Deregulation of promyelocytic leukemia zinc finger protein (PLZF), a tumor suppressor gene, was reported in different types of solid tumors. This study for the first time explored the reduced expression of PLZF and its effects in non-small-cell lung cancer (NSCLC) carcinogenesis. PLZF was found to be down-regulated by 62.8% in 87.1% of 154 paired NSCLC samples by quantitative real-time PCR, and its expression was found to be associated with the sex of the patient (P=0.02). Further analysis showed that down-regulation of PLZF in 35.6% NSCLC samples (31 out of 87) was triggered by hypermethylation in the promoter region. This was validated by demethylation analysis using the A549 cell line. Dual-luciferase reporter assay indicated that CTCF binding to the promoter region could activate PLZF transcription. Overexpression of PLZF in both A549 and LTEP lung cancer cell lines was found to inhibit proliferation and increase apoptosis. Therefore, reduced expression of PLZF was found to be common in NSCLC. PLZF down-regulation was partially correlated with hypermethylation in the promoter region. Decreased levels of PLZF expression may contribute to the pathogenesis of NSCLC by promoting cell survival. Therefore, the restoration of PLZF expression may serve as a new strategy for NSCLC therapy.
BackgroundAdenomatous polyposis coli (APC) has been reported to be a candidate tumor suppressor in many cancers. However, the diagnostic role of APC promoter methylation in non-small cell lung cancer (NSCLC) remains unclear. We systematically integrated published articles and DNA methylation microarray data to investigate the diagnostic performance of the APC methylation test for NSCLC. Two thousand two hundred and fifty-nine NSCLC tumor samples and 1,039 controls were collected from 17 published studies and TCGA NSCLC data. The association between APC promoter methylation and NSCLC was evaluated in a meta-analysis. An independent DNA methylation microarray dataset from TCGA project, in which five CpG sites located in the promoter region of APC were involved, was used to validate the results of the meta-analysis.ResultsA significant association was observed between APC promoter hypermethylation and NSCLC, with an aggregated odds ratio (OR) of 3.79 (95% CI: 2.22 to 6.45) in a random effects model. Pooled sensitivity and specificity were 0.548 (95% CI: 0.42 to 0.67, P < 0.0001) and 0.776 (95% CI: 0.62 to 0.88, P < 0.0001), respectively. Each of the five CpG sites was much better in prediction (area under the curve, AUC: 0.71 to 0.73) in lung adenocarcinoma (Ad) than in lung squamous cell carcinoma (Sc) (AUC: 0.45 to 0.61). The AUCs of the logistic prediction model based on these five CpGs were 0.73 and 0.60 for Ad and Sc, respectively. Integrated analysis indicated that CpG site location, heterogeneous or autogenous controls, and the proportion of adenocarcinoma in samples were the most significant heterogeneity sources.ConclusionsThe methylation status of APC promoter was strongly associated with NSCLC, especially adenocarcinoma. The APC methylation test could be applied in the clinical diagnosis of lung adenocarcinoma.
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