LncRNA MAGI2-AS3 Is Regulated by BRD4 and Promotes Gastric Cancer Progression via Maintaining ZEB1 Overexpression by Sponging miR-141/200a

Dandan Li; Jingjie Wang; Meixin Zhang; Xinhui Hu; Jiajun She; Xuemei Qiu; Xudong Zhang; Li Xu; Ying Liu; Shanshan Qin

doi:10.1016/j.omtn.2019.11.003

LncRNA MAGI2-AS3 Is Regulated by BRD4 and Promotes Gastric Cancer Progression via Maintaining ZEB1 Overexpression by Sponging miR-141/200a

Mol Ther Nucleic Acids. 2020 Mar 6:19:109-123. doi: 10.1016/j.omtn.2019.11.003. Epub 2019 Nov 15.

Authors

Dandan Li¹, Jingjie Wang¹, Meixin Zhang², Xinhui Hu², Jiajun She², Xuemei Qiu², Xudong Zhang², Li Xu³, Ying Liu⁴, Shanshan Qin⁵

Affiliations

¹ School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China; School of Biomedical Engineering, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China.
² School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China.
³ School of Biomedical Engineering, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China.
⁴ School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China; School of Biomedical Engineering, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China. Electronic address: ying_liu1002@163.com.
⁵ School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China; School of Biomedical Engineering, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China. Electronic address: qinss77@163.com.

Abstract

Long non-coding RNAs (lncRNAs) play critical roles in tumorigenesis and tumor progression. However, the biological function of most lncRNAs remains unknown in human gastric cancer. This study here aims to explore the unknown function of lncRNA MAGI2-AS3 in gastric cancer. First, bioinformatics analysis showed that lncRNA MAGI2-AS3 was overexpressed in gastric cancer tissues, and the overexpression of MAGI2-AS3 has been shown to be associated with poor prognosis in all three independent gastric cancer cohorts (The Cancer Genome Atlas stomach cancer [TCGA_STAD], GEO: GSE62254 and GSE15459). The multivariate analysis indicated that lncRNA MAGI2-AS3 was an independent prognostic factor for both overall survival and disease-free survival of gastric cancer patients. Moreover, MAGI2-AS3 was identified to be an epithelial-mesenchymal transition (EMT)-related lncRNA and was highly co-expressed with ZEB1/2 in both gastric cancer tissues and normal stomach tissues. Loss-of-function and gain-of-function studies showed that lncRNA MAGI2-AS3 could positively regulate ZEB1 expression and the process of cell migration and invasion in gastric cancer. Subcellular location assay showed that lncRNA MAGI2-AS3 was mainly located in the cytoplasm of gastric cancer cells. Bioinformatics analysis and functional experiments revealed that lncRNA MAGI2-AS3 was negatively correlated with miR-141/200a expression and negatively regulated miR-141/200a-3p expression in gastric cancer. Therefore, we speculate that lncRNA MAGI2-AS3 promotes tumor progression through sponging miR-141/200a and maintaining overexpression of ZEB1 in gastric cancer. Nevertheless, we identified that BRD4 is a transcriptional regulator of lncRNA MAGI2-AS3 in gastric cancer. Additionally, our findings highlight that lncRNA MAGI2-AS3 is an ideal biomarker and could be a potential therapeutic target for gastric cancer.

Keywords: BRD4; ZEB1; gastric cancer; lncRNA MAGI2-AS3; miR-141; miR-200a.