Functional Role of a Novel Long Noncoding RNA <i>TTN-AS1</i> in Esophageal Squamous Cell Carcinoma Progression and Metastasis

Abstract

<b>Purpose:</b> Emerging studies demonstrate that long noncoding RNAs (lncRNA) participate in the regulation of various cancers. In the current study, a novel <i>lncRNA-TTN-AS1</i> has been identified and explored in esophageal squamous cell carcinoma (ESCC).<b>Experimental Design:</b> To discover a new regulatory circuitry in which RNAs crosstalk with each other, the transcriptome of lncRNA-miRNA-mRNA from ESCC and adjacent nonmalignant specimens were analyzed using multiple microarrays and diverse bioinformatics platforms. The functional role and mechanism of a novel <i>lncRNA-TTN-AS1</i> were further investigated by gain-of-function and loss-of-function assays <i>in vivo</i> and <i>in vitro</i> An ESCC biomarker panel, consisting of <i>lncRNA-TTN-AS1</i>, <i>miR-133b</i>, and <i>FSCN1</i>, was validated by qRT-PCR and <i>in situ</i> hybridization using samples from 148 patients.<b>Results:</b><i>lncRNA-TTN-AS1</i> as an oncogene is highly expressed in ESCC tissues and cell lines, and promotes ESCC cell proliferation and metastasis. Mechanistically, <i>lncRNA-TTN-AS1</i> promotes expression of transcription factor Snail1 by competitively binding <i>miR-133b</i>, resulting in the epithelial-mesenchymal transition (EMT) cascade. Moreover, <i>lncRNA-TTN-AS1</i> also induces FSCN1 expression by sponging <i>miR-133b</i> and upregulation of mRNA-stabilizing protein HuR, which further promotes ESCC invasion cascades. We also discovered and validated a clinically applicable ESCC biomarker panel, consisting of <i>lncRNA-TTN-AS1</i>, <i>miR-133b</i>, and <i>FSCN1</i>, that is significantly associated with overall survival and provides additional prognostic evidence for ESCC patients.<b>Conclusions:</b> As a novel regulator, <i>lncRNA-TTN-AS1</i> plays an important role in ESCC cell proliferation and metastasis. The <i>lncRNA-TTN-AS1/miR133b/FSCN1</i> regulatory axis provides bona fide targets for anti-ESCC therapies. <i>Clin Cancer Res; 24(2); 486-98. ©2017 AACR</i>.