TP53 Mutation Analysis in Gastric Cancer and Clinical Outcomes of Patients with Metastatic Disease Treated with Ramucirumab/Paclitaxel or Standard Chemotherapy

Loss of p53 promotes vascular endothelial growth factor (VEGF)-A up-regulation and the angiogenic potential of cancer cells. We investigated TP53 somatic mutations in 110 primary gastric adenocarcinomas of two retrospective metastatic series including 48 patients treated with second-line Ramucirumab/Paclitaxel and 62 patients who received first-line chemotherapy with Cisplatin or Oxaliplatin plus 5-Fluorouracil. Missense mutations were classified by tumor protein p53 (TP53) mutant-specific residual transcriptional activity scores (TP53RTAS) and used to stratify patients into two groups: transcriptionally TP53Active and TP53Inactive. The primary endpoint was overall survival (OS). An additional analysis was addressed to measure VEGF/VEGF receptor 2 (VEGFR2) expression levels in relation to the TP53RTAS. In the Ramucirumab/Paclitaxel group, 29/48 (60.4%) patients had TP53 mutations. Ten patients with TP53Inactive mutations showed better OS than carriers of other TP53 mutations. This effect was retained in the multivariate model analysis (Hazard Ratio = 0.29, 95% confidence interval = 0.17–0.85, p = 0.02). In the chemotherapy group, 41/62 (66%) patients had TP53 mutations, and the 11 carriers of TP53Inactive mutations showed the worst OS (Hazard Ratio = 2.64, 95% confidence interval = 1.17–5.95, p = 0.02). VEGF-A mRNA expression levels were significantly increased in TP53Inactive cases. Further studies are warranted to explore the effect of TP53Inactive mutations in different anti-cancer regimens. This information would lead to new tailored therapy strategies for this lethal disease.

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TP53 mutation analysis in gastric cancer and clinical outcomes of patients with metastatic disease treated with anti-angiogenic or standard chemotherapy regimens.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e16571 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e16571-e16571

Author(s):

Nicholas William Fischer ◽

Francesco Graziano ◽

Irene Bagaloni ◽

Maria Di Bartolomeo ◽

Sara Lonardi ◽

...

Keyword(s):

Confidence Interval ◽

Tp53 Mutation ◽

Current Data ◽

Hazard Ratio ◽

Control Group ◽

First Line ◽

Primary Tumors ◽

Tp53 Mutations ◽

Angiogenic Potential ◽

Therapy Strategies

e16571 Background: Current data support the angiogenic potential of cancer cells with mutant p53 and VEGF-A up-regulation in solid tumors. These findings have renewed interest in the p53 role as a predictive/prognostic factor in cancer therapy. We investigated TP53 mutations in gastric adenocarcinoma (GA) samples of metastatic patients (pts) who underwent anti-angiogenic Paclitaxel-Ramucirumab (PR) therapy. The analysis was also performed in a control group of pts who received first-line chemotherapy (CT) with platinum derivates and fluoropyrimidines. Methods: TP53 mutations were identified by next-generation sequencing in 110 GA primary tumors of two retrospective metastatic series including 48 pts who were treated with second-line PR and 62 pts who received first-line CT with Cisplatin or Oxaliplatin plus 5-Fluorouracil or Capecitabine. Detected TP53 mutations were classified for TP53 mutant-specific residual transcriptional activity scores ( TP53 RTAS) (Fischer NW et al JCI Insight 2018). TP53 RTAS results were used for stratifying pts in survival analyses. Primary end-point was overall survival (OS). Results: In the PR group, TP53 mutations were detected in 29 out of 48 tumor samples (60.4%) with 10 having TP53 RTAS 0%-to-<1%. In the CT group, TP53 mutations were found in 40 out of 62 tumor samples (64.5%) with 11 having TP53 RTAS 0%-to-<1%. In the PR group, the 10 cases with a TP53 mutation causing no residual or minimal activity ( TP53 RTAS 0%-to-<1%) showed better OS in comparison with pts in the remaining groups (wild-type and TP53 RTAS > 1%). This effect was retained in the multivariate model analysis (Hazard Ratio = 0.29, 95% confidence interval 0.17-0.85, p = 0.02). An opposite effect was seen in the CT group with the worst OS in carriers of TP53 RTAS 0%-to-<1% mutations (Hazard Ratio = 2.64, 95% confidence interval 1.17-5.95, p = 0.02). Notably, in the whole group of 110 pts, TP53 mutations (any type) occurred more frequently in the intestinal-type GA group (p = 0.02). Conclusions: Additional studies are warranted to explore the favorable role of TP53 mutations in cancer pts undergoing anti-angiogenic therapies. TP53 mutations frequently occur in GA and these findings would lead to novel tailored therapy strategies in this lethal disease.

