Abstract
Angiogenesis is one hallmark of cancer. Vascular endothelial growth factor (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, the Wilms’ tumor suppressor 1 (WT1) suppresses the Serine/arginine-rich protein-specific splicing factor kinase (SRPK1), and indirectly Serine/arginine-rich splicing factor 1 (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. In conclusion, Wt1 activates Srpk1 and Srsf1 and induces expression of angiogenic VEGF isoforms in tumor endothelium.
Highlights
Tumor growth as well as development and organ homeostasis require vascular proliferation
Vascular endothelial growth factor A (VEGF) transcription during tumor growth is stimulated by hypoxia [13,14], which is mediated via hypoxia inducible factor 1 (Hif-1) [14] and the Wilms’ tumor suppressor 1 (Wt1) [15,16]
In agreement with our previous reports [22,29], we found quantitative significantly higher Wt1 expression in endothelial cells from tumors compared to normal lung endothelium
Summary
Tumor growth as well as development and organ homeostasis require vascular proliferation (reviewed in [1,2]). Vascular endothelial growth factor A (VEGF), which was initially identified as vascular permeability factor [3,4], is the best-known factor inducing endothelial cell proliferation and angiogenesis [5,6]. Normal VEGF levels are required for embryonic development [7,8,9,10,11] and anti-angiogenic therapies targeting VEGF are widely used for the treatment of cancers (reviewed in [12]). VEGF transcription during tumor growth is stimulated by hypoxia [13,14], which is mediated via hypoxia inducible factor 1 (Hif-1) [14] and the Wilms’ tumor suppressor 1 (Wt1) [15,16]. Additional non-coding transcripts in the promoter region modulate expression of VEGF mRNA [17].
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