Alternative splicing changes promoted by NOVA2 upregulation in endothelial cells and relevance for gastric cancer
Angiogenesis is crucial for cancer progression and anti-angiogenic drugs are in use for its treatment. However, their clinical benefits are unsatisfactory. Thus, a deeper understanding of the mechanisms sustaining cancer vessel growth is crucial to identify better biomarkers and novel therapeutic targets. Alternative Splicing (AS) is an essential modifier of human proteome diversity. Nevertheless, its contribution to tumor vasculature development is poorly known. NOVA2 is an important AS regulator of angiogenesis and vascular development and it is up-regulated in tumor endothelial cells (ECs) of different cancers, thus representing a potential driver of tumor blood vessels 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), with its expression correlating with poor overall survival of the GC patients. We also found that the AS of the newly identified NOVA2 target RapGEF6 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 represent a potential source of biomarkers and therapeutics for novel anti-angiogenic GC treatments. Overall design: Comparative gene expression profiling analysis of RNA-seq data for endothelial cells (control n=2) with Nova2 overexpression (n=2) .