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Association of p53 mutations with progression-free survival (PFS) and overall survival (OS) in EGFR-mutated non-small cell lung cancer (NSCLC) patients (p) treated with erlotinib.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e18143 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e18143-e18143 ◽

Cited By ~ 1

Author(s):

Amaya Gasco ◽

Miguel Angel Molina-Vila ◽

Jordi Bertran-Alamillo ◽

Clara Mayo ◽

Carlota Costa ◽

...

Keyword(s):

Advanced Nsclc ◽

Egfr Mutations ◽

Mrna Levels ◽

Missense Mutations ◽

P53 Mutations ◽

T790m Mutation ◽

Expression Levels ◽

Tp53 Mutations ◽

Egfr Mutated ◽

Mdm2 Mrna

e18143 Background: Advanced NSCLC p with EGFR mutations have a median PFS of 14 months (m) and OS of 27 m when treated with erlotinib. In NSCLC cell lines, tyrosine kinase inhibitors (TKIs) induce p53 translocation from the cytoplasm to the nucleus and subsequent upregulation of Fas and caspase activation leading to apoptosis, but this mechanism was defective in p53-null cells. We tested whether TP53 mutations influence outcome to erlotinib in EGFR-mutated p. Expression levels of the p53 repressor MDM2 were also examined. Methods: We assessed p53 status in pretreatment paraffin-embedded tumor samples from 93 erlotinib-treated, EGFR-mutated advanced NSCLC p. Mutations in exons 5, 6, 7 and 8 were screened by High Resolution Melting analysis followed by sequencing of the amplified products with non-wild-type (wt) melt curves. All mutant samples were re-confirmed by standard PCR and sequencing. Expression levels of MDM2 mRNA were determined by quantitative RT-PCR. Results: Mutations in exons 5-8 of TP53 were detected in 26 of 93 p (28%). We found an unusually high frequency of in-frame and frameshift deletions (23% of mutations), indicating that the spectrum of p53 mutations might be different in EGFR-mutated NSCLC. Mutations were less frequent in p with ECOG PS >2 and more frequent in p with the T790M mutation. OS was 15 m in the 16 p with missense mutations 31 m in p with wt p53 and not reached in p with non-missense mutations (P=0.04). PFS was 9 m for 14 p with mutations in one of the p53 DNA binding motifs (DBMs), compared to 19 m for wt p and 27 m for p with non-DBM mutations. MDM2 mRNA levels were significantly lower in tumors with p53 mutations, especially in DBM mutations. In the case of wt p, high MDM2 expression correlated with longer PFS and OS in p with wt p53. Conclusions: TP53 mutations co-exist with EGFR mutations in a significant number of p; missense mutations correlate with shorter OS and mutations in DBMs correlate with shorter PFS. This finding paves the way for the possibility of combining erlotinib with a drug restoring p53 function in those p harboring certain types of mutations in the TP53 gene.

