ETS2 mediated tumor suppressive function and MET oncogene inhibition in human non-small cell lung cancer.
ETS2 mediated tumor suppressive function and MET oncogene inhibition in human non-small cell lung cancer.
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DOI：
10.1158/1078-0432.ccr-13-0341
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发表时间：
2013-07-01
期刊：
影响因子：
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通讯作者：
Kadara H
中科院分区：
文献类型：
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作者：
Kabbout M;Garcia MM;Fujimoto J;Liu DD;Woods D;Chow CW;Mendoza G;Momin AA;James BP;Solis L;Behrens C;Lee JJ;Wistuba II;Kadara H
ETS 2转录因子是一种进化上保守的基因，在癌症中失调。我们通过表达谱分析肺腺癌和正常肺组织的转录组，发现ETS 2在腺癌中显著下调。在这项研究中，我们探讨了ETS 2在肺癌发病机制中尚未发现的功能作用。使用Affytechnic Human Gene 1.0 ST平台分析肺腺癌（n=80）和正常肺组织（n=30）。进行免疫组织化学（IHC）分析以确定NSCLC组织学组织标本（n=201）中的ETS 2蛋白表达。基于ETS 2 IHC表达，使用对数秩和Kaplan-Meier检验对患者临床结局进行统计学评估。采用RNA干扰和过表达策略来评估ETS 2表达对转录组和各种恶性表型的影响。与正常肺相比，肺腺癌中ETS 2表达显著降低（p<0.001）。低ETS 2 IHC表达是NSCLC（p=0.009，HR=1.89）和腺癌（p=0.03，HR=1.86）中至复发时间较短的显著预测因子。此外，发现ETS 2显著抑制肺癌细胞生长、迁移和侵袭（p<0.05），并且微阵列和途径分析揭示了在ETS 2敲低后HGF途径的显著（p<0.001）活化。此外，发现ETS 2抑制MET磷酸化并且MET表达的敲低显著减弱（p<0.05）由ETS 2特异性siRNA介导的细胞侵袭。此外，ETS 2的敲低增强了HGF诱导的MET磷酸化、细胞迁移和侵袭。我们的研究结果指出，通过抑制MET原癌基因，ETS 2在人类NSCLC发病机制中具有肿瘤抑制作用。
The ETS2 transcription factor is an evolutionarily conserved gene that is deregulated in cancer. We analyzed the transcriptome of lung adenocarcinomas and normal lung tissue by expression profiling and found that ETS2 was significantly down-regulated in adenocarcinomas. In this study, we probed the yet unknown functional role of ETS2 in lung cancer pathogenesis. Lung adenocarcinomas (n=80) and normal lung tissues (n=30) were profiled using the Affymetrix Human Gene 1.0 ST platform. Immunohistochemical (IHC) analysis was performed to determine ETS2 protein expression in NSCLC histological tissue specimens (n=201). Patient clinical outcome, based on ETS2 IHC expression, was statistically assessed using the log-rank and Kaplan-Meier tests. RNA interference and over-expression strategies were employed to assess effects of ETS2 expression on the transcriptome and on various malignant phenotypes. ETS2 expression was significantly reduced in lung adenocarcinomas compared to normal lung (p<0.001). Low ETS2 IHC expression was a significant predictor of shorter time to recurrence in NSCLC (p=0.009, HR=1.89) and adenocarcinoma (p=0.03, HR=1.86). Moreover, ETS2 was found to significantly inhibit lung cancer cell growth, migration and invasion (p<0.05), and microarray and pathways analysis revealed significant (p<0.001) activation of the HGF pathway following ETS2 knockdown. In addition, ETS2 was found to suppress MET phosphorylation and knockdown of MET expression significantly attenuated (p<0.05) cell invasion mediated by ETS2-specific siRNA. Furthermore, knockdown of ETS2 augmented HGF-induced MET phosphorylation, cell migration and invasion. Our findings point to a tumor suppressor role for ETS2 in human NSCLC pathogenesis through inhibition of the MET proto-oncogene.