A Positive Feedback Loop of lncRNA- <i>PVT1</i> and FOXM1 Facilitates Gastric Cancer Growth and Invasion

Abstract

<b>Purpose:</b> The long, noncoding RNA (lncRNA) <i>PVT1</i> is an important epigenetic regulator with a critical role in human tumors. Here, we aimed to investigate the clinical application and the potential molecular mechanisms of <i>PVT1</i> in gastric cancer tumorigenesis and progression.<b>Experimental Design:</b> The expression level of <i>PVT1</i> was determined by RT-qPCR analysis in 190 pairs of gastric cancer tissues and adjacent normal gastric mucosa tissues (ANT). The biologic functions of <i>PVT1</i> were assessed by <i>in vitro</i> and <i>in vivo</i> functional experiments. RNA protein pull-down assays and LS/MS mass spectrometry analysis were performed to detect and identify the <i>PVT1</i><b>-</b> interacting protein FOXM1. Protein-RNA immunoprecipitation assays were conducted to examine the interaction of FOXM1 and <i>PVT1</i> Chromatin immunoprecipitation (ChIP) and luciferase analyses were utilized to identify the binding site of FOXM1 on the <i>PVT1</i> promoter.<b>Results:</b> The lncRNA <i>PVT1</i> was significantly upregulated in gastric cancer tissues compared with ANTs. High expression of <i>PVT1</i> predicted poor prognosis in patients with gastric cancer. <i>PVT1</i> enhanced gastric cancer cell proliferation and invasion <i>in vitro</i> and <i>in vivo</i><i>PVT1</i> directly bound FOXM1 protein and increased FOXM1 posttranslationally. Moreover, <i>PVT1</i> is also a FOXM1-responsive lncRNA, and FOXM1 directly binds to the <i>PVT1</i> promoter to activate its transcription. Finally, <i>PVT1</i> fulfilled its oncogenic functions in a FOXM1-mediated manner.<b>Conclusions:</b> Our study suggests that <i>PVT1</i> promotes tumor progression by interacting with FOXM1. <i>PVT1</i> may be a valuable prognostic predictor for gastric cancer, and the positive feedback loop of <i>PVT1</i>-FOXM1 could be a therapeutic target in pharmacologic strategies. <i>Clin Cancer Res; 23(8); 2071-80. ©2016 AACR</i>.