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Overexpression of junctional adhesion molecule-A and EphB2 predicts poor survival in lung adenocarcinoma patients

Tumor Biology ◽

10.1177/1010428317691000 ◽

2017 ◽

Vol 39 (2) ◽

pp. 101042831769100 ◽

Cited By ~ 4

Author(s):

Chen Zhao ◽

Aili Wang ◽

Funian Lu ◽

Hongxia Chen ◽

Pin Fu ◽

...

Keyword(s):

Overall Survival ◽

Mortality Rate ◽

Confidence Interval ◽

Lung Adenocarcinoma ◽

Adhesion Molecules ◽

Adhesion Molecule ◽

Hazard Ratio ◽

High Expression ◽

Poor Overall Survival ◽

Expression Levels

Junctional adhesion molecules are important components of tight junctions, and Eph/ephrin proteins constitute the largest family of receptor tyrosine kinases. Both junctional adhesion molecules and Eph/ephrin are involved in normal tissue development and cancer progression. However, the expression levels and clinical significances of junctional adhesion molecule-A, a member of junctional adhesion molecules, and EphB2, a member of Eph/ephrin family, in lung adenocarcinoma patients are unclear. Therefore, in this study, we aimed to identify the expression and prognostic values of junctional adhesion molecule-A and EphB2 in lung adenocarcinoma patients’ cohort. In our study, 70 (55.6%) showed high expression of junctional adhesion molecule-A protein and 51 (40.5%) showed high expression of EphB2 protein in 126 lung adenocarcinoma tissues. Junctional adhesion molecule-A and EphB2 expressions were both significantly increased in tumor tissues compared with noncancerous lung tissues. Kaplan–Meier analysis and log-rank test indicated that low expression of junctional adhesion molecule-A and EphB2 proteins can predict better survival and low mortality rate of lung adenocarcinomas. In univariate analysis, high expression levels of junctional adhesion molecule-A and EphB2 were both found to be significantly correlated with poor overall survival of lung adenocarcinoma patients (hazard ratio = 1.791, 95% confidence interval = 1.041–3.084, p = 0.035; hazard ratio = 1.762, 95% confidence interval = 1.038–2.992, p = 0.036, respectively). The multivariate Cox proportional hazard model demonstrated that EphB2 expression is an independent prognosis parameter in lung adenocarcinoma patients (hazard ratio = 1.738, 95% confidence interval = 1.023–2.952, p = 0.016). Taken together, high expression of junctional adhesion molecule-A and EphB2 can predict poor overall survival and high mortality rate, and EphB2 is an independent prognostic biomarker in lung adenocarcinoma patients.

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High Expression of Lymphoid Enhancer-Binding Factor 1 (LEF1) Is a Novel, Favorable Prognostic Marker in Cytogenetically Normal AML and Is Associated with Upregulation of T-Lymphoid Lineage Markers in AML Blasts.

Blood ◽

10.1182/blood.v114.22.398.398 ◽

2009 ◽

Vol 114 (22) ◽

pp. 398-398

Author(s):

Klaus H. Metzeler ◽

Bernhard Heilmeier ◽

Konstantin Petropoulos ◽

Maria C. Sauerland ◽

Achim Heinecke ◽

...

Keyword(s):

