Dataset Information

SNHG17, as an EMT-related lncRNA, promotes the expression of c-Myc by binding to c-Jun in esophageal squamous cell carcinoma.

ABSTRACT: Dysregulation of long noncoding RNA SNHG17 is associated with the occurrence of several tumors; however, its role in esophageal squamous cell carcinoma (ESCC) remains obscure. The present study demonstrated that SNHG17 was upregulated in ESCC tissues and cell lines, induced by TGF-β1, and associated with poor survival. It is also involved in the epithelial-to-mesenchymal transition (EMT) process. The mechanism underlying SNHG17-regulated c-Myc was detected by RNA immunoprecipitation, RNA pull-down, chromatin immunoprecipitation, and luciferase reporter assays. SNHG17 was found to directly regulate c-Myc transcription by binding to c-Jun protein and recruiting the complex to specific sequences of the c-Myc promoter region, thereby increasing its expression. Moreover, SNHG17 hyperactivation induced by TGF-β1 results in PI3K/AKT pathway activation, promoting cells EMT, forming a positive feedback loop. Furthermore, SNHG17 facilitated ESCC tumor growth in vivo. Overall, this study demonstrated that the SNHG17/c-Jun/c-Myc axis aggravates ESCC progression and EMT induction by TGF-β1 and may serve as a new therapeutic target for ESCC.

SUBMITTER: Shen S

PROVIDER: S-EPMC8748231 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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SNHG17, as an EMT-related lncRNA, promotes the expression of c-Myc by binding to c-Jun in esophageal squamous cell carcinoma.

Shen Supeng S Liang Jia J Liang Xiaoliang X Wang Gaoyan G Feng Bo B Guo Wei W Guo Yanli Y Dong Zhiming Z

Cancer science 20211112 1

Dysregulation of long noncoding RNA SNHG17 is associated with the occurrence of several tumors; however, its role in esophageal squamous cell carcinoma (ESCC) remains obscure. The present study demonstrated that SNHG17 was upregulated in ESCC tissues and cell lines, induced by TGF-β1, and associated with poor survival. It is also involved in the epithelial-to-mesenchymal transition (EMT) process. The mechanism underlying SNHG17-regulated c-Myc was detected by RNA immunoprecipitation, RNA pull-do ...[more]

PMID: 34714590

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Project description:Esophageal squamous cell carcinoma (ESCC) is the main subtype of esophageal cancer. Long noncoding RNAs (lncRNAs) are thought to play a critical role in cancer development. Recently, lncRNA CASC9 was shown to be dysregulated in many cancer types, but the mechanisms whereby this occurs remain largely unknown. In this study, we found that CASC9 was significantly upregulated in ESCC tissues, with further analysis revealing that elevated CASC9 expression was associated with ESCC prognosis and metastasis. Furthermore, we found that CASC9 knockdown significantly repressed ESCC migration and invasion in vitro and metastasis in nude mice in vivo. A microarray analysis and mechanical experiments indicated that CASC9 preferentially affected gene expression linked to ECM-integrin interactions, including LAMC2, an upstream inducer of the integrin pathway. We demonstrated that LAMC2 was consistently upregulated in ESCC and promoted ESCC metastasis. LAMC2 overexpression partially compromised the decrease of cell migration and invasion capacity in CASC9 knockdowns. In addition, we found that both CASC9 and LAMC2 depletion reduced the phosphorylation of FAK, PI3K, and Akt, which are downstream effectors of the integrin pathway. Moreover, the reduction in phosphorylation caused by CASC9 depletion was rescued by LAMC2 overexpression, further confirming that CASC9 exerts a pro-metastatic role through LAMC2. Mechanistically, RNA pull-down and RNA-binding protein immunoprecipitation (RIP) assay indicated that CASC9 could bind with the transcriptional coactivator CREB-binding protein (CBP) in the nucleus. Chromatin immunoprecipitation (ChIP) assay additionally illustrated that CASC9 increased the enrichment of CBP and H3K27 acetylation in the LAMC2 promoter, thereby upregulating LAMC2 expression. In conclusion, we demonstrate that CASC9 upregulates LAMC2 expression by binding with CBP and modifying histone acetylation. Our research reveals the prognostic and pro-metastatic roles for CASC9 in ESCC, suggesting that CASC9 could serve as a biomarker for prognosis and a target for metastasis treatment.

Project description:BackgroundEpithelial-mesenchymal transition (EMT) is significantly associated with the invasion and development of esophageal squamous cell carcinoma (ESCC). However, the importance of EMT-related long noncoding RNA (lncRNA) is little known in ESCC.MethodsGSE53624 (N = 119) and GSE53622 (N = 60) datasets retrieved from the Gene Expression Omnibus (GEO) database were used as training and external validation cohorts, respectively. GSE53624 and GSE53622 datasets were all sampled from China. Then, the prognostic value of EMT-related lncRNA was comprehensively investigated by weighted coexpression network analysis (WGCNA) and COX regression model.ResultsHigh expression of PLA2G4E-AS1, AC063976.1, and LINC01592 significantly correlated with the favorable overall survival (OS) of ESCC patients, and LINC01592 had the greatest contribution to OS. Importantly, ESCC patients were divided into low- and high-risk groups based on the optimal cut-off value of risk score estimated by the multivariate COX regression model of these three lncRNA. Patients with high risk had a shorter OS rate and restricted mean survival time (RMST) than those with low risk. Moreover, univariate and multivariate COX regression revealed that risk stratification, age, and TNM were independent prognostic predictors, which were used to construct a nomogram model for individualized and visualized prognosis prediction of ESCC patients. The calibration curves and time-dependent ROC curves in the training and validation cohorts suggested that the nomogram model had a good performance. Interestingly, clear trends indicated that risk score positively correlated with tumor microenvironment (TME) scores and immune checkpoints TIGIT, CTLA4, and BTLA. In addition, the Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that PLA2G4E-AS1, AC063976.1, and LINC01592 were primarily associated with TNF signaling pathway, NF-kappa B signaling pathway, and ECM-receptor interaction.ConclusionWe developed EMT-related lncRNA PLA2G4E-AS1, AC063976.1, and LINC01592 for prognostic prediction and risk stratification of Chinese ESCC patients, which might provide deep insight for personalized prognosis prediction in Chinese ESCC patients and be potential biomarkers for designing novel therapy.

Dataset Information

SNHG17, as an EMT-related lncRNA, promotes the expression of c-Myc by binding to c-Jun in esophageal squamous cell carcinoma.

Publications

SNHG17, as an EMT-related lncRNA, promotes the expression of c-Myc by binding to c-Jun in esophageal squamous cell carcinoma.

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