Long Noncoding RNA GAPLINC Regulates CD44-dependent Cell Invasiveness and Associates With Poor Prognosis of Gastric Cancer

Abstract

Gastric cancer is the second leading cause of cancer related mortality in the world. To improve gastric cancer early diagnosis and targeted therapy, an in-depth understanding of molecular underpinnings of the disease is required. It is increasingly evident that long noncoding (lnc) RNAs have causative roles in carcinogenesis.In this study, we identify deregulated lncRNAs in gastric cancer that are associated with copy number variations or oncogenic transcription factors. We report findings implicating a novel lncRNA in gastric cancer, termed GAPLINC (gastric adenocarcinoma predictive long intergenic noncoding RNA), based on the use of global microarray and in situ hybridization analyses to identify aberrantly expressed lncRNA in human gastric cancer specimens. GAPLINC is a 924-bp-long lncRNA that is highly expressed in gastric cancer tissues. GAPLINC suppression and with gene expression profiling in gastric cancer cells revealed alterations in cell migration pathways, with CD44 expression the most highly correlated. Manipulating GAPLINC expression altered CD44 mRNA abundance, and the effects of GAPLINC on cell migration and proliferation were neutralized by suppressing CD44 expression. Mechanistic investigations revealed that GAPLINC regulates CD44 as a molecular decoy for miR211-3p, a microRNA that targets both CD44 and GAPLINC. Tissue in situ hybridization analysis suggested that GAPLINC overexpression defines a subgroup of patients with gastric cancer with very poor survival. Gastric cancer is the second leading cause of cancer related mortality in the world. To improve gastric cancer early diagnosis and targeted therapy, an in-depth understanding of molecular underpinnings of the disease is required. It is increasingly evident that long noncoding (lnc) RNAs have causative roles in carcinogenesis. In this study, we identify deregulated lncRNAs in gastric cancer that are associated with copy number variations or oncogenic transcription factors. We report findings implicating a novel lncRNA in gastric cancer, termed GAPLINC (gastric adenocarcinoma predictive long intergenic noncoding RNA), based on the use of global microarray and in situ hybridization analyses to identify aberrantly expressed lncRNA in human gastric cancer specimens. GAPLINC is a 924-bp-long lncRNA that is highly expressed in gastric cancer tissues. GAPLINC suppression and with gene expression profiling in gastric cancer cells revealed alterations in cell migration pathways, with CD44 expression the most highly correlated. Manipulating GAPLINC expression altered CD44 mRNA abundance, and the effects of GAPLINC on cell migration and proliferation were neutralized by suppressing CD44 expression. Mechanistic investigations revealed that GAPLINC regulates CD44 as a molecular decoy for miR211-3p, a microRNA that targets both CD44 and GAPLINC. Tissue in situ hybridization analysis suggested that GAPLINC overexpression defines a subgroup of patients with gastric cancer with very poor survival.