scholarly journals VEGFA’s distal enhancer regulates its alternative splicing in CML

NAR Cancer ◽  
2021 ◽  
Vol 3 (3) ◽  
Author(s):  
Sara Dahan ◽  
Aveksha Sharma ◽  
Klil Cohen ◽  
Mai Baker ◽  
Nadeen Taqatqa ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Cancer Progression ◽  
Opposite Effect ◽  
Elongation Rate ◽  
Vascular Endothelial ◽  
Distal Enhancer ◽  
Enhancer Activity ◽  
Splicing Isoforms ◽  
Endothelial Growth Factor ◽  
First Time

Abstract Enhancer demethylation in leukemia has been shown to lead to overexpression of genes which promote cancer characteristics. The vascular endothelial growth factor A (VEGFA) enhancer, located 157 Kb downstream of its promoter, is demethylated in chronic myeloid leukemia (CML). VEGFA has several alternative splicing isoforms with different roles in cancer progression. Since transcription and splicing are coupled, we wondered whether VEGFA enhancer activity can also regulate the gene’s alternative splicing to contribute to the pathology of CML. Our results show that mutating the VEGFA +157 enhancer promotes exclusion of exons 6a and 7 and activating the enhancer by tethering a chromatin activator has the opposite effect. In line with these results, CML patients present with high expression of +157 eRNA and inclusion of VEGFA exons 6a and 7. In addition, our results show that the positive regulator of RNAPII transcription elongation, CCNT2, binds VEGFA’s promoter and enhancer, and its silencing promotes exclusion of exons 6a and 7 as it slows down RNAPII elongation rate. Thus our results suggest that VEGFA’s +157 enhancer regulates its alternative splicing by increasing RNAPII elongation rate via CCNT2. Our work demonstrates for the first time a connection between an endogenous enhancer and alternative splicing regulation of its target gene.

scholarly journals Structural insights into the modulation of PDGF/PDGFR-β complexation by hyaluronan derivatives

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Kanagasabai Balamurugan ◽  
Linda Koehler ◽  
Jan-Niklas Dürig ◽  
Ute Hempel ◽  
Jörg Rademann ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cancer Progression ◽  
Computational Analysis ◽  
Vascular Endothelial ◽  
Receptor Recognition ◽  
Dynamics Simulations ◽  
Endothelial Growth Factor ◽  
Structural Insights ◽  
Important Physiological Process ◽  
Computational Predictions

Abstract Angiogenesis is an important physiological process playing a crucial role in wound healing and cancer progression. Vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) are key players in angiogenesis. Based on previous findings regarding the modulation of VEGF activity by glycosaminoglycans (GAG), here we explore the interaction of hyaluronan (HA)-based GAG with PDGF and its receptor PDGFR-β by applying molecular modeling and dynamics simulations in combination with surface plasmon resonance (SPR). Computational analysis on the interaction of oligo-hyaluronan derivatives with different sulfation pattern and functionalization shows that these GAG interact with PDGF in relevant regions for receptor recognition, and that high sulfation as well as modification with the TAMRA group convey stronger binding. On the other hand, the studied oligo-hyaluronan derivatives are predicted to scarcely recognize PDGFR-β. SPR results are in line with the computational predictions regarding the binding pattern of HA tetrasaccharide (HA4) derivatives to PDGF and PDGFR-β. Furthermore, our experimental results also show that the complexation of PDGF to PDGFR-β can be modulated by HA4 derivatives. The results found open the path for considering HA4 derivatives as potential candidates to be exploited for modulation of the PDGF/PDGFR-β signaling system in angiogenesis and related disease conditions.

