The biological players involved in angiogenesis are only partially defined. Here, we report that endothelial cells (ECs) express a novel isoform of the cell-surface adhesion molecule L1CAM, termed L1-DTM. The splicing factor NOVA2, which binds directly to L1CAM pre-mRNA, is necessary and sufficient for the skipping of L1CAM transmembrane domain in ECs, leading to the release of soluble L1-DTM. The latter exerts high angiogenic function through both autocrine and paracrine activities. Mechanistically, L1-DTM-induced angiogenesis requires fibroblast growth factor receptor-1 signaling, implying a crosstalk between the two molecules. NOVA2 and L1-DTM are overexpressed in the vasculature of ovarian cancer, where L1-DTM levels correlate with tumor vascularization, supporting the involvement of NOVA2-mediated L1-DTM production in tumor angiogenesis. Finally, high NOVA2 expression is associated with poor outcome in ovarian cancer patients. Our results point to L1-DTM as a novel, EC-derived angiogenic factor which may represent a target for innovative antiangiogenic therapies.

A novel L1CAM isoform with angiogenic activity generated by NOVA2-mediated alternative splicing / Angiolini, F; Belloni, E; Giordano, M; Campioni, M; Forneris, F; Paronetto, Mp; Lupia, M; Brandas, C; Pradella, D; Di Matteo, A; Giampietro, C; Jodice, G; Luise, C; Bertalot, G; Freddi, S; Malinverno, M; Irimia, M; Moulton, Jd; Summerton, J; Chiapparino, A; Ghilardi, C; Giavazzi, R; Nyqvist, D; Gabellini, D; Dejana, E; Cavallaro, U; Ghigna, C. - In: ELIFE. - ISSN 2050-084X. - STAMPA. - 8:(2019), pp. e4430501-e4430527. [10.7554/eLife.44305.001]

A novel L1CAM isoform with angiogenic activity generated by NOVA2-mediated alternative splicing

Bertalot G;
2019-01-01

Abstract

The biological players involved in angiogenesis are only partially defined. Here, we report that endothelial cells (ECs) express a novel isoform of the cell-surface adhesion molecule L1CAM, termed L1-DTM. The splicing factor NOVA2, which binds directly to L1CAM pre-mRNA, is necessary and sufficient for the skipping of L1CAM transmembrane domain in ECs, leading to the release of soluble L1-DTM. The latter exerts high angiogenic function through both autocrine and paracrine activities. Mechanistically, L1-DTM-induced angiogenesis requires fibroblast growth factor receptor-1 signaling, implying a crosstalk between the two molecules. NOVA2 and L1-DTM are overexpressed in the vasculature of ovarian cancer, where L1-DTM levels correlate with tumor vascularization, supporting the involvement of NOVA2-mediated L1-DTM production in tumor angiogenesis. Finally, high NOVA2 expression is associated with poor outcome in ovarian cancer patients. Our results point to L1-DTM as a novel, EC-derived angiogenic factor which may represent a target for innovative antiangiogenic therapies.
2019
Angiolini, F; Belloni, E; Giordano, M; Campioni, M; Forneris, F; Paronetto, Mp; Lupia, M; Brandas, C; Pradella, D; Di Matteo, A; Giampietro, C; Jodice, G; Luise, C; Bertalot, G; Freddi, S; Malinverno, M; Irimia, M; Moulton, Jd; Summerton, J; Chiapparino, A; Ghilardi, C; Giavazzi, R; Nyqvist, D; Gabellini, D; Dejana, E; Cavallaro, U; Ghigna, C
A novel L1CAM isoform with angiogenic activity generated by NOVA2-mediated alternative splicing / Angiolini, F; Belloni, E; Giordano, M; Campioni, M; Forneris, F; Paronetto, Mp; Lupia, M; Brandas, C; Pradella, D; Di Matteo, A; Giampietro, C; Jodice, G; Luise, C; Bertalot, G; Freddi, S; Malinverno, M; Irimia, M; Moulton, Jd; Summerton, J; Chiapparino, A; Ghilardi, C; Giavazzi, R; Nyqvist, D; Gabellini, D; Dejana, E; Cavallaro, U; Ghigna, C. - In: ELIFE. - ISSN 2050-084X. - STAMPA. - 8:(2019), pp. e4430501-e4430527. [10.7554/eLife.44305.001]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/361782
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