Long noncoding RNA DLGAP1-AS2 facilitates Wnt1 transcription through physically interacting with Six3 and drives the malignancy of gastric cancer

Jiawei Lu,Pengcheng Jiang,Heteng Zhang,Tao Rui,Wenbo Zhang,Yinbing Tang,Ji Mao,Beibei Wang,Ying Xu,Wenjie Xie

doi:10.1038/s41420-021-00649-z

Abstract

The long noncoding RNA (lncRNA) DLGAP1-AS2 has recently been characterized as an oncogenic lncRNA in several cancers. However, its biological roles and clinical significance in gastric cancer (GC) remains barely understood. In this study, we performed a systematic analysis of DLGAP1-AS2 expression with data from the TCGA and GEO database as well as our clinic GC samples. In agreement with previous studies, our findings demonstrated that DLGAP1-AS2 was significantly up-regulated in GC and its high expression was associated with poor prognosis, suggesting that DLGAP1-AS2 might be a putative oncogenic lncRNA of GC. Loss of DLGAP1-AS2 restricted cell proliferation, migration, and invasion in GC cell lines. Mechanically, Wnt1 was identified as the downstream target of DLGAP1-AS2 by using bioinformatics analysis coupled with qPCR and Western blot assays. Furthermore, DLGAP1-AS2 was found to directly interact with the transcriptional repressor Six3, and this interaction hampered Six3 binding to the promoter regions of the Wnt1 gene, thereby leading to transcriptional activation of Wnt1. Consequently, GC cells lacking DLGAP1-AS2 showed a decreased Wnt1 expression and weakened Wnt/β-catenin signaling. Further, Six3 silencing could reverse the above effects, highlighting a pivotal role of Six3 in the DLGAP1-AS2-mediated activation of Wnt/β-catenin signaling. Either genetic (Wnt1 knockdown) or pharmacological (LF3) inhibition of Wnt/β-catenin signaling could effectively abolish the activation of Wnt/β-catenin signaling by Six3 depletion, thereby preventing GC cell malignant transformation. Taken together, our results suggest that DLGAP1-AS2 functions as an oncogenic factor by directly interacting with Six3 to relieve its suppression on Wnt1 expression, thereby driving the malignancy of GC. DLGAP1-AS2/Six3/Wnt1/β-catenin signaling axis might serve as a promising diagnostic and therapeutic target for GC.

Highlights

Gastric cancer (GC) is a growing public health concern worldwide, ranked as the fifth most common malignant tumor and the third most common cause of cancer death globally [1]
Acting either as oncogene or tumor suppressor, many long noncoding RNA (lncRNA) have been shown to be implicated in the regulation of GC carcinogenesis and progression
We aimed to explore the role of DLGAP1-AS2 in GC development, which has shown to be significantly increased in GC tumorous tissues, plasmas, and cell lines

Summary

Introduction

Gastric cancer (GC) is a growing public health concern worldwide, ranked as the fifth most common malignant tumor and the third most common cause of cancer death globally [1]. China Cancer Data Report in 2015 shows that the estimated number of new cases of GC in China was 679,000, and the number of deaths was 498,000 [2]. Such high morbidity and mortality are not surprising because the initial signs and symptoms of GC are not obvious and the diagnosis rate of early GC is relatively low [3]. Cytoplasmic protein Dvl/Disheveled (Dsh) is recruited to the cell membrane and activated by phosphorylation, and promoting β-catenin translocation to the nucleus, where it interacts with coregulators of transcription, including

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