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Regulatory non-coding somatic mutations as drivers of neuroblastoma
Annalaura Montella1,2, Matilde Tirelli1,2, Vito Alessandro Lasorsa2
1University of Naples Federico II, Department of Molecular Medicine and Medical Biotechnology, Naples, Italy.
Background:
Emerging evidence suggests that non-coding somatic single nucleotide variants (SNVs) in cis-regulatory elements (CREs) contribute to cancer by disrupting gene expression networks. However, the role of non-coding SNVs in cancer, particularly neuroblastoma, remains largely unclear.
Methods:
SNVs effect on CREs activity was evaluated by luciferase assays. Motif analysis and ChIP-qPCR experiments were employed to reveal the transcription factors (TFs) involved in these processes. We exploited CRISPR-Cas9 experiments to elucidate the role of these SNVs on the CREs target genes expression. Cell proliferation and invasion assays were performed to assess their role in neuroblastoma tumorigenesis.
Results:
Our findings demonstrate that non-coding SNVs modify the transcriptional activity of two CREs altering the binding of STAT3 and SIN3A. Therefore, these SNVs reduce the expression of CTTNBP2 and MCF2L. We demonstrate that these two genes act as tumor suppressor in neuroblastoma. These pathogenetic SNVs may serve as oncogenic drivers by impairing the transcriptional programs essential for neuronal development and differentiation in which both the investigated TFs and target genes are involved.
Conclusion:
Overall, the understanding of the functional role of non-coding variants elucidates their impact on tumorigenesis and can uncover new potential targets of cancer therapeutic strategies.
Insights
Non-coding single nucleotide variants (SNVs) in regulatory elements disrupt gene expression, driving neuroblastoma. These SNVs impair tumor suppressor genes, offering potential therapeutic targets.
Area of Science:
- Genomics
- Cancer Biology
- Neuroscience
Background:
- Non-coding somatic single nucleotide variants (SNVs) in cis-regulatory elements (CREs) are increasingly implicated in cancer by altering gene expression.
- The specific role of non-coding SNVs in neuroblastoma pathogenesis is not well understood.
Purpose of the Study:
- To investigate the functional impact of non-coding SNVs in CREs on neuroblastoma development.
- To identify the molecular mechanisms by which these SNVs contribute to tumorigenesis.
Main Methods:
- Luciferase assays to assess SNV effects on CRE activity.
- Motif analysis and ChIP-qPCR to identify transcription factor (TF) binding.
- CRISPR-Cas9 to evaluate SNV impact on target gene expression.
- Cell proliferation and invasion assays to assess tumorigenesis.
Main Results:
- Non-coding SNVs alter CRE transcriptional activity by modifying STAT3 and SIN3A binding.
- These SNVs decrease the expression of CTTNBP2 and MCF2L, identified as tumor suppressors in neuroblastoma.
- Pathogenic SNVs act as oncogenic drivers by disrupting neuronal development and differentiation programs.
Conclusions:
- Understanding the functional roles of non-coding variants is crucial for elucidating their impact on cancer.
- These findings highlight potential novel therapeutic targets for neuroblastoma treatment.
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