Gene Expression ◽

Confidence Interval ◽

Prognostic Marker ◽

Hazard Ratio ◽

Wnt Signalling ◽

Inverse Association ◽

Acute Leukemias ◽

Transcript Levels ◽

Expression Levels ◽

Binding Factor

Abstract Abstract 398 In recent years, the classification of cytogenetically normal acute myeloid leukemia (CN-AML) has seen a turnaround from morphological characterisation towards the identification of novel molecular prognostic factors. Besides the well-recognized prognostic influence of mutations in NPM1, CEPBA, FLT3 and other genes, high transcript levels of ERG, MN1 or BAALC recently have been associated with inferior outcome. However, our understanding of the pathogenetic mechanisms that underlie the prognostic relevance of these markers is limited. The canonical WNT signalling pathway not only plays an important role in embryonic development but is also implicated in almost one third of all human cancers including many subtypes of leukemias. Expression of β-catenin, a key player in the WNT pathway, in AML blasts has been associated with enhanced clonogenic potential and inferior patient survival. Lymphoid enhancer-binding factor 1 (LEF1) is a transcription factor that directly interacts with β-catenin during WNT signalling. Recently, we showed that Lef-1 is an important regulatory factor in early hematopoiesis and that its constitutive expression in murine hematopoetic cells causes both myeloid and lymphoid acute leukemias, which originate from a leukemic stem cell with lymphoid characteristics (Petropoulos et al., J Exp Med 2008). In the present study, we analysed the association of LEF1 expression with clinical outcomes in a cohort of 210 adult patients (median age, 59 years) with CN-AML. All patients were treated in two consecutive multicenter studies of the German AML Cooperative Group (AMLCG), and the median follow-up for surviving patients was 46 months. LEF1 expression levels were extracted from gene expression profiles (obtained using Affymetrix HG-U133A or HG-U133plus2 oligonucleotide microarrays). Patients were classified as LEF1high or LEF1low according to the median of all samples. We found that LEF1 expression was inversely correlated with the leukocyte count at diagnosis, and the frequency of FLT3 ITD mutations was significantly lower among patients with high LEF1 transcript levels than among those with low LEF1 expression (59% vs. 24%, respectively; P<0.001). LEF1high patients, as compared with LEF1low patients, showed a significantly prolonged overall survival (OS) (median, 36 vs. 8.6 months, P<0.001) and relapse-free survival (RFS) (median, 27 vs. 6.7 months, P<0.001). The correlation of LEF1 transcript levels with OS could not solely be explained by its inverse association with FLT3 ITD status, since in multivariate analyses, high LEF1 expression remained an independent predictor of prolonged OS (hazard ratio for death, 0.59; 95% confidence interval, 0.40 – 0.88; P=0.01) after adjustment for age, FLT3 status, and ERG expression levels. Moreover, there was no statistically significant interaction between the effects of LEF1 expression levels and FLT3 ITD status or treatment group assignment on OS. High LEF1 levels also were predictive of longer RFS (hazard ratio, 0.49; 95% confidence interval, 0.31 - 0.79; P=0.003) after adjustment for age and the NPM1mutant/FLT3 ITDnegative genotype. We then tried to identify genes that are differentially regulated in LEF1high versus LEF1low low patients. Among the genes that showed the most prominent transcriptional upregulation in LEF1high samples, there were several markers of T-lymphoid differentiation (e.g., CD2, CD3, CD5, and the interleukin 2 receptor beta chain). Statistically significant upregulation of the T-lymphoid markers CD2, cyCD3 and CD7 in LEF1high AML was confirmed by immunophenotyping of the leukemic cells. In contrast, there was no correlation between immunologically detected B-lymphoid markers (e.g. CD19, cyCD22, cyCD79a) and the LEF1 expression level. In summary, our data indicate that high LEF1 expression is an independent favorable prognostic marker in CN-AML, and that it is associated with a distinct gene expression profile and immunophenotype, characterized by upregulation of lymphoid cell antigens. Disclosures: No relevant conflicts of interest to declare.

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Expression Profile of VEGF-C, VEGF-D, and VEGFR-3 in Different Grades of Endometrial Cancer

Current Pharmaceutical Biotechnology ◽

10.2174/1389201020666190718164431 ◽

2019 ◽

Vol 20 (12) ◽

pp. 1004-1010

Author(s):

Marcin Oplawski ◽

Konrad Dziobek ◽

Nikola Zmarzły ◽

Beniamin Grabarek ◽

Tomasz Halski ◽

...

