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A Long Noncoding RNA TTN-AS1 Controls Esophageal Squamous Cell Carcinomas by Functioning as a Competing Endogenous RNA and Scaffolding mRNA Stabilizing Protein HuR [Affymetrix]

ABSTRACT: BACKGROUND & AIMS: Emerging long non-coding RNAs (lncRNAs) have been demonstrated to be associated with progression of various cancers. In the current study, we identified a novel lncRNA-TTN-AS1 and dissected the underlying mechanisms by which lncRNA-TTN-AS1 induced carcinogenesis of esophageal squamous cell carcinoma (ESCC). METHODS: ESCC and adjacent non-malignant specimens from 7 ESCC patients were chosen to analyze the expression profiles of lncRNA-miRNA-mRNA using multiple microarrays. The novel lncRNA-TTN-AS1 was identified using multiple bioinformatics platforms. Levels of lncRNA-TTN-AS1 in tissues from 148 ESCC patients were verified by qRT-PCR and in situ hybridization. The biological function and mechanism of action of lncRNA-TTN-AS1 were performed both in vivo and in vitro using gain-of and loss-of function assays on TE-13 cells and KYSE-410 cells, luciferase reporter assays, RNA immunoprecipitation (RIP) assays and RNA pull-down assays. RESULTS: lncRNA-TTN-AS1 levels were upregulated in ESCC tissues compared with adjacent non-malignant tissues, and correlated with poor prognosis. LncRNA-TTN-AS1, as an oncogene, promoted ESCC cell proliferation and prevented apoptosis. Additionally, lncRNA-TTN-AS1 increased snail1 levels by competitively binding to miR-133b, thereby facilitating epithelial-mesenchymal transition (EMT) cascades. Sharing miR-133b binding sites, lncRNA-TTN-AS1 as a ceRNA also derepressed FSCN1 mediated by miR-133b. Notably, lncRNA-TTN-AS1 stabilized FSCN1 mRNA by interacting directly with the mRNA stabilizing protein HuR, resulting in ESCC invasion-cascades and activation of FSCN1/β-catenin. CONCLUSION: lncRNA-TTN-AS1 sponges miR-133b to govern the expression of snial1 and FSCN1, which promotes ESCC cell proliferation and metastasis. It also combines with HuR to modulate FSCN1 in ESCC cell lines. Our findings may provide a novel target for ESCC anti-metastatic therapies.

ORGANISM(S): synthetic construct Homo sapiens

PROVIDER: GSE97049 | GEO | 2017/03/28

SECONDARY ACCESSION(S): PRJNA380703

REPOSITORIES: GEO

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Project description:Background: Esophageal squamous cell carcinoma (ESCC) is a common invasive malignancy worldwide with poor clinical outcomes. Increasing amount of long non-coding RNAs (lncRNAs) have been reported to be involved in cancer development. However, lncRNAs that are functional in ESCC and the underlying molecular mechanisms remain largely unknown. Methods: Transcriptomic analysis was performed to identify dysregulated lncRNAs in ESCC tissue samples. The high expression of LINC00680 in ESCC was validated by RT-qPCR, and the oncogenic functions of LINC00680 was investigated by cell proliferation, colony formation, migration and invasion assays in ESCC cells in vitro and xenografts derived from ESCC cells in mice. RNA-seq, competitive endogenous RNA (ceRNA) network analysis, and luciferase reporter assays were carried out to identify LINC00680 target genes and the microRNAs (miRNAs) bound to LINC00680. Antisense oligonucleotides (ASOs) were used for in vivo treatment. Results: Transcriptome profiling revealed that a large number of lncRNAs was dysregulated in ESCC tissues. Notably, LINC00680 was highly expressed, and upregulation of LINC00680 was associated with large tumor size, advanced tumor stage, and poor prognosis. Functionally, knockdown of LINC00680 restrained ESCC cell proliferation, colony formation, migration, and invasion in vitro and inhibited tumor growth in vivo. Mechanistically, LINC00680 was found to act as a ceRNA by sponging miR-423-5p to regulate PAK6 (p21-activated kinase 6) expression in ESCC cells. The cell viability and motility inhibition induced by LINC00680 knockdown was significantly reversed upon PAK6 restoration and miR-423-5p inhibition. Furthermore, ASO targeting LINC00680 substantially suppressed ESCC both in vitro and in vivo. Conclusions: An oncogenic lncRNA, LINC00680, was identified in ESCC, which functions as a ceRNA by sponging miR-423-5p to promote PAK6 expression and ESCC. LINC00680/miR-423-5p/PAK6 axis may serve as promising diagnostic and prognostic biomarkers and therapeutic targets for ESCC.

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A Long Noncoding RNA TTN-AS1 Controls Esophageal Squamous Cell Carcinomas by Functioning as a Competing Endogenous RNA and Scaffolding mRNA Stabilizing Protein HuR [Affymetrix]

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