Oncogenic KRAS-induced epiregulin overexpression contributes to aggressive phenotype and is a promising therapeutic target in non-small-cell lung cancer.
Oncogenic KRAS-induced epiregulin overexpression contributes to aggressive phenotype and is a promising therapeutic target in non-small-cell lung cancer.
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DOI：
10.1038/onc.2012.402
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发表时间：
2013-08-22
期刊：
影响因子：
8
通讯作者：
Mori, M.
中科院分区：
文献类型：
--
作者：
Sunaga, N.;Kaira, K.;Imai, H.;Shimizu, K.;Nakano, T.;Shames, D. S.;Girard, L.;Soh, J.;Sato, M.;Iwasaki, Y.;Ishizuka, T.;Gazdar, A. F.;Minna, J. D.;Mori, M.
KRAS 突变是非小细胞肺癌 (NSCLC) 中最常见的驱动突变之一，寻找可药物靶分子来抑制致癌 KRAS 信号传导是 NSCLC 治疗中的重大挑战。我们最近发现上皮调节蛋白（EREG）是 KRAS 突变 NSCLC 细胞和表达异位突变 KRAS 的永生化支气管上皮细胞中致癌 KRAS 信号传导的几个假定转录靶标之一。在当前的研究中，我们发现与野生型KRAS/BRAF/EGFR突变的NSCLC相比，EREG在携带KRAS、BRAF或EGFR突变的NSCLC中过表达。靶向突变型 KRAS 的小干扰 RNA (siRNA)（而非靶向野生型 KRAS 的 siRNA）显着降低了 KRAS 突变型和 EREG 过表达 NSCLC 细胞系中的 EREG 表达。在这些细胞系中，MEK 和 ERK 抑制剂下调了 EREG 表达。重要的是，KRAS 突变 NSCLC 细胞系中 EREG 表达与 KRAS 表达或 KRAS 拷贝数显着相关。对 89 例 NSCLC 标本的进一步表达分析表明，EREG 主要在胸膜受累、淋巴管渗透或血管侵犯的 NSCLC 以及 KRAS 突变腺癌中表达。此外，多变量分析显示，EREG 表达是一个独立的预后标志物，EREG 过度表达与 KRAS 突变相结合与肺腺癌患者的不良预后相关。在 KRAS 突变和 EREG 过表达 NSCLC 细胞中，siRNA 介导的 EREG 沉默抑制贴壁依赖性和非依赖性生长并诱导细胞凋亡。我们的研究结果表明，致癌 KRAS 诱导的 EREG 过度表达有助于形成侵袭性表型，并且可能成为致癌 KRAS 驱动的 NSCLC 的有前途的治疗靶点。
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.
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