MicroRNA-449a functions as a tumor suppressor in pancreatic cancer by the epigenetic regulation of ATDC expression

Abstract

A growing body of evidence has suggested that microRNAs (miRNAs) play a pivotal role in the development and progression of pancreatic cancer. miRNA-449a (miR-449a) has attracted particular interest due to its critical role in regulating cancer biology in numerous cancer types. However, whether miR-449a is involved in the regulation of pancreatic cancer development and progression remains unknown. In this study, we aimed to investigate the expression pattern and potential biological function of miR-449a in pancreatic cancer. Our results showed that miR-449a levels were significantly down-regulated in pancreatic cancer tissues and cell lines. The overexpression of miR-449a significantly inhibited the proliferation and invasion of pancreatic cancer cells, whereas miR-449a inhibition promoted the proliferation and invasion of pancreatic cancer cells. Bioinformatic analysis predicted that ataxia-telangiectasia group D complementing gene (ATDC) was a potential target gene of miR-449a. The dual-luciferase reporter assay revealed that miR-449a directly binds to the 3′-untranslated region of ATDC. Further analysis demonstrated that miR-449a negatively controls the mRNA and protein expression of ATDC in pancreatic cancer cells. In addition, an inverse correlation between miR-449a and ATDC expression was observed in clinical tissues. Notably, the overexpression of ATDC partially reversed the antitumor effect of miR-449a overexpression, while the silencing of ATDC abrogated the oncogenic effect of miR-449a inhibition in pancreatic cancer cells. In addition, the overexpression of miR-449a inhibited the accumulation of β-catenin and blocked the activation of Wnt signaling by targeting ATDC. Taken together, our study reveals a tumor suppressive role of miR-449a in pancreatic cancer, and demonstrates that the antitumor role of miR-449a is associated with its regulatory effect on ATDC expression. Our study suggests that the miR-449a/ATDC axis may play an important role in the development and progression of pancreatic cancer and may provide potential targets for the development of cancer therapies.