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Co-expression analysis identifies long noncoding RNA SNHG1 as a novel predictor for event-free survival in neuroblastoma.

ABSTRACT: Despite of the discovery of protein therapeutic targets and advancement in multimodal therapy, the survival chance of high-risk neuroblastoma (NB) patients is still less than 50%. MYCN amplification is a potent driver of NB, which exerts its oncogenic activity through either activating or inhibiting the transcription of target genes. Recently, long noncoding RNAs (lncRNAs) are reported to be altered in cancers including NB. However, lncRNAs that are altered by MYCN amplification and associated with outcome in high-risk NB patients are limitedly discovered. Herein, we examined the expression profiles of lncRNAs and protein-coding genes between MYCN amplified and MYCN non-amplified NB from microarray (n = 47) and RNA-seq datasets (n = 493). We identified 6 lncRNAs in common that were differentially expressed (adjusted P ? 0.05 and fold change ? 2) and subsequently validated by RT-qPCR. The co-expression analysis reveals lncRNA, SNHG1 and coding gene, TAF1D highly co-expressed in NB. Kaplan-Meier analysis shows that higher expression of SNHG1 is significantly associated with poor patient survival. Importantly, multivariate analysis confirms high expression of SNHG1 as an independent prognostic marker for event-free survival (EFS) (HR = 1.58, P = 2.36E-02). In conclusion, our study unveils that SNHG1 is up-regulated by MYCN amplification and could be a potential prognostic biomarker for high-risk NB intervention.

SUBMITTER: Sahu D

PROVIDER: S-EPMC5295409 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Co-expression analysis identifies long noncoding RNA SNHG1 as a novel predictor for event-free survival in neuroblastoma.

Sahu Divya D Hsu Chia-Lang CL Lin Chen-Ching CC Yang Tz-Wen TW Hsu Wen-Ming WM Ho Shinn-Ying SY Juan Hsueh-Fen HF Huang Hsuan-Cheng HC

Oncotarget 20160901 36

Despite of the discovery of protein therapeutic targets and advancement in multimodal therapy, the survival chance of high-risk neuroblastoma (NB) patients is still less than 50%. MYCN amplification is a potent driver of NB, which exerts its oncogenic activity through either activating or inhibiting the transcription of target genes. Recently, long noncoding RNAs (lncRNAs) are reported to be altered in cancers including NB. However, lncRNAs that are altered by MYCN amplification and associated w ...[more]

PMID: 27517149

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Project description:Neuroblastoma (NB) is an embryonal tumor with various clinical presentations and behaviors. Several genomic alterations has been well-studied in NB, among which genomic amplification of MYCN oncogene, is a strong prognostic biomarker with worsens outcome. Long noncoding RNAs (lncRNAs), constitute major proportion of the cellular transcripts with no coding capacity. One of their function is to guide transcription factors to the target genes and facilitate gene expression. However, relative contribution of lncRNA and MYCN to the advanced NB has remained unclear. Herein, by applying a network-based integrative analysis on MYCN amplified and MYCN nonamplified lncRNA expression profile from both RNA-seq and microarray platform, we identified lncRNA, SNHG1 to be differentially expressed and strongly correlated with MYCN in MYCN-amplified NB. The expression of SNHG1 was validated by RT-qPCR in NB cell lines. Survival analysis revealed that higher expression of SNHG1 significantly associates with poor patient survival. Moreover, knockdown of MYCN in MYCN-amplified NB cell lines inhibited SNHG1 expression. Furthermore, to unravel the role of SNHG1 in NB, we extracted SNHG1-interacting proteins by RNA-protein pull down assay coupled with doi:10.6342/NTU201701980 ! ! VI liquid chromatography-tandem mass spectrometry (LC-MS/MS). We identified 27 SNHG1-interacting proteins in common from three NB cell lines. However, only three SNHG1-interacting proteins, MATR3, YBX1 and HHRNPL have binding site detected by DeepBind motif analysis. Western blot confirms interaction of MATR3 with SNHG1. Additionally, we further validated the direct interaction between MATR3 and SNHG1 by RNA-immunoprecipation (IP). MATR3 is known to be involved in RNA transport and stabilization. Therefore, we proposed that MATR3 after interacting with SNHG1 might help in SNHG1 transcription and stabilization. In conclusion, our study unveils that SNHG1 could be a prognostic marker for high-risk NB and possibly stabilized by MATR3. Our results might provide future directions for the development of therapeutic strategies against high-risk NB.

Project description:Neuroblastoma (NB), considered the most common non-intracranial solid tumor in children, accounts for nearly 8% of pediatric malignancies. This study aimed to develop a simple and practical nomogram to predict event-free survival (EFS) in NB patients and establish a new risk stratification system. In this study, 763 patients primarily diagnosed with NB in the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database were included and randomly assigned to a training set (70%) and a validation set (30%) in a 7:3 ratio. First, the independent prognostic factors of EFS for NB patients were identified through univariate and multivariate Cox regression analyses. Second, a nomogram was created based on these factors and was validated for calibration capability, discriminative, and clinical significance by C-curves, receiver operating characteristic (ROC) curves, and decision curve analysis. Finally, a new risk stratification system was established for NB patients based on the nomogram. The univariate Cox analysis demonstrated that NB patients with age at diagnosis >318 days, International Neuroblastoma Staging System (INSS) stage 4, DNA diploidy, MYCN amplification status, and children oncology group (COG) high-risk group had a relatively poor prognosis. However, according to the multivariate Cox regression analysis, only age, INSS stage, and DNA ploidy were independent predictive factors in NB patients regarding EFS, and a nomogram was created based on these factors. The area under the curve (AUC) values of the ROC curves for the 3-, 5-, and 10-year EFS of this nomogram were 0.681, 0.706, and 0.720, respectively. Additionally, the AUC values of individual independent prognostic factors of EFS were lower than those of the nomogram, suggesting that the developed nomogram had a higher predictive reliability for prognosis. In addition, a new risk stratification system was developed to better stratify NB patients and provide clinical practitioners with a better reference for clinical decision-making. NB patients' EFS could be predicted more accurately and easily through the constructed nomogram and event-occurrence risk stratification system, allowing clinicians to better differentiate NB patients and establish individualized treatment plans to maximize patient benefits.

Dataset Information

Co-expression analysis identifies long noncoding RNA SNHG1 as a novel predictor for event-free survival in neuroblastoma.

Publications

Co-expression analysis identifies long noncoding RNA SNHG1 as a novel predictor for event-free survival in neuroblastoma.

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