Keyword(s):

Endometrial Cancer ◽

Optical Density ◽

Metastatic Potential ◽

Vegf Receptor ◽

Vascular Endothelial ◽

Tumor Lymphangiogenesis ◽

Neoplastic Process ◽

The One ◽

Post Hoc ◽

Endothelial Growth Factor

Background: Vascular endothelial growth factor (VEGF)-C, -D, and VEGF receptor-3 are proteins characterized as crucial for tumor lymphangiogenesis. It is accompanied by angiogenesis during wound healing, but also in the neoplastic process. The research studies have shown that the lymphatic system plays a key role in the progression of carcinogenesis. Objective: The aim of this study was to evaluate changes in the expression of VEGF-C, VEGF-D and VEGFR-3 in different grades of endometrial cancer (G1-G3). Methods: The study included 45 patients diagnosed with endometrial cancer (G1=17; G2=15; G3=13) and 15 patients without neoplastic changes. The expression of VEGF-C, VEGF-D, and VEGFR-3 was assessed using microarray technique and immunohistochemistry. Statistical analysis was performed using the one-way ANOVA and Tukey's post-hoc test. Results: Statistically significant changes in the expression at the transcriptome level were found only in the case of VEGF-C (G1 vs. C, fold change - FC = -1.15; G2 vs. C, FC = -2.33; G3 vs. C, FC = - 1.68). However, VEGF-D and VEGFR-3 were expressed at the protein level. Analysis of VEGF-D expression showed that the optical density of the reaction product in G1 reached 101.7, while the values in G2 and G3 were 142.7 and 184.4, respectively. For VEGF-R3, the optical density of the reaction product reached the following levels: 72 in control, 118.77 in G1, 145.8 in G2, and 170.9 in G3. Conclusion: : An increase in VEGF-D and VEGFR-3 levels may indicate that VEGF-D-dependent processes are intensified along with the dedifferentiation of tumor cells. The lack of VEGF-C expression in endometrial cancer samples may suggest that this tumor is characterized by a different mechanism of metastasis than EMT. Our study emphasizes that when analyzing the metastatic potential of cancer, the expression of more than one factor should be taken into account.

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Mutated p53 in HGSC—From a Common Mutation to a Target for Therapy

Cancers ◽

10.3390/cancers13143465 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3465

Author(s):

Aya Saleh ◽

Ruth Perets

Keyword(s):

Cancer Progression ◽

Target Genes ◽

P53 Protein ◽

Genetic Alterations ◽

Common Mutation ◽

Missense Mutations ◽

P53 Expression ◽

Histologic Subtype ◽

Tp53 Mutations

Mutations in tumor suppressor gene TP53, encoding for the p53 protein, are the most ubiquitous genetic variation in human ovarian HGSC, the most prevalent and lethal histologic subtype of epithelial ovarian cancer (EOC). The majority of TP53 mutations are missense mutations, leading to loss of tumor suppressive function of p53 and gain of new oncogenic functions. This review presents the clinical relevance of TP53 mutations in HGSC, elaborating on several recently identified upstream regulators of mutant p53 that control its expression and downstream target genes that mediate its roles in the disease. TP53 mutations are the earliest genetic alterations during HGSC pathogenesis, and we summarize current information related to p53 function in the pathogenesis of HGSC. The role of p53 is cell autonomous, and in the interaction between cancer cells and its microenvironment. We discuss the reduction in p53 expression levels in tumor associated fibroblasts that promotes cancer progression, and the role of mutated p53 in the interaction between the tumor and its microenvironment. Lastly, we discuss the potential of TP53 mutations to serve as diagnostic biomarkers and detail some more advanced efforts to use mutated p53 as a therapeutic target in HGSC.

