Hyperglycemia-induced oxidative stress promotes tumor metastasis by upregulating vWF expression in endothelial cells through the transcription factor GATA1

Jeong, Hyunjo; Lee, Da-Hye; Kim, Seung‐Hoon; Lee, Changhan; Shin, Hyun Mu; Kim, Hang Rae; Cho, Chung–Hyun

doi:10.1038/s41388-022-02207-y

Cited by 18 publications

(15 citation statements)

References 63 publications

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“…A study [20] using mouse models of cancer and hyperglycemia found that high blood sugar levels significantly increase metastasis by enhancing the adhesiveness of endothelial cells, facilitating tumor cell adhesion and migration. VWF, upregulated in endothelial cells due to oxidative stress from hyperglycemia, is critical in this process, making it a potential target for managing hyperglycemia-induced tumor metastasis.…”

Section: Discussionmentioning

confidence: 99%

Utilizing machine learning algorithms to identify biomarkers associated with diabetic nephropathy: A review

Dong,

Liu,

2024

Medicine

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Diabetic nephropathy (DN), a multifaceted disease with various contributing factors, presents challenges in understanding its underlying causes. Uncovering biomarkers linked to this condition can shed light on its pathogenesis and support the creation of new diagnostic and treatment methods. Gene expression data were sourced from accessible public databases, and Weighted Gene Co-expression Network Analysis (WGCNA)was employed to pinpoint gene co-expression modules relevant to DN. Subsequently, various machine learning techniques, such as random forest, lasso regression algorithm (LASSO), and support vector machine-recursive feature elimination (SVM-REF), were utilized for distinguishing DN cases from controls using the identified gene modules. Additionally, functional enrichment analyses were conducted to explore the biological roles of these genes. Our analysis revealed 131 genes showing distinct expression patterns between controlled and uncontrolled groups. During the integrated WCGNA, we identified 61 co-expressed genes encompassing both categories. The enrichment analysis highlighted involvement in various immune responses and complex activities. Techniques like Random Forest, LASSO, and SVM-REF were applied to pinpoint key hub genes, leading to the identification of VWF and DNASE1L3. In the context of DN, they demonstrated significant consistency in both expression and function. Our research uncovered potential biomarkers for DN through the application of WGCNA and various machine learning methods. The results indicate that 2 central genes could serve as innovative diagnostic indicators and therapeutic targets for this disease. This discovery offers fresh perspectives on the development of DN and could contribute to the advancement of new diagnostic and treatment approaches.

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Section: Discussionmentioning

confidence: 99%

Utilizing machine learning algorithms to identify biomarkers associated with diabetic nephropathy: A review

Dong,

Liu,

2024

Medicine

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“…Moreover, we cannot ignore that binding of viral spike protein to ACE2, which is no longer available to cleave Ang II, increases intracellular reactive oxygen species (ROS) production [31] that enhances endothelial vWF levels [28,57]. Therefore, our data suggest the use of siRNA‐based vWF gene silencing might halt the sustained and self‐perpetuating loop of endothelial susceptibility to SARS‐CoV‐2 infection due to enhanced ACE2 expression.…”

Section: Discussionmentioning

confidence: 99%

Gene silencing of endothelial von Willebrand factor reduces the susceptibility of human endothelial cells to SARS‐CoV‐2 infection

