4 Journal of Nucleic Acids Figure 2: Existing and putative therapies targeting angiogenesis in RCC. VEGFxxx forms homodimers and interacts with their receptors inducing the activation of signalling pathways leading to increased angiogenesis. Homodimers of VEGFxxxb can bind the receptors blocking angiogenesis. However, the existence and function of potential VEGFxxx/VEGFxxxb heterodimers remain unclear. The monoclonal antibody Bevacizumab targets VEGFxxx blocking the VEGFR signalling pathways but also interacts with VEGFxxxb. Sorafenib and Sunitinib are Receptor Tyrosine Kinase inhibitors that interact with the kinase domain of VEGFR and thus inactivate the downstream signalling pathways. The VEGF gene is transcribed into a pre-mRNA that undergoes diﬀerent splicing events leading to diﬀerent isoforms. Splicing at Exon 8 will determinate the pro- or anti-angiogenic property of the produced protein. Hence, the use of the proximal splicing site (PSS) by in particular the splicing factor ASF/SF2 leads to pro-angiogenic -VEGFxxx- forms while the use of the distal splicing site (DSS) by another SR protein, SRp55 provides the anti-angiogenic -VEGFxxxb- forms. Combining all of this knowledge leads to propose that by acting on the VEGFxxx/VEGFxxxb ratio through the modulation of splicing, we could modify the angiogenic potential. as ASF/SF2 and SRp55. ASF/SF2, which is upregulated in most tumour types [58–60], favours the production of the pro-angiogenic isoforms, while SRp55 favours the production of the anti-angiogenic isoforms in normal cells [58]. Furthermore, TGFβ treatment leads to an increase in the VEGFxxxb expression through an increase of SRp55 by the activation of the p38MAPK pathway. In contrast, IGF- 1 stimulation leads to an increase in activated ASF/SF2 by phosphorylation and thus an increase of VEGFxxx isoforms [58]. All of the SR proteins are mainly regulated by SRPK and Clk kinases. Depending on the type of SR proteins, their phosphorylation can be mediated by speciﬁc kinases. Thus, the IGF-1-dependent increase of VEGFxxx could be blocked by the use of speciﬁc inhibitors of SRPK and/or Clk kinases. Thereby, TG0003 mainly inhibits Clk kinases and SRPIN340 inhibiting SRPK kinase, mainly involved in ASF/SF2 activation [60]. Furthermore, chromatin structure and associated modiﬁcations may inﬂuence the splicing [61]. The balance of splicing and transcription regulation depends on several other contributing factors, such as recruitment of RNA recognition, motif-containing proteins, or potential associated cofactors [62]. In addition, the sequence and the length of introns and exons play a major role for the splicing and the following translation of the mRNA. The use of Histone Deacetylase (HDAC) inhibitors such as sodium butyrate has been shown to promote the production of speciﬁc splice variants from a single pre-mRNA [63]. In the same manner, treatment of human lung microvascular endothelial cells (HLMECs) with sodium butyrate showed an increase of anti-angiogenic isoforms of VEGF suggesting that the treatment may act via a change of splicing factors acting on the balance of pro- and anti-angiogenic isoforms [64]. Thus, treatments already used in the clinic such as sunitinib or sorafenib may act through the same mechanisms leading to an increase of VEGFxxxb isoforms. Furthermore, when expressed, VEGFxxxb may be sequestered within the