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Factors that contribute to urban–rural gradients in risk of schizophrenia: Comparing Danish and Western Australian registers

Australian & New Zealand Journal of Psychiatry ◽

10.1177/00048674211009615 ◽

2021 ◽

pp. 000486742110096

Author(s):

Oleguer Plana-Ripoll ◽

Patsy Di Prinzio ◽

John J McGrath ◽

Preben B Mortensen ◽

Vera A Morgan

Keyword(s):

Confidence Interval ◽

Western Australia ◽

Urban Areas ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Hazard Ratio ◽

Indigenous Status ◽

Increased Risk ◽

The Relationship ◽

Western Australian

Introduction: An association between schizophrenia and urbanicity has long been observed, with studies in many countries, including several from Denmark, reporting that individuals born/raised in densely populated urban settings have an increased risk of developing schizophrenia compared to those born/raised in rural settings. However, these findings have not been replicated in all studies. In particular, a Western Australian study showed a gradient in the opposite direction which disappeared after adjustment for covariates. Given the different findings for Denmark and Western Australia, our aim was to investigate the relationship between schizophrenia and urbanicity in these two regions to determine which factors may be influencing the relationship. Methods: We used population-based cohorts of children born alive between 1980 and 2001 in Western Australia ( N = 428,784) and Denmark ( N = 1,357,874). Children were categorised according to the level of urbanicity of their mother’s residence at time of birth and followed-up through to 30 June 2015. Linkage to State-based registers provided information on schizophrenia diagnosis and a range of covariates. Rates of being diagnosed with schizophrenia for each category of urbanicity were estimated using Cox proportional hazards models adjusted for covariates. Results: During follow-up, 1618 (0.4%) children in Western Australia and 11,875 (0.9%) children in Denmark were diagnosed with schizophrenia. In Western Australia, those born in the most remote areas did not experience lower rates of schizophrenia than those born in the most urban areas (hazard ratio = 1.02 [95% confidence interval: 0.81, 1.29]), unlike their Danish counterparts (hazard ratio = 0.62 [95% confidence interval: 0.58, 0.66]). However, when the Western Australian cohort was restricted to children of non-Aboriginal Indigenous status, results were consistent with Danish findings (hazard ratio = 0.46 [95% confidence interval: 0.29, 0.72]). Discussion: Our study highlights the potential for disadvantaged subgroups to mask the contribution of urban-related risk factors to risk of schizophrenia and the importance of stratified analysis in such cases.

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THE RELATIONSHIP BETWEEN INFLAMMATORY DIETARY PATTERN AND INCIDENCE OF PERIODONTITIS

British Journal Of Nutrition ◽

10.1017/s0007114520005231 ◽

2021 ◽

pp. 1-36

Author(s):

Ahmed A. Alhassani ◽

Frank B. Hu ◽

Bernard A. Rosner ◽

Fred K. Tabung ◽

Walter C. Willett ◽

...

Keyword(s):

Confidence Interval ◽

Periodontal Disease ◽

Secondary Analysis ◽

Hazard Ratio ◽

Reduced Rank Regression ◽

Rank Regression ◽

Increased Risk ◽

Cox Proportional Hazard Models ◽

Study Population

ABSTRACT The long-term inflammatory impact of diet could potentially elevate the risk of periodontal disease through modification of systemic inflammation. The aim of the present study was to prospectively investigate the associations between a food based, reduced rank regression (RRR) derived, empirical dietary inflammatory pattern (EDIP) and incidence of periodontitis. The study population was composed of 34,940 men from the Health Professionals Follow-Up Study, who were free of periodontal disease and major illnesses at baseline (1986). Participants provided medical and dental history through mailed questionnaires every 2 years, and dietary data through validated semi-quantitative food frequency questionnaires every 4 years. We used Cox proportional hazard models to examine the associations between EDIP scores and validated self-reported incidence of periodontal disease over a 24-year follow-up period. No overall association between EDIP and the risk of periodontitis was observed; the hazard ratio comparing the highest EDIP quintile (most proinflammatory diet) to the lowest quintile was 0.99 (95% confidence interval: 0.89 -1.10, p-value for trend = 0.97). A secondary analysis showed that among obese non-smokers (i.e. never and former smokers at baseline), the hazard ratio for periodontitis comparing the highest EDIP quintile to the lowest was 1.39 (95% confidence interval: 0.98 -1.96, p-value for trend = 0.03). In conclusion, no overall association was detected between EDIP and incidence of self-reported periodontitis in the study population. From the subgroups evaluated EDIP was significantly associated with increased risk of periodontitis only among nonsmokers who were obese. Hence, this association must be interpreted with caution.

