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Updated: Jul 30, 2025
Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
Published on: April 26, 2017
Alternative Splicing Changes Promoted by NOVA2 Upregulation in Endothelial Cells and Relevance for Gastric Cancer
Anna Di Matteo1, Elisa Belloni1, Davide Pradella1
1Istituto di Genetica Molecolare "Luigi Luca Cavalli-Sforza", Consiglio Nazionale delle Ricerche, 27100 Pavia, Italy.
Abstract:
Angiogenesis is crucial for cancer progression. While several anti-angiogenic drugs are in use for cancer treatment, their clinical benefits are unsatisfactory. Thus, a deeper understanding of the mechanisms sustaining cancer vessel growth is fundamental to identify novel biomarkers and therapeutic targets. Alternative splicing (AS) is an essential modifier of human proteome diversity. Nevertheless, AS contribution to tumor vasculature development is poorly known. The Neuro-Oncological Ventral Antigen 2 (NOVA2) is a critical AS regulator of angiogenesis and vascular development. NOVA2 is upregulated in tumor endothelial cells (ECs) of different cancers, thus representing a potential driver of tumor blood vessel aberrancies. Here, we identified novel AS transcripts generated upon NOVA2 upregulation in ECs, suggesting a pervasive role of NOVA2 in vascular biology. In addition, we report that NOVA2 is also upregulated in ECs of gastric cancer (GC), and its expression correlates with poor overall survival of GC patients. Finally, we found that the AS of the Rap Guanine Nucleotide Exchange Factor 6 (RapGEF6), a newly identified NOVA2 target, is altered in GC patients and associated with NOVA2 expression, tumor angiogenesis, and poor patient outcome. Our findings provide a better understanding of GC biology and suggest that AS might be exploited to identify novel biomarkers and therapeutics for anti-angiogenic GC treatments.
Insights
Neuro-Oncological Ventral Antigen 2 (NOVA2) regulates tumor angiogenesis. Upregulation of NOVA2 in gastric cancer correlates with poor survival and altered splicing of Rap Guanine Nucleotide Exchange Factor 6 (RapGEF6), suggesting novel therapeutic targets.
Area of Science:
- Molecular Biology
- Cancer Research
- Vascular Biology
Background:
- Angiogenesis is vital for cancer progression, but current anti-angiogenic therapies have limitations.
- Alternative splicing (AS) impacts proteome diversity, yet its role in tumor vasculature is unclear.
- The RNA-binding protein NOVA2 is a known regulator of angiogenesis and vascular development.
Purpose of the Study:
- To investigate the role of NOVA2 in tumor angiogenesis and identify its downstream targets.
- To explore the contribution of AS to gastric cancer (GC) vascularization.
- To assess NOVA2 and its targets as potential biomarkers and therapeutic strategies for GC.
Main Methods:
- Analysis of NOVA2 expression in tumor endothelial cells (ECs) across various cancers.
- Identification of novel AS transcripts regulated by NOVA2 in ECs.
- Correlation analysis of NOVA2 expression, AS events, and patient survival in gastric cancer.
Main Results:
- NOVA2 is upregulated in tumor ECs of multiple cancers, suggesting a role in aberrant tumor vasculature.
- NOVA2 is upregulated in gastric cancer ECs and associated with poor patient survival.
- Altered AS of Rap Guanine Nucleotide Exchange Factor 6 (RapGEF6), a NOVA2 target, is linked to NOVA2 expression, angiogenesis, and poor outcomes in GC.
Conclusions:
- NOVA2 plays a significant role in regulating tumor angiogenesis and vascular development.
- NOVA2 dysregulation and associated AS events, like those in RapGEF6, are implicated in gastric cancer progression.
- Targeting NOVA2-mediated AS may offer novel therapeutic avenues for anti-angiogenic cancer treatments.
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