P3.01-036 Eukaryotic Translation Initiation Factors Impact Non-Small Cell Lung Cancer: Topic: Functional Biology in Lung Cancer

Abstract

Non-small cell lung cancer (NSCLC) belongs to the most frequently diagnosed cancer entities and is one of the leading causes of cancer related death worldwide. Deregulation of protein synthesis has received considerable attention as a major step in cancer development and progression. Protein synthesis is regulated at multiple stages, including translation of mRNA into proteins. Studies suggest that ribosomal protein synthesis plays a direct role during tumor-initiation. Crucial for this translation process are eukaryotic initiation factors (eIFs), which ensure the correct 80S ribosome assembly. eIFs are linked to the MAPK and the mTOR signalling pathways, which have become major targets in cancer therapy. Mutations or deregulated expression of eIFs influence cell growth and proliferation, and contribute to carcinogenesis. We hypothesized that eIFs represent crossroads for carcinogenesis in lung cancer and might serve as potential biomarker. Expression profiling of paired NSCLC and non-neoplastic lung tissue (NNLT) from 1.000 individuals were studied by immunohistochemistry on tissue micro arrays (TMAs) with antibodies against the eIF subunits 2α; 3C; 3H; 3M; 4E and 6. eIF expression was evaluated with respect to the staining intensity (intensity score 0-3; 0: no staining, 1: weak, 2: moderate and 3: strong) and percentage of positive tumor cells (proportion score; 0-100%). In addition, the protein and mRNA expression levels of eIFs and mTOR pathway members were determined in 25 patients by Western Blot analysis and qRT-PCR. For the statistical analysis α was set to 5%. Western Blot analysis of NSCLC revealed a significant up-regulation of mTOR and the eIF subunits p2α, 2α, 1A, 4A, and eIF6 compared to NNLT (p< 0,05). The mRNA levels of NSCLC also displayed a significant upregulation of the eIF subunits 2α, 4A, and eIF6 compared to NNLT. Immunohistochemistry highlighted a stronger staining in neoplastic cells for eIF2α, eIF4E, eIF3H and eIF6. Our data indicated that eIFs are significantly upregulated in NSCLC, suggesting an important contribution of eIFs and mTOR signalling to the development and progression of lung carcinomas. A better understanding of the molecular mechanisms in pulmonary carcinogenesis is necessary for the development of novel treatment strategies.