title: Oncogenic KRAS-induced epiregulin overexpression contributes to aggressive phenotype and is a promising therapeutic target in non-small-cell lung cancer.
abstract: KRAS mutations are one of the most common driver mutations in non-small-cell lung cancer (NSCLC) and finding druggable target molecules to inhibit oncogenic KRAS signaling is a significant challenge in NSCLC therapy. We recently identified 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, significantly 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 significantly 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 findings suggest that oncogenic KRAS-induced EREG overexpression contributes to an aggressive phenotype and could be a promising therapeutic target in oncogenic KRAS-driven NSCLC.
authors.affiliation: Department of Medicine and Molecular Science, Gunma University School of Medicine, Gunma, Japan. nsunaga@showa.gunma-u.ac.jp
authors.forename: N
authors.initials: N
authors.lastname: Sunaga
authors.forename: K
authors.initials: K
authors.lastname: Kaira
authors.forename: H
authors.initials: H
authors.lastname: Imai
authors.forename: K
authors.initials: K
authors.lastname: Shimizu
authors.forename: T
authors.initials: T
authors.lastname: Nakano
authors.forename: D S
authors.initials: DS
authors.lastname: Shames
authors.forename: L
authors.initials: L
authors.lastname: Girard
authors.forename: J
authors.initials: J
authors.lastname: Soh
authors.forename: M
authors.initials: M
authors.lastname: Sato
authors.forename: Y
authors.initials: Y
authors.lastname: Iwasaki
authors.forename: T
authors.initials: T
authors.lastname: Ishizuka
authors.forename: A F
authors.initials: AF
authors.lastname: Gazdar
authors.forename: J D
authors.initials: JD
authors.lastname: Minna
authors.forename: M
authors.initials: M
authors.lastname: Mori
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000235:genetics; D002070:Butadienes / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000235:genetics* / Q000378:metabolism; D066260:Epiregulin; D066246:ErbB Receptors / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009154:Mutation; D009570:Nitriles / Q000494:pharmacology; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011720:Pyrazoles / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D034622:RNA Interference; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D002070:Butadienes; C587880:EREG protein, human; D066260:Epiregulin; C505241:FR 180204; C117307:KRAS protein, human; D009570:Nitriles; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011724:Pyridazines; C113580:U 0126; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins