Endothelial CDS2 deficiency causes VEGFA-mediated vascular regression and tumor inhibition

Zhao, Wanli; Cao, Liqin; Ying, Hanru; Zhang, Wenjuan; Li, Dantong; Zhu, Xiaolong; Xue, Wenzhi; Wu, Shuang; Cao, Mengye; Fu, Cong; Qi, Huayu; Hao, Yimei; Tang, Yun‐Chi; Qin, Jun; Zhong, Tao; Lin, Xiaoxi; Yu, Luyang; Li, Xuri; Li, Lin; Wu, Dianqing; Pan, Weijun

doi:10.1038/s41422-019-0229-5

Cited by 43 publications

(32 citation statements)

References 93 publications

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“…We hypothesized that FGF2 and HGF protein levels were decreased in OC-2 KO cell lines, which in turn inhibited the activation of HIF-1α to some extent. Then, the expression of VEGFA, the strongest pro-angiogenic growth factor, was down-regulated, destroying the angiogenesis networks ( 40 ). Importantly, the results of the qRT-PCR assay merely indicated that OC-2 positively regulated the expression of VEGFA, FGF2, HGF, and HIF-1α at the transcriptional level, but the accurate relationships among OC-2 and these pro-angiogenic growth factors required further investigation.…”

Section: Discussionmentioning

confidence: 99%

RETRACTED: CRISPR/Cas9-Mediated OC-2 Editing Inhibits the Tumor Growth and Angiogenesis of Ovarian Cancer

Zhang

Zhu

et al. 2020

Front. Oncol.

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Ovarian cancer is the leading cancer-related cause of death in women worldwide. It is of great relevance to understand the mechanism responsible for tumor progression and identify unique oncogenesis markers for a higher chance of preventing this malignant disease. The high-expression OC-2 gene has been shown to be a potential candidate for regulating oncogenesis and angiogenesis in ovarian cancer. Hence, we wished to investigate the impact of OC-2 gene on ovarian cancer aggressiveness. CRISPR/Cas9, a gene editing tool, allows for direct ablation of OC-2 at the genomic level, and we successfully generated OC-2 KO cell lines from SKOV3 and CAOV3 cells. In an apoptosis assay, OC-2 KO induced the apoptosis activation of tumor cells, with the up-regulation of Bax/Caspase-8 and the down-regulation of Bcl-2. Consequently, the proliferation, migration, and invasion of OC-2 KO cell lines were significantly inhibited. Assays of qRT-PCR and Western blotting showed that the expression levels of pro-angiogenic growth factors VEGFA, FGF2, HGF, and HIF-1α and the activation of Akt/ERK pathways were significantly down-regulated at the loss of OC-2. In the xenograft model, OC-2 KO potently suppressed the subcutaneous tumor growth, with the inhibition exceeding 56%. The down-regulation of CD31 and relevant pro-angiogenic growth factors were observed in OC-2 KO tumor tissues. Taken together, OC-2 depletion negatively regulated the ovarian cancer progression possibly by apoptosis activation and angiogenesis inhibition. This work revealed a pivotal regulator of apoptosis and angiogenesis networks in ovarian cancer, and we applied the CRISPR/Cas9 system to the transcription factor pathway for developing a broad-acting anti-tumor gene therapy.

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Section: Discussionmentioning

confidence: 99%

RETRACTED: CRISPR/Cas9-Mediated OC-2 Editing Inhibits the Tumor Growth and Angiogenesis of Ovarian Cancer

Zhang

Zhu

et al. 2020

Front. Oncol.

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“…In this line, the small GTPase Rac1, regulator of actin polymerization and cell migration, is required for vessel regression in the zebrafish brain (Chen et al, 2012) and polarized Rac1 subcellular gradients are induced by laminar (15 dyn/cm 2 ) but not disturbed flow in endothelial cells in vitro (Shao et al, 2017). Similarly, phosphoinositide gradients are required for a balanced capillary pruning induced by VEGF since the absence of CDP-diacylglycerol synthase-2 (CDS2), a metabolic enzyme that controls phosphoinositide recycling, in mouse and zebrafish showed increased endothelial cell migration and vessel regression (Zhao et al, 2019). VEGF was considered an essential player in vascular regression occurring after deprivation of VEGF or VEGF-induced signals which led to endothelial cell apoptosis in different tissues and contexts (Meeson et al, 1999;Tang et al, 2004;Baffert et al, 2006).…”

Section: Mechanisms In Blood Flow-driven Capillary