et al. 2023

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Mechanisms underlying vascular endothelial susceptibility to infection by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) are not fully understood. Emerging evidence indicates that patients lacking von Willebrand factor (vWF), an endothelial hallmark, are less severely affected by SARS‐CoV‐2 infection, yet the precise role of endothelial vWF in modulating coronavirus entry into endothelial cells is unknown. In the present study, we demonstrated that effective gene silencing by short interfering RNA (siRNA) for vWF expression in resting human umbilical vein endothelial cells (HUVECs) significantly reduced by 56% the cellular levels of SARS‐CoV‐2 genomic RNA. Similar reduction in intracellular SARS‐CoV‐2 genomic RNA levels was observed in non‐activated HUVECs treated with siRNA targeting angiotensin‐converting enzyme 2 (ACE2), the cellular gateway to coronavirus. By integrating quantitative information from real‐time PCR and high‐resolution confocal imaging, we demonstrated that ACE2 gene expression and its plasma membrane localization in HUVECs were both markedly reduced after treatment with siRNA anti‐vWF or anti‐ACE2. Conversely, siRNA anti‐ACE2 did not reduce endothelial vWF gene expression and protein levels. Finally, SARS‐CoV‐2 infection of viable HUVECs was enhanced by overexpression of vWF, which increased ACE2 levels. Of note, we found a similar increase in interferon‐β mRNA levels following transfection with untargeted, anti‐vWF or anti‐ACE2 siRNA and pcDNA3.1‐WT‐VWF. We envision that siRNA targeting endothelial vWF will protect against productive endothelial infection by SARS‐CoV‐2 through downregulation of ACE2 expression and might serve as a novel tool to induce disease resistance by modulating the regulatory role of vWF on ACE2 expression.

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“…vWF can mediate the adhesion of platelets to endothelial cells (52) . It has been shown that oxidative stress can increase (53) and lead to endothelial damage (54) under stress conditions, and oxidative stress can up-regulate the expression of vWF in endothelial cells (55) . vWF aggregates to form ultra-large vWF multimers.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of glucocorticoid receptor activation regulated expression of thrombospondin-1

Zhang

Wang

Song

et al. 2023

Preprint

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Objective: Thrombospondin-1 (TSP-1) plays an important role in platelet activation and aggregation and aggravates thrombosis. Chronic stress can cause a variety of diseases, including coagulation disorders, increased thrombosis, atherosclerosis, and a series of cardiovascular and cerebrovascular diseases. However, it is still unknown how chronic stress regulates the expression of TSP-1 after glucocorticoid receptor activation. Approach and Results: rats chronic unpredictable mild stress model was applied and the changes of TSP-1 and microRNAs in plasma were examined. Effects of glucocorticoid receptor activation on human umbilical vein endothelial cells and platelets were observed. Glucocorticoid receptor (GR) activation upregulated the expression of TSP-1 and downregulated the expression of microRNA-1-3p accompanied with increase of phosphorylation of p38 mitogen-activated protein kinase (MAPK) and argonaute-2 (AGO-2). Blockade of p38 MAPK phosphorylation resulted in decrease of phosphorylation level of AGO-2, increase of microRNA-1-3p expression, and decrease of TSP-1 expression. Transfection of AGO-2 Y393F point mutant plasmid, increased microRNA-1-3p expression and decreased TSP-1 expression, transfection of microRNA-1-3p mimic also decreased TSP-1 expression, while transfection of microRNA-1-3p inhibitor increased TSP-1 expression. Finally, GR activation led to an increase in the phosphorylation level of p38 MAPK in platelets and an increase in the level of TSP-1 in the supernatant. Conclusions: our study demonstrates that GR activation in HUVEC stimulates the phosphorylation of p38 MAPK, which in turn promotes the phosphorylation of AGO-2 and inhibits the maturation of microRNA-1-3p, leading to elevated expression of TSP-1, GR activation in platelets leads to the release of TSP-1.

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Hyperglycemia-induced oxidative stress promotes tumor metastasis by upregulating vWF expression in endothelial cells through the transcription factor GATA1

Cited by 18 publications

References 63 publications

Utilizing machine learning algorithms to identify biomarkers associated with diabetic nephropathy: A review

Utilizing machine learning algorithms to identify biomarkers associated with diabetic nephropathy: A review

Gene silencing of endothelial von Willebrand factor reduces the susceptibility of human endothelial cells to SARS‐CoV‐2 infection

Mechanism of glucocorticoid receptor activation regulated expression of thrombospondin-1

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