Functional Role of A Novel Long Noncoding RNA TTN-AS1 in Esophageal Squamous Cell Carcinoma Progression and Metastasis

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

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