Abstract
BackgroundThis study was aimed at identifying prognostic biomarkers for stage II-IIIA non-small cell lung cancer (NSCLC) according to histology and at investigating the effect of vorinostat on the expression of these biomarkers.MethodsExpression levels of cyclin D1, cyclin A2, cyclin E, and p16 proteins that are involved in the G1-to-S phase progression of cell cycle were analyzed using immunohistochemistry in formalin-fixed paraffin-embedded tissues from 372 samples of stage II-IIIA NSCLC. The effect of vorinostat on the expression of these proteins, impacts on cell cycle, and histone modification was explored in lung cancer cells.ResultsAbnormal expression of cyclin A2, cyclin D1, cyclin E, and p16 was found in 66, 47, 34, and 51 % of 372 cases, respectively. Amongst the four proteins, only cyclin D1 overexpression was significantly associated with poor recurrence-free survival (adjusted hazard ratio = 1.87; 95 % confidence interval = 1.12 – 2.69, P = 0.02) in adenocarcinoma but not in squamous cell carcinoma (P = 0.44). Vorinostat inhibited cell cycle progression to the S-phase and induced down-regulation of cyclin D1 in vitro. The down-regulation of cyclin D1 by vorinostat was comparable to a siRNA-mediated knockdown of cyclin D1 in A549 cells, but vorinostat in the presence of benzo[a]pyrene showed a differential effect in different lung cancer cell lines. Cyclin D1 down-regulation by vorinostat was associated with the accumulation of dimethyl-H3K9 at the promoter of the gene.ConclusionsThe present study suggests that cyclin D1 may be an independent prognostic factor for recurrence-free survival in stage II-IIIA adenocarcinoma of lung and its expression may be modulated by vorinostat.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-2001-7) contains supplementary material, which is available to authorized users.
Highlights
This study was aimed at identifying prognostic biomarkers for stage II-IIIA non-small cell lung cancer (NSCLC) according to histology and at investigating the effect of vorinostat on the expression of these biomarkers
Expression patterns of the four proteins A total of 372 patients with stage II-IIIA NSCLC participated in this study
Given that adjuvant chemotherapy is effective in some patients with stage II-IIIA NSCLC, discovery of novel chemotherapeutic agents has become increasingly important in improving patient survival
Summary
This study was aimed at identifying prognostic biomarkers for stage II-IIIA non-small cell lung cancer (NSCLC) according to histology and at investigating the effect of vorinostat on the expression of these biomarkers. In the last 10 years, adjuvant chemotherapy for patients with completely resected stage II-IIIA NSCLC has. Two recent meta-analysis of randomized controlled trials showed an absolute 5-year survival benefit of 5 to 10 % irrespective of the associated drugs such as vinorelbine or etoposide, with the main survival advantage being in the patients with stage II-IIIA NSCLC [4, 5]. Histone deacetylase inhibitors (HDACIs) modify the acetylation state of histone tails and induce cell cycle arrest at both G1 and G2 phases. Vorinostat causes cell growth inhibition, differentiation, and apoptosis of lung cancer cells in vitro through various mechanisms [7,8,9,10]
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