VEGF165b, a splice variant of VEGF-A, promotes lung tumor progression and escape from anti-angiogenic therapies through a Œ≤1 integrin/VEGFR autocrine loop
Authors: Denis Moro-Sibilot
Elisabeth Brambilla
Sandra Manet
Eva Faurobert
Chlo√© Didier
Anne-Claire Toffart
Jean-Luc Coll
V√©ronique Josserand
Sylvie Gazzeri
Michelle Keramidas
Tao Jia
Nicolas Lema√Ætre
Cherine Abou Faycal
Christian Brambilla
Beatrice Eymin
Corinne Albiges-Rizo
Stephanie Gout
Asma Boudria
Journal: Oncogene (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: VEGF-A; pre-mRNA splicing; splice variants; VEGFxxx; VEGFxxxb
Affiliations: INSERM U1209, UMR CNRS 5309, Team RNA splicing, Cell Signaling and Response to Therapies, Grenoble, 38042, France., Universit√© Grenoble Alpes, Institut Pour l'Avanc√©e des Biosciences, Grenoble, 38041, France., INSERM, U1209, UMR CNRS 5309, Team Cancer Targets and Experimental Therapeutics, Grenoble, 38042, France., INSERM U1209, UMR CNRS 5309, Team Tumor Molecular Pathology and Biomarkers, Grenoble, 38042, France., INSERM U1209, UMR CNRS 5309, Team Cell Adhesion Dynamics and Differentiation, Grenoble, 38042, France., INSERM U1209, UMR CNRS 5309, Team RNA splicing, Cell Signaling and Response to Therapies, Grenoble, 38042, France. ., Universit√© Grenoble Alpes, Institut Pour l'Avanc√©e des Biosciences, Grenoble, 38041, France. .

Abstract:  Vascular endothelial growth factor-A (VEGF-A) is highly subjected to alternative pre-mRNA splicing that generates several splice variants. The VEGFxxx and VEGFxxxb families encode splice variants of VEGF-A that differ only at the level of six amino acids in their C-terminal part. The expression level of VEGFxxx splice variants and their function as pro-angiogenic factors during tumor neo-angiogenesis have been well-described. The role of VEGFxxxb isoforms is less well known, but they have been shown to inhibit VEGFxxx-mediated angiogenesis, while being partial or weak activators of VEGFR receptors in endothelial cells. On the opposite, their role on tumor cells expressing VEGFRs at their surface remains largely unknown. In this study, we find elevated levels of VEGF165b, the main VEGFxxxb isoform, in 36% of non-small cell lung carcinoma (NSCLC), mainly lung adenocarcinoma (46%), and show that a high VEGF165b/VEGF165 ratio correlates with the presence of lymph node metastases. At the molecular level, we demonstrate that VEGF165b stimulates proliferation and invasiveness of two lung tumor cell lines through a VEGFR/Œ≤1 integrin loop. We further provide evidence that the isoform-specific knockdown of VEGF165b reduces tumor growth, demonstrating a tumor-promoting autocrine role for VEGF165b in lung cancer cells. Importantly, we show that bevacizumab, an anti-angiogenic compound used for the treatment of lung adenocarcinoma patients, increases the expression of VEGF165b and activates the invasive VEGFR/Œ≤1 integrin loop. Overall, these data highlight an unexpected role of the VEGF165b splice variant in the progression of lung tumors and their response to anti-angiogenic therapies. 

Retracted: No

PubPeer comments:
 Figure 2e (control) and 6c (bevacizumab treated) appear to show an overlapping image, after 180u00b0 rotation. ***  ,