Abstract
Amplification and overexpression of putative oncogenes confer growth advantages for tumor development. We used a functional genomic approach that integrated simultaneous genomic and transcript microarray, proteomics, and tissue microarray analyses to directly identify putative oncogenes in lung adenocarcinoma. We first identified 183 genes with increases in both genomic copy number and transcript in six lung adenocarcinoma cell lines. Next, we used two-dimensional polyacrylamide gel electrophoresis and mass spectrometry to identify 42 proteins that were overexpressed in the cancer cells relative to normal cells. Comparing the 183 genes with the 42 proteins, we identified four genes – PRDX1, EEF1A2, CALR, and KCIP-1 – in which elevated protein expression correlated with both increased DNA copy number and increased transcript levels (all r>0.84, two-sided P<0.05). These findings were validated by Southern, Northern, and Western blotting. Specific inhibition of EEF1A2 and KCIP-1 expression with siRNA in the four cell lines tested suppressed proliferation and induced apoptosis. Parallel fluorescence in situ hybridization and immunohistochemical analyses of EEF1A2 and KCIP-1 in tissue microarrays from patients with lung adenocarcinoma showed that gene amplification was associated with high protein expression for both genes and that protein overexpression was related to tumor grade, disease stage, Ki-67 expression, and a shorter survival of patients. The amplification of EEF1A2 and KCIP-1 and the presence of overexpressed protein in tumor samples strongly suggest that these genes could be oncogenes and hence potential targets for diagnosis and therapy in lung adenocarcinoma.
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Acknowledgements
This work was supported by National Institutes of Health Grant CA113707-01, an institutional research grant from The University of Texas MD Anderson Cancer Center, a Developmental Project/Career Development Award from The University of Texas Specialized Programs of Research Excellence in Lung Cancer P50 CA70907, and an M Keck Center for Cancer Gene Therapy Award (all to FJ). We thank Christine F Wogan of the Department of Scientific Publications for editorial review of this manuscript.
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Li, R., Wang, H., Bekele, B. et al. Identification of putative oncogenes in lung adenocarcinoma by a comprehensive functional genomic approach. Oncogene 25, 2628–2635 (2006). https://doi.org/10.1038/sj.onc.1209289
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DOI: https://doi.org/10.1038/sj.onc.1209289
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