Ladomery Lab RNA Biology Group


Ladomery Lab
Southwest UK RNA Club

Research Papers

Altered VEGF splicing isoform balance in tumor endothelium involves activation of splicing factors Srpk1 and Srsf1 by the Wilms’ tumor suppressor Wt1

Cells, accepted; ref: cells-412427 (2019) -

Authors: Kay-Dietrich Wagner, Mounir El Maï, Michael Ladomery, Tareg Belali, Nathalie Leccia, Jean-François Michiels, Nicole Wagner

Abstract

Angiogenesis is one hallmark of cancer. VEGF is a known inducer of angiogenesis. Many patients benefit from antiangiogenic therapies, which however have limitations. Although VEGF is overexpressed in most tumors, different VEGF isoforms with distinct angiogenic properties are produced through alternative splicing. In podocytes, WT1 suppresses the splicing factor kinase SRPK1, and indirectly Srsf1 activity, and alters VEGF splicing. We analyzed VEGF isoforms, Wt1, Srpk1, and Srsf1 in normal and tumor endothelium. Wt1, Srpk1, Srsf1, and the angiogenic VEGF164a isoform were highly expressed in tumor endothelium compared to normal lung endothelium. Nuclear expression of Srsf1 was detectable in the endothelium of various tumor types, but not in healthy tissues. Inducible conditional vessel-specific knockout of Wt1 reduced Wt1, Srpk1, and Srsf1 expression in endothelial cells and induced a shift towards the antiangiogenic VEGF120 isoform. Wt1-KTS directly binds and activates both the promoters of Srpk1 and Srsf1 in endothelial cells.

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