The interaction between miR‑148a and DNMT1 suppresses cell migration and invasion by reactivating tumor suppressor genes in pancreatic cancer

Abstract

DNA methylation is an epigenetic mechanism that cells use to control gene expression, which serves an important role in tumorigenesis. DNA methyltransferase 1 (DNMT1) is responsible for the maintenance of the pattern of DNA methylation. Overexpression of DNMT1 is observed in numerous malignant tumors, including pancreatic cancer, and results in silencing of several key tumor suppressor genes (TSGs). Recent studies have suggested that microRNAs (miRNAs/miRs) contribute to the regulation of DNMT1 expression, and promoter hypermethylation caused by DNMT1 overexpression is associated with the dysfunction of some miRNAs. The present study aimed to reveal the interaction between miR‑148a and DNMT1, and its effects on cell proliferation, migration and invasion of pancreatic cancer cells. Initially, the expression levels of DNMT1 and miR‑148a were detected in pancreatic cancer tissues and AsPC‑1 cells by reverse transcription‑quantitative polymerase chain reaction (PCR). Secondly, the regulatory effects of DNMT1 on miR‑148a were evaluated using methylation‑specific PCR. Furthermore, bioinformatics analysis and dual luciferase reporter assay were used to verify the target relationship between miR‑148a and DNMT1. Finally, in vitro rescue experiments were conducted to evaluate the effects of miR‑148a on the expression of TSGs and the malignant phenotype in AsPC‑1 cells. The results demonstrated that DNMT1 was aberrantly upregulated in pancreatic cancer, and was responsible for hypermethylation of the miR‑148a promoter. Furthermore, DNMT1 was revealed as a direct target of miR‑148a by dual luciferase reporter assay, and restoration of miR‑148a could reactivate TSGs, such as p16, preproenkephalin and Ras association domain family member 1 by targeting DNMT1 in the AsPC‑1 pancreatic cancer cell line. These results indicated that an interaction exists between miR‑148a and DNMT1 in pancreatic cancer. Notably, miR‑148a overexpression significantly inhibited cell proliferation, migration and invasion in AsPC‑1 cells. Therefore, miR‑148a may serve as a novel therapeutic target for the treatment of pancreatic cancer.

Methylation of the miR‑29b‑3p promoter contributes to angiogenesis, invasion, and migration in pancreatic cancer

“…DNA methylation is a form of epigenetic modification and an important mechanism of gene expression regulation (3,4). The occurrence and development of tumors are closely related to DNA methylation abnormalities, which are mainly manifested as a decrease in the overall genomic methylation level in tumor cells and an increase in the methylation level of the promoter region of specific genes (5)(6)(7)(8). Previous studies have shown that methylation abnormalities in multiple promoter regions are closely related to the development of pancreatic cancer (5,6).…”

“…As a member of the DNA methyltransferases (DNMTs), DNMT1 plays an important role in mediating gene expression and chromatin structure, by preserving existing DNA methylation during DNA replication (7). DNMT1 was found to be upregulated in various types of cancer, including pancreatic cancer (8). A study of pancreatic cancer demonstrated that lower expression of DNMT1 reversed the resistance to 5-azadeoxycytidine (9).…”

A novel epigenetic signature for predicting the prognosis of pancreatic ductal adenocarcinoma

“…Many reports suggested that aberrant DNA methylation is involved in the development and progression of pancreatic cancer. Tumor suppressor genes often show hypermethylation of the promoter, thereby suppressing its expression and contributing to the pathogenesis of PDAC [16,17]. Zhou et al [17] found that methylation frequencies of CpG sites within promoter of LITAF were signi cantly higher in PDAC tissues, and LITAF promoter hypermethylation was associated with low LITAF expression.…”

Epigenetic Landscape in Pancreatic Ductal Adenocarcinoma: On the Way to Overcoming Drug Resistance?

“…DNMT1 overexpression was observed in approximately 80% of pancreatic carcinomas [41], where many promoters of key tumor suppressor genes (TSGs) were hypermethylated [42]. Overexpression of DNMT1 was reported to be responsible for silencing key tumor suppressor genes such as p16, PENK, and RASSF1 [43]. Moreover, several studies on PDAC have reported an increase in non-specific and targeted gene-specific 5-hydroxymethylation.…”