Abstract
Long non-coding RNAs (lncRNAs) play important roles in various biological processes and human diseases, including cancer. In this study, we demonstrated a regulatory relationship between lncRNA GRIK1-AS1 and miR-375/IFIT2 axis in gastric cancer. Our results show a decreased expression of GRIK1-AS1 in gastric cancer tissues compared to adjacent normal gastric tissues. Gastric cell lines also have reduced levels of GRIK1-AS1 compared to gastric epithelial cell line GES-1. Ectopic expression of GRIK1-AS1 in gastric cancer cell lines significantly inhibits cellular viability, migration, and invasion. RNA-pull down and the luciferase activity assays show that GRIK1-AS1 mainly interacts specifically with miR-375. We further demonstrate a negatively regulatory relationship between lncRNA GRIK1-AS1 and miR-375. We discovered that IFIT2 was one of the direct key downstream target genes of miR-375, and established the important role of the GRIK1-AS1/miR-375/IFIT2 axis in the progression of gastric cancer. Taken together, our results revealed a novel mechanism of GRIK1-AS1 as a sponge to miR-375 that impacts gastric cancer progression via modulating target mRNA IFIT2 translation, and as a result, opens a new strategy to future GRIK1-AS1 based therapeutic development.
Highlights
Gastric cancer is the second most common cancer-related mortality after lung cancer worldwide [1,2,3]
We discovered a novel regulatory mechanism of long noncoding RNAs (lncRNAs) GRIK1-AS1 with miR-375 and functional impact on gastric cancer through IFIT2 as the major target
LncRNA H19, HOXA11-AS, and SNHG12 were all associated with gastric cancer progression [17, 18]
Summary
Gastric cancer is the second most common cancer-related mortality after lung cancer worldwide [1,2,3]. LncRNAs have diverse functions which can act as guides, decoys, scaffolds, and tethers of other biological molecules [8,9,10]. LncRNAs can competitively sponge miRNAs from their target mRNA transcripts [11]. Growing evidence supports the critical functions of lncRNAs in human cancers. Previous studies have identified several deregulated lncRNA expression in gastric cancer with critical functions [14]. SNHG12 was demonstrated to regulate cancer progression by sponging miR320 [15]. The lncRNA GRIK1-AS1 (Glutamate Ionotropic Receptor Kainate Type Subunit 1-Antisense RNA1, ENSG00000174680) is located at chr21q21.3, and has been previously reported to be downregulated in gastric cancer tissues [14]. The biological function of lncRNA GRIK1-AS1 in gastric cancer progression remains elusive
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