Expression of eukaryotic initiation factor 4E in atypical adenomatous hyperplasia and adenocarcinoma of the human...

The overexpression of eukaryotic initiation factor 4E (eIF4E), a key regulator of protein synthesis, is involved in the malignant progression of various human cancers. We investigated eIF4E expression in atypical adenomatous hyperplasia (AAH) and adenocarcinomas of the human peripheral lung. On the basis of the WHO criteria with minor modifications, adenocarcinomas were classified as bronchioloalveolar carcinoma (BAC), mixed subtypes with a bronchioloalveolar pattern and minor invasion (early MX), and mixed subtypes with a papillary pattern and marked invasion (overt MX). eIF4E immunohistochemistry was performed in 143 tissue samples (31 AAH, 38 BAC, 43 early MX, and 31 overt MX). Both tumoral and stromal eIF4E levels were elevated from AAH, BAC, and early MX to overt MX and significantly associated with histological grade (P < 0.001 and P < 0.001, respectively). Tumoral and stromal eIF4E staining intensities were significantly correlated (P < 0.01). Immunoblot analysis of 51 tissue samples (2 AAH, 11 BAC, 18 early MX, and 20 overt MX) demonstrated that eIF4E expression in adenocarcinomas was 3.4-7.4-fold higher than in normal lung and that its expression progressively increased in the following order: AAH (lowest expression), BAC, early MX, and overt MX (highest expression). Multiple regression analysis revealed that both tumoral and stromal eIF4E expressions were significant independent factors for the histological subtype (P < 0.01 and P < 0.01, respectively). These results suggest that translational control is dysregulated during the development of peripheral lung adenocarcinoma and that progressive increases of tumoral and stromal eIF4E may be part of a positive feedback loop for malignant progression.