MiR-10a-5p targets TFAP2C to promote gemcitabine resistance in pancreatic ductal adenocarcinoma

Guangbing Xiong,Mengyu Feng,Suli Zheng,Taiping Zhang,Yupei Zhao,Ya Hu,Lianfang Zheng,Lei You,Hua Huang,Gang Yang

doi:10.1186/s13046-018-0739-x

Abstract

BackgroundBy regulating target genes, microRNAs play essential roles in carcinogenesis and drug resistance in human pancreatic ductal adenocarcinoma (PDAC). Previous studies have shown that microRNA-10a-5p (miR-10a-5p) is overexpressed in PDAC and acts as an oncogene to promote the metastatic behavior of PDAC cells. However, the role of miR-10a-5p in PDAC chemoresistance remains unclear.MethodsThe effects of miR-10a-5p on biological behaviors were analyzed. MiR-10a-5p and TFAP2C levels in tissues were detected, and the clinical value was evaluated.ResultsWe found that miR-10a-5p is up-regulated in gemcitabine-resistant PDAC cells and enhances PDAC cell gemcitabine resistance in vitro and vivo. Meanwhile, we also determined that miR-10a-5p promotes the migratory and invasive ability of PDAC cells. Next, we confirmed that transcription factor activating protein 2 gamma (TFAP2C) is a target of miR-10a-5p, and TFAP2C overexpression resensitizes PDAC cells to gemcitabine, which is initiated by miR-10a-5p. Further studies revealed that TFAP2C also decreased PDAC cell migration and invasion capability. Finally, survival analysis demonstrated that high miR-10a-5p expression levels and low TFAP2C expression levels were both independent adverse prognostic factors in patients with PDAC.ConclusionTogether, these results indicate that miR-10a-5p/TFAP2C may be new therapeutic target and prognostic marker in PDAC.

Highlights

By regulating target genes, microRNAs play essential roles in carcinogenesis and drug resistance in human pancreatic ductal adenocarcinoma (PDAC)
MiR-10a-5p enhances gemcitabine resistance in vitro and in vivo To determine if miR-10a-5p is potentially associated with gemcitabine resistance in PDAC, we first performed quantitative RT–PCR to validate miR-10a-5p expression in the previously established gemcitabine-resistant PDAC cell line AsPC-1-Gem
Compared with cells transfected with inhibitor controls, PDAC cells transfected with miR-10a-5p inhibitors were more sensitive to gemcitabine (Fig. 1d and h)

Summary

Introduction

MicroRNAs play essential roles in carcinogenesis and drug resistance in human pancreatic ductal adenocarcinoma (PDAC). Previous studies have shown that microRNA-10a-5p (miR-10a-5p) is overexpressed in PDAC and acts as an oncogene to promote the metastatic behavior of PDAC cells. Pancreatic ductal adenocarcinoma (PDAC) is the most deadly malignancy, with a overall survival rate of 7% 5 years after diagnosis [1]. MicroRNAs (miRNAs) are a class of small non-coding RNAs that are composed of 19~ 25 nucleotides. They negatively regulate genes at the post-transcriptional level by binding to the 3′ or 5′ untranslated region (UTR) of target mRNAs. In recent years, many studies have revealed that miRNA dysregulation is involved in PDAC carcinogenesis and drug resistance by serving as

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