Vasodilator effect and mechanism of action of vascular endothelial growth factor in skin vasculature

2004 ◽  
Vol 286 (3) ◽  
pp. H946-H954 ◽  
Author(s):  
Homa Ashrafpour ◽  
Ning Huang ◽  
Peter C. Neligan ◽  
Christopher R. Forrest ◽  
Patrick D. Addison ◽  
...  
Keyword(s):  
Skin Flap ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Skin Flaps ◽  
Skin Perfusion ◽  
Potent Vasodilator ◽  
Or Gene ◽  
Endothelial Growth Factor ◽  
Endothelial Nitric Oxide ◽  
First Time

Various laboratories have reported that local subcutaneous or subdermal injection of VEGF165 at the time of surgery effectively attenuated ischemic necrosis in rat skin flaps, but the mechanism was not studied and enhanced angiogenesis was implicated. In the present study, we used the clinically relevant isolated perfused 6 × 16-cm pig buttock skin flap model to 1) test our hypothesis that VEGF165 is a potent vasodilator and acute VEGF165 treatment increases skin perfusion; and 2) investigate the mechanism of VEGF165-induced skin vasorelaxation. We observed that VEGF165 (5 × 10–16–5 × 10–11 M) elicited a concentration-dependent decrease in perfusion pressure (i.e., vasorelaxation) in skin flaps preconstricted with a submaximal concentration of norepinephrine (NE), endothelin-1, or U-46619. The VEGF165-induced skin vasorelaxation was confirmed using a dermofluorometry technique for assessment of skin perfusion. The vasorelaxation potency of VEGF165 in NE-preconstricted skin flaps (pD2 = 13.57 ± 0.31) was higher ( P < 0.05) than that of acetylcholine (pD2 = 7.08 ± 0.24). Human placental factor, a specific VEGF receptor-1 agonist, did not elicit any vasorelaxation effect. However, a specific antibody to VEGF receptor-2 (1 μg/ml) or a specific VEGF receptor-2 inhibitor (5 × 10–6 M SU-1498) blocked the vasorelaxation effect of VEGF165 in NE-preconstricted skin flaps. These observations indicate that the potent vasorelaxation effect of VEGF165 in the skin vasculature is initiated by the activation of VEGF receptor-2. Furthermore, using pharmacological probes, we observed that the postreceptor signaling pathways of VEGF165-induced skin vasorelaxation involved activation of phospholipase C and protein kinase C, an increase in inositol 1,4,5-trisphosphate activity, release of the intra-cellular Ca2+ store, and synthesis/release of endothelial nitric oxide, which predominantly triggered the effector mechanism of VEGF165-induced vasorelaxation. This information provides, for the first time, an important insight into the mechanism of VEGF165 protein or gene therapy in the prevention/treatment of ischemia in skin flap surgery and skin ischemic diseases.

scholarly journals Design and Properties of Ligand-Conjugated Guanine Oligonucleotides for Recovery of Mutated G-Quadruplexes

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3228
Author(s):  
Shuntaro Takahashi ◽  
Boris Chelobanov ◽  
Ki Kim ◽  
Byeang Kim ◽  
Dmitry Stetsenko ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Polyaromatic Hydrocarbons ◽  
Fine Tuning ◽  
Vascular Endothelial ◽  
Quadruplex Dna ◽  
Guanine Quadruplex ◽  
Anthracene Derivatives ◽  
Novel Strategy ◽  
Endothelial Growth Factor ◽  
Unfolding Kinetics

The formation of a guanine quadruplex DNA structure (G4) is known to repress the expression of certain cancer-related genes. Consequently, a mutated G4 sequence can affect quadruplex formation and induce cancer progression. In this study, we developed an oligonucleotide derivative consisting of a ligand-containing guanine tract that replaces the mutated G4 guanine tract at the promoter of the vascular endothelial growth factor (VEGF) gene. A ligand moiety consisting of three types of polyaromatic hydrocarbons, pyrene, anthracene, and perylene, was attached to either the 3′ or 5′ end of the guanine tract. Each of the ligand-conjugated guanine tracts, with the exception of anthracene derivatives, combined with other intact guanine tracts to form an intermolecular G4 on the mutated VEGF promoter. This intermolecular G4, exhibiting parallel topology and high thermal stability, enabled VEGF G4 formation to be recovered from the mutated sequence. Stability of the intramolecular G4 increased with the size of the conjugated ligand. However, suppression of intermolecular G4 replication was uniquely dependent on whether the ligand was attached to the 3′ or 5′ end of the guanine tract. These results indicate that binding to either the top or bottom guanine quartet affects unfolding kinetics due to polarization in DNA polymerase processivity. Our findings provide a novel strategy for recovering G4 formation in case of damage, and fine-tuning processes such as replication and transcription.

