Abstract
BackgroundLong noncoding RNAs (lncRNAs) have emerged as important regulators of tumorigenesis and cancer progression. Recently, the lncRNA AGAP2-AS1 was identified as an oncogenic lncRNA in human non-small cell lung cancer (NSCLC) and its elevated expression was linked to NSCLC development and progression. However, the expression pattern and molecular mechanism of AGAP2-AS1 in gastric cancer (GC) have not been characterized.MethodsBioinformatic analysis was performed to determine AGAP2-AS1 expression levels in the GC and normal tissues using gene profiling data from the Gene Expression Omnibus. Quantitative real-time polymerase chain reaction was used to validate AGAP2-AS1 expression in the GC tissues/cell lines compared with that in the adjacent nontumorous tissues/normal epithelial cells. Loss- and gain-of-function approaches were performed to investigate the effect of AGAP2-AS1 on GC cell phenotypes. The effect of AGAP2-AS1 on cell proliferation was evaluated by MTT, colony formation, flow cytometry, and in vivo tumor formation assays. The effects of AGAP2-AS1 on cell migration and invasion were examined using Transwell assays. Chromatin immunoprecipitation, luciferase reporter assays, RNA pull-down, and RNA immunoprecipitation were used to investigate the factors involved in AGAP2-AS1 dysregulation and the mechanism of action of AGAP2-AS1 in the GC cells.ResultsAGAP2-AS1 was highly expressed in the GC tissues and cell lines, and patients with higher AGAP2-AS1 expression had a poorer prognosis and shorter overall survival. Furthermore, knockdown of AGAP2-AS1 significantly inhibited GC cell proliferation, migration, and invasion in vitro and tumor growth in vivo. AGAP2-AS1 overexpression promoted cell growth and invasion. In addition, the transcription factor SP1 activated AGAP2-AS1 expression in the GC cells. AGAP2-AS1 functions as an oncogenic lncRNA by interacting with LSD1 and EZH2 and suppressing CDKN1A (P21) and E-cadherin transcription.ConclusionsTaken together, these findings imply that AGAP2-AS1 upregulated by SP1 plays an important role in GC development and progression by suppressing P21 and E-cadherin, which suggests that AGAP2-AS1 is a potential diagnostic marker and therapeutic target for GC patients.
Highlights
IntroductionLong noncoding RNAs (lncRNAs) have emerged as important regulators of tumorigenesis and cancer progression
Long noncoding RNAs have emerged as important regulators of tumorigenesis and cancer progression
AGAP2-AS1 is upregulatd in the gastric cancer (GC) tissues and associated with poor prognosis To determine the expression pattern of AGAP2-AS1 in the human GC tissues, we first analyzed its expression in two public gene profiling datasets (GSE65801 [21] and GSE51575 [22]) from Gene Expression Omnibus (GEO) database
Summary
Long noncoding RNAs (lncRNAs) have emerged as important regulators of tumorigenesis and cancer progression. The lncRNA AGAP2-AS1 was identified as an oncogenic lncRNA in human non-small cell lung cancer (NSCLC) and its elevated expression was linked to NSCLC development and progression. Numerous efforts have been made to improve the diagnosis and survival of GC patients, this disease remains a major challenge due to the limited therapeutic options, tumor metastasis, and recurrence [3]. Increasing evidence has revealed that these noncoding RNAs such as miRNAs play critical roles in human cancer development [8]. LncRNAs have been highlighted as critical regulators of tumorigenesis and cancer progression, and numerous lncRNAs have been found to function as oncogenes, tumor suppressors, or both depending on the circumstances [12] Numerous studies have linked lncRNA dysregulation with human diseases, especially cancer [11]. lncRNAs have been highlighted as critical regulators of tumorigenesis and cancer progression, and numerous lncRNAs have been found to function as oncogenes, tumor suppressors, or both depending on the circumstances [12]
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