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Τετάρτη 11 Ιουλίου 2018

Altered cell-cycle control, inflammation and adhesion in high-risk persistent bronchial dysplasia

Persistent bronchial dysplasia (BD) is associated with increased risk of developing invasive squamous cell carcinoma (SCC) of the lung. In this study, we hypothesized that differences in gene expression profiles between persistent and regressive BD would identify cellular processes that underlie progression to SCC. RNA expression arrays comparing baseline biopsies from 32 bronchial sites that persisted/progressed to 31 regressive sites showed 395 differentially expressed genes (ANOVA, FDR ≤ 0.05). 31 pathways showed significantly altered activity between the two groups, many of which were associated with cell cycle control and proliferation, inflammation, or epithelial differentiation/cell-cell adhesion. Cultured persistent BD cells exhibited increased expression of polo-like kinase 1 (PLK1), which was associated with multiple cell cycle pathways. Treatment with PLK1 inhibitor induced apoptosis and G2/M arrest and decreased proliferation compared to untreated cells; these effects were not seen in normal or regressive BD cultures. Inflammatory pathway activity was decreased in persistent BD, and the presence of an inflammatory infiltrate was more common in regressive BD. Regressive BD were also associated with trends toward overall increases in macrophages and T lymphocytes and altered polarization of these inflammatory cell subsets. Increased desmoglein 3 and plakoglobin expression was associated with higher grade and persistence of BD. These results identify alterations in the persistent subset of BD that are associated with high risk for progression to invasive SCC. These alterations may serve as strong markers of risk and as effective targets for lung cancer prevention.

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