scholarly journals MBNL1 alternative splicing isoforms play opposing roles in cancer

2018 ◽  
Vol 1 (5) ◽  
pp. e201800157 ◽  
Author(s):  
Tommaso Tabaglio ◽  
Diana HP Low ◽  
Winnie Koon Lay Teo ◽  
Pierre Alexis Goy ◽  
Piotr Cywoniuk ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Gene Function ◽  
Dominant Negative ◽  
Individual Gene ◽  
Cancer Types ◽  
Splicing Isoforms ◽  
Isoform Switching ◽  
And Migration

The extent of and the oncogenic role played by alternative splicing (AS) in cancer are well documented. Nonetheless, only few studies have attempted to dissect individual gene function at an isoform level. Here, we focus on the AS of splicing factors during prostate cancer progression, as these factors are known to undergo extensive AS and have the potential to affect hundreds of downstream genes. We identified exon 7 (ex7) in the MBNL1 (Muscleblind-like 1) transcript as being the most differentially included exon in cancer, both in cell lines and in patients' samples. In contrast, MBNL1 overall expression was down-regulated, consistently with its described role as a tumor suppressor. This observation holds true in the majority of cancer types analyzed. We first identified components associated to the U2 splicing complex (SF3B1, SF3A1, and PHF5A) as required for efficient ex7 inclusion and we confirmed that this exon is fundamental for MBNL1 protein homodimerization. We next used splice-switching antisense oligonucleotides (AONs) or siRNAs to compare the effect of MBNL1 splicing isoform switching with knockdown. We report that whereas the absence of MBNL1 is tolerated in cancer cells, the expression of isoforms lacking ex7 (MBNL1 Δex7) induces DNA damage and inhibits cell viability and migration, acting as dominant negative proteins. Our data demonstrate the importance of studying gene function at the level of alternative spliced isoforms and support our conclusion that MBNL1 Δex7 proteins are antisurvival factors with a defined tumor suppressive role that cancer cells tend to down-regulate in favor of MBNL +ex7 isoforms.

scholarly journals YAP and TAZ maintain PROX1 expression in the developing lymphatic and lymphovenous valves in response to VEGF-C signaling

Development ◽  
2020 ◽  
Vol 147 (23) ◽  
pp. dev195453
Author(s):  
Boksik Cha ◽  
Yen-Chun Ho ◽  
Xin Geng ◽  
Md. Riaj Mahamud ◽  
Lijuan Chen ◽  
...  
Keyword(s):  
Feedback Loop ◽  
Lymphatic Vessels ◽  
Vascular Endothelial ◽  
Valve Development ◽  
Prox1 Expression ◽  
Homeobox Transcription Factor ◽  
Lymphatic Vasculature ◽  
Factor C ◽  
Endothelial Growth Factor ◽  
First Time

