Hypermethylation of the Wnt inhibitory factor-1 (WIF-1) promoter has been implicated in the overactivation of the Wnt pathway in human lung cancer. Curcuminoids exert anti-cancer effects and have been reported to act as hypomethylating agents. Previously, we have investigated and compared the demethylation effects of three curcuminoids and observed that bisdemethoxycurcumin exhibited the strongest demethylation potency. In this study, we used lung cancer cell lines with WIF-1 promoter hypermethylated as a model to study the demethylating effect of bisdemethoxycurcumin on WIF-1 restoration, Wnt signaling activity and cell death. Bisdemethoxycurcumin directly suppressed the activity of DNA methyltransferase-1 (DNMT1) but did not influence DNMT1 expression. In addition, it induced WIF-1 promoter demethylation and protein re-expression. WIF-1 restoration in lung cancer cells down-regulated nuclear β-catenin and the canonical Wnt cascade. Furthermore, we also showed that down-regulation of Wnt signaling by WIF-1 was required for bisdemethoxycurcumin-induced apoptosis in certain lung cancer cell types. This report is the first to show that bisdemethoxycurcumin induces apoptosis by reactivating WIF-1 from a silenced state. Our results provide new insights into the anti-cancer actions of bisdemethoxycurcumin.
Different subtypes of non-small cell lung cancer (NSCLC) have distinct sites of origin, histologies, genetic and epigenetic changes. In this study, we explored the mechanisms of ECT2 dysregulation and compared its prognostic value in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). In addition, we also investigated the enrichment of ECT2 co-expressed genes in KEGG pathways in LUAD and LUSC. Bioinformatic analysis was performed based on data from the Cancer Genome Atlas (TCGA)-LUAD and TCGA-LUSC. Results showed that ECT2 expression was significantly upregulated in both LUAD and LUSC compared with normal lung tissues. ECT2 expression was considerably higher in LUSC than in LUAD. The level of ECT2 DNA methylation was significantly lower in LUSC than in LUAD. ECT2 mutation was observed in 5% of LUAD and in 51% of LUSC cases. Amplification was the predominant alteration. LUAD patients with ECT2 amplification had significantly worse disease-free survival (p = 0.022). High ECT2 expression was associated with unfavorable overall survival (OS) (p<0.0001) and recurrence-free survival (RFS) (p = 0.001) in LUAD patients. Nevertheless, these associations were not observed in patients with LUSC. The following univariate and multivariate analysis showed that the high ECT2 expression was an independent prognostic factor for poor OS (HR: 2.039, 95%CI: 1.457–2.852, p<0.001) and RFS (HR: 1.715, 95%CI: 1.210–2.432, p = 0.002) in LUAD patients, but not in LUSC patients. Among 518 genes co-expressed with ECT2 in LUAD and 386 genes co-expressed with ECT2 in LUSC, there were only 98 genes in the overlapping cluster. Some of the genes related KEGG pathways in LUAD were not observed in LUSC. These differences might help to explain the different prognostic value of ECT2 in LUAD and LUSC, which are also worthy of further studies.
Purpose: was demonstrated to be aberrantly expressed and affected cell activities in some types of diseases, including cancer. However, the role of miR-4284 in non-small cell lung cancer (NSCLC) is largely unknown. The aim of this study was to investigate the expression and biological role of miR-4284 in NSCLC. Patients and Methods: The qRT-PCR assay was applied to detect the expression of miR-4284 in NSCLC tissues and cell lines. Kaplan-Meier curve method and multiple Cox regression analyses were used to explore the prognostic factors for postoperative NSCLC patients. The CCK-8 assay was carried out to measure the proliferative abilities of A549 and H1299 cells. Transwell migration and invasion assays were used to determine the cell migratory and invasive capabilities of NSCLC cells. Results: miR-4284 expression was upregulated in NSCLC tissues and cell lines. High expression of miR-4284 was correlated with poor differentiation, positive lymph node metastasis, and advanced TNM stages. In addition, postoperative patients with higher expression of miR-4284 exhibited a shorter overall survival time than those with lower expression of miR-4284. Moreover, the upregulation of miR-4284 accelerated cell proliferative, migratory, and invasive abilities of A549 and H1299 cells, while the downregulation of miR-4284 inhibited these cellular capabilities. Conclusion: miR-4284 was noticeably upregulated in NSCLC and associated with a poor prognosis of postoperative NSCLC patients. miR-4284 promoted the proliferation, migration, and invasion of A549 and H1299 cells. This study indicated that miR-4284 might serve as a prognostic biomarker and a potential therapeutic target for postoperative NSCLC patients.
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