Data from ETS2 Mediated Tumor Suppressive Function and MET Oncogene Inhibition in Human Non–Small Cell Lung Cancer

<div>Abstract<p><b>Purpose:</b> The <i>ETS2</i> 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 <i>ETS2</i> was significantly downregulated in adenocarcinomas. In this study, we probed the yet unknown functional role of <i>ETS2</i> in lung cancer pathogenesis.</p><p><b>Experimental Design:</b> Lung adenocarcinomas (<i>n</i> = 80) and normal lung tissues (<i>n</i> = 30) were profiled using the Affymetrix Human Gene 1.0 ST platform. Immunohistochemical (IHC) analysis was conducted to determine ETS2 protein expression in non–small cell lung cancer (NSCLC) histologic tissue specimens (<i>n</i> = 201). Patient clinical outcome, based on ETS2 IHC expression, was statistically assessed using the log-rank and Kaplan–Meier tests. RNA interference and overexpression strategies were used to assess the effects of <i>ETS2</i> expression on the transcriptome and on various malignant phenotypes.</p><p><b>Results:</b><i>ETS2</i> expression was significantly reduced in lung adenocarcinomas compared with normal lung (<i>P</i> < 0.001). Low ETS2 IHC expression was a significant predictor of shorter time to recurrence in NSCLC (<i>P</i> = 0.009, HR = 1.89) and adenocarcinoma (<i>P</i> = 0.03, HR = 1.86). Moreover, <i>ETS2</i> was found to significantly inhibit lung cancer cell growth, migration, and invasion (<i>P</i> < 0.05), and microarray and pathways analysis revealed significant (<i>P</i> < 0.001) activation of the <i>HGF</i> pathway following <i>ETS2</i> knockdown. In addition, <i>ETS2</i> was found to suppress MET phosphorylation and knockdown of <i>MET</i> expression significantly attenuated (<i>P</i> < 0.05) cell invasion mediated by <i>ETS2</i>-specific siRNA. Furthermore, knockdown of <i>ETS2</i> augmented HGF-induced MET phosphorylation, cell migration, and invasion.</p><p><b>Conclusion(s):</b> Our findings point to a tumor suppressor role for <i>ETS2</i> in human NSCLC pathogenesis through inhibition of the <i>MET</i> proto-oncogene. <i>Clin Cancer Res; 19(13); 3383–95. ©2013 AACR</i>.</p></div>