ABSTRACTLymphatic vasculature is an integral part of digestive, immune and circulatory systems. The homeobox transcription factor PROX1 is necessary for the development of lymphatic vessels, lymphatic valves (LVs) and lymphovenous valves (LVVs). We and others previously reported a feedback loop between PROX1 and vascular endothelial growth factor-C (VEGF-C) signaling. PROX1 promotes the expression of the VEGF-C receptor VEGFR3 in lymphatic endothelial cells (LECs). In turn, VEGF-C signaling maintains PROX1 expression in LECs. However, the mechanisms of PROX1/VEGF-C feedback loop remain poorly understood. Whether VEGF-C signaling is necessary for LV and LVV development is also unknown. Here, we report for the first time that VEGF-C signaling is necessary for valve morphogenesis. We have also discovered that the transcriptional co-activators YAP and TAZ are required to maintain PROX1 expression in LVs and LVVs in response to VEGF-C signaling. Deletion of Yap and Taz in the lymphatic vasculature of mouse embryos did not affect the formation of LVs or LVVs, but resulted in the degeneration of these structures. Our results have identified VEGF-C, YAP and TAZ as a crucial molecular pathway in valve development.

scholarly journals Vascular endothelial growth factor correlation with clinicopathological parameters in ovarian cancer

2019 ◽  
Vol 8 (4) ◽  
pp. 1700
Author(s):  
Mahy Egiz ◽  
Alaa Masoud ◽  
Hamed Ellakwa ◽  
Mohamed Adel Elsayed
Keyword(s):  
Ovarian Cancer ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Cancer Progression ◽  
Clinicopathological Parameters ◽  
Vascular Endothelial ◽  
Variable Parameters ◽  
Gynecology And Obstetrics ◽  
Endothelial Growth Factor

Epithelial ovarian cancer (EOC) is one of the most lethal gynaecologic malignancies with an increasing incidence worldwide; there is an increasing need for the identification of novel prognostic biomarkers in EOC patients. Given the key role of angiogenesis and growth factors in the biology of tumorigenesis, vascular endothelial growth factor (VEGF) is considered a milestone in the process of ovarian cancer progression and invasiveness. Authors aimed in the present study to evaluate the relevance of serum level of VEGF with clinicopathological parameters in patients with EOC. VEGF is reported to be correlated with variable parameters in EOC patients including International Federation of Gynecology and Obstetrics (FIGO) classification, lymph nodal involvement and ascites formation. In the following review, authors discussed these correlations and distinguished the possible future role of VEGF as a promising prognostic biomarker for EOC patients.

In vivo perspective study about the effects of weekly low dose administration of zoledronic acid (ZA) on angiogenesis

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3558-3558
Author(s):  
D. Santini ◽  
B. Vincenzi ◽  
F. Battistoni ◽  
S. Galluzzo ◽  
L. Rocci ◽  
...  
Keyword(s):  
Zoledronic Acid ◽  
Cancer Patients ◽  
Serum Levels ◽  
Vascular Endothelial ◽  
Low Doses ◽  
Dose Administration ◽  
Before And After ◽  
Endothelial Growth Factor ◽  
First Time

3558 Purpose: Recent data have demonstrated in preclinical tumor models an antiangiogenic and antitumor activity of low weekly doses of ZA. As a consequence, the purpose of this study was to confirm these data, evaluating in cancer patients the modifications in angiogenic cytokines levels following repeated weekly low doses of ZA. Experimental Design: 26 consecutive cancer patients with bone metastases treated, for the first time, with four weekly doses of 1 mg of ZA followed by standard doses (4 mg every 28 days) were prospectively evaluated for circulating levels of vascular endothelial growth factor (VEGF) at different time points: just before and after 1, 7, 14, 21, 28, 56 and 84 days following the first disphosphonate infusion. Results: Basal serum VEGF median levels were significantly decreased just after 7 days (-29.7%) (with only one weekly infusion) (P=0.038), This significant decrease of circulating VEGF levels persisted 14(-33.2%), 21 (-39.4%), 28(-31.8%), 56(-33.6%) and 84(-27.9%) days after the first infusion (respectively, P=0.002, P=0.001, P=0.008, P=0.002, P=0.014). Conclusions: This study confirms, for the first time in humans, that weekly low doses of zoledronic acid could have antiangiogenic properties through a significant and long lasting decrease of VEGF serum levels. No significant financial relationships to disclose.

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