The prognosis of pancreatic ductal adenocarcinoma (PDAC) remains poor even among patients with the same Tumor-Node-Metastasis stage. Thus, it is necessary to identify biomarkers that can accurately predict outcomes. There is accumulating evidence suggesting that microRNA (miR) expression influences overall survival (OS) time in patients with PDAC, via the regulation of tumor suppressor genes and oncogene expression. Specifically, miR-608 expression is hypothesized to regulate PDAC progression via the downregulation of bromodomain-containing protein 4 (BRD4) expression and the promotion of cell apoptosis. The present study aimed to investigate this theory. Thus, whole genome expression microarray analysis was performed on three patient samples with OS time >30 months, and compared with three samples with <12 months, in order to identify differentially expressed miRNAs (DEMs), via EdgeR analysis. A total of 591 DEMs were identified that exhibited a fold change >1, including 390 upregulated and 201 downregulated genes. Subsequently, 10 DEMs were identified using quantitative PCR in a different population of 68 tissues, collected from patients with PDAC. Notably, a high level of miRNA-608 expression was associated with longer OS times (P<0.05). Bioinformatics analysis was then performed to predict the molecular mechanism underlying the regulation of cell apoptosis by miRNA-608, and a dual-luciferase assay determined that overexpression of mimics in the Panc-1 and Bxpc-3 pancreatic cancer cell lines increased levels of apoptosis compared with the control. Additionally, high miRNA-608 expression decreased the protein level of BRD4. A luciferase reporting assay was used to elucidate whether miRNA-608 may directly inhibit the expression of BRD4 by binding to the 3'-untranslated region of its mRNA in the same cell lines. A subsequent rescue experiment indicated that the upregulation of BRD4 may reverse the apoptosis-promoting effect induced by miRNA-608. In summary, the present study revealed that miRNA-608 promotes apoptosis in PDAC via the negative regulation of BRD4. The results of the present study provide a theoretical basis that may improve the prediction of prognosis in patients with PDAC, and also indicate an opportunity to develop individualized treatment and investigate novel therapeutics that target these mechanisms.
Keywords: apoptosis; bromodomain-containing protein 4; microRNA-608; pancreatic ductal adenocarcinoma.
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