Significance of epiregulin expression induced by KRAS or EGFR mutation in non-small-cell lung cancer

与小细胞肺癌(SCLC)或野生型KRAS/BRAF/EGFR突变的非小细胞肺癌(NSCLC)相比，携带KRAS、BRAF或EGFR突变的非小细胞肺癌(NSCLC)中高表达。下调突变型KRAS、BRAF或EGFR或抑制MEK或ERK可降低NSCLC细胞中ERG的表达。KRAS突变型NSCLC中Ereg表达与KRAS拷贝数呈正相关。ERG主要表达于伴有胸膜受累、淋巴管渗出或血管侵犯的非小细胞肺癌以及KRAS基因突变的腺癌。Ereg的表达是一个独立的预后指标，Ereg的过度表达和KRAS突变与肺腺癌患者的不良预后相关。在KRAS突变型和ERG高表达的NSCLC中，ERG衰减抑制肿瘤生长并诱导细胞凋亡。这些结果表明，致癌KRAS诱导的ERG过度表达有助于侵袭性表型，并可能成为致癌KRAS驱动的非小细胞肺癌的治疗靶点。

EREG is overexpressed in non-small-cell lung cancers (NSCLCs) harboring KRAS, BRAF or EGFR mutations compared with small-cell lung cancers (SCLCs) or NSCLCs with wild-type KRAS/BRAF/EGFR. EREG expression was reduced by knockdown of mutant KRAS, BRAF or EGFR or by MEK or ERK inhibition in NSCLC cells. EREG expression positively correlated with KRAS copy number in KRAS-mutant NSCLCs. EREG was predominantly expressed in NSCLC tumors with pleural involvement, lymphatic permeation or vascular invasion and in KRAS-mutant adenocarcinomas. EREG expression is an independent prognostic marker and EREG overexpression along with KRAS mutations correlated with an unfavorable prognosis for lung adenocarcinoma patients. In KRAS-mutant and EREG overexpressing NSCLCs, EREG attenuation suppressed tumor growth and induced apoptosis. These results suggest that oncogenic KRAS-induced EREG overexpression contributes to an aggressive phenotype and could be a therapeutic target in oncogenic KRAS-driven NSCLC.