Di Matteo, AnnaBelloni, ElisaPradella, DavideChiaravalli, Anna MariaPini, Giacomo MariaBugatti, MattiaAlfieri, RobertaBarzan, ChiaraFranganillo Tena, ElenaBione, SilviaTerenzani, ElisaSessa, FaustoWyatt, Christopher Douglas Robert, 1988-Vermi, WilliamGhigna, Claudia2023-06-212023-06-212023Di Matteo A, Belloni E, Pradella D, Chiaravalli AM, Pini GM, Bugatti M, Alfieri R, Barzan C, Franganillo Tena E, Bione S, Terenzani E, Sessa F, Wyatt CDR, Vermi W, Ghigna C. Alternative splicing changes promoted by NOVA2 upregulation in endothelial cells and relevance for gastric cancer. Int J Mol Sci. 2023 Apr 30;24(9):8102. DOI: 10.3390/ijms240981021422-0067http://hdl.handle.net/10230/57284Angiogenesis 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.application/pdfeng© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).info:eu-repo/semantics/articlehttp://dx.doi.org/10.3390/ijms24098102RNA binding proteinsAlternative splicingAngiogenesisCancer biomarkersGastric cancerTumor vasculatureinfo:eu-repo/semantics/openAccess