh6,9, M Sato8, Y Iwasaki1, T Ishizuka1, AF Gazdar6, JD Minna4,5,7 and M Mori1
KRAS mutations are one of the most common driver mutations in non-small-cell lung cancer (NSCLC) and nding druggable target molecules to inhibit oncogenic KRAS signaling is a signicant challenge in NSCLC therapy. We recently identied epiregulin (EREG) as one of several putative transcriptional targets of oncogenic KRAS signaling in both KRAS-mutant NSCLC cells and immortalized bronchial epithelial cells expressing ectopic mutant KRAS. In the current study, we found that EREG is overexpressed in NSCLCs harboring KRAS, BRAF or EGFR mutations compared with NSCLCs with wild-type KRAS/BRAF/EGFR. Small interfering RNAs (siRNAs) targeting mutant KRAS, but not an siRNA targeting wild-type KRAS, signicantly reduced EREG expression in KRAS-mutant and EREG-overexpressing NSCLC cell lines. In these cell lines, EREG expression was downregulated by MEK and ERK inhibitors. Importantly, EREG expression signicantly correlated with KRAS expression or KRAS copy number in KRAS-mutant NSCLC cell lines. Further expression analysis using 89 NSCLC specimens showed that EREG was predominantly expressed in NSCLCs with pleural involvement, lymphatic permeation or vascular invasion and in KRAS-mutant adenocarcinomas. In addition, multivariate analysis revealed that EREG expression is an independent prognostic marker and EREG overexpression in combination with KRAS mutations was associated with an unfavorable prognosis for lung adenocarcinoma patients. In KRAS-mutant and EREG overexpressing NSCLC cells, siRNA-mediated EREG silencing inhibited anchorage-dependent and -independent growth and induced apoptosis. Our ndings suggest that oncogenic KRAS-induced EREG overexpression contributes to an aggressive phenotype and could be a promising therapeutic target in oncogenic KRAS-driven NSCLC.
Oncogene (2013) 32, 40344042; doi:http://dx.doi.org/10.1038/onc.2012.402
Web End =10.1038/onc.2012.402 ; published online 10 September 2012
Keywords: NSCLC; KRAS; EREG; therapeutic target
INTRODUCTIONLung cancer is the leading cause of cancer-related deaths worldwide.1 Lung cancer comprises two major histological types: small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), and the latter represents 8085% of all lung cancers.2 NSCLC is further histologically classied into three major sub-types: adenocarcinoma, squamous cell carcinoma and...