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Inhibition of Hippo Signaling Improves Skin Lesions in a Rosacea-Like Mouse Model

International Journal of Molecular Sciences ◽

10.3390/ijms22020931 ◽

2021 ◽

Vol 22 (2) ◽

pp. 931

Author(s):

Jihyun Lee ◽

Yujin Jung ◽

Seo won Jeong ◽

Ga Hee Jeong ◽

Gue Tae Moon ◽

...

Keyword(s):

Mouse Model ◽

Signaling Pathway ◽

Normal Skin ◽

Skin Lesions ◽

Hippo Signaling ◽

Vascular Endothelial ◽

Expression Levels ◽

Hippo Signaling Pathway ◽

Endothelial Growth Factor

The Hippo signaling pathway plays a key role in regulating organ size and tissue homeostasis. Hippo and two of its main effectors, yes-associated protein (YAP) and WWTR1 (WW domain-containing transcription regulator 1, commonly listed as TAZ), play critical roles in angiogenesis. This study investigated the role of the Hippo signaling pathway in the pathogenesis of rosacea. We performed immunohistochemical analyses to compare the expression levels of YAP and TAZ between rosacea skin and normal skin in humans. Furthermore, we used a rosacea-like BALB/c mouse model induced by LL-37 injections to determine the roles of YAP and TAZ in rosacea in vivo. We found that the expression levels of YAP and TAZ were upregulated in patients with rosacea. In the rosacea-like mouse model, we observed that the clinical features of rosacea, including telangiectasia and erythema, improved after the injection of a YAP/TAZ inhibitor. Additionally, treatment with a YAP/TAZ inhibitor reduced the expression levels of YAP and TAZ and diminished vascular endothelial growth factor (VEGF) immunoreactivity in the rosacea-like mouse model. Our findings suggest that YAP/TAZ inhibitors can attenuate angiogenesis associated with the pathogenesis of rosacea and that both YAP and TAZ are potential therapeutic targets for patients with rosacea.

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Lipid Raft Association Stabilizes VEGF Receptor 2 in Endothelial Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22020798 ◽

2021 ◽

Vol 22 (2) ◽

pp. 798

Author(s):

Ibukunoluwapo O. Zabroski ◽

Matthew A. Nugent

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Lipid Rafts ◽

Vegf Receptor ◽

Vascular Endothelial ◽

Potential Mechanism ◽

Lysosomal Degradation ◽

Extracellular Signal ◽

The Stability ◽

Endothelial Growth Factor

The binding of vascular endothelial growth factor A (VEGF) to VEGF receptor-2 (VEGFR-2) stimulates angiogenic signaling. Lipid rafts are cholesterol-dense regions of the plasma membrane that serve as an organizational platform for biomolecules. Although VEGFR2 has been shown to colocalize with lipid rafts to regulate its activation, the effect of lipid rafts on non-activated VEGFR2 has not been explored. Here, we characterized the involvement of lipid rafts in modulating the stability of non-activated VEGFR2 in endothelial cells using raft disrupting agents: methyl-β-cyclodextrin, sphingomyelinase and simvastatin. Disrupting lipid rafts selectively decreased the levels of non-activated VEGFR2 as a result of increased lysosomal degradation. The decreased expression of VEGFR2 translated to reduced VEGF-activation of the extracellular signal-regulated protein kinases (ERK). Overall, our results indicate that lipid rafts stabilize VEGFR2 and its associated signal transduction activities required for angiogenesis. Thus, modulation of lipid rafts may provide a means to regulate the sensitivity of endothelial cells to VEGF stimulation. Indeed, the ability of simvastatin to down regulate VEGFR2 and inhibit VEGF activity suggest a potential mechanism underlying the observation that this drug improves outcomes in the treatment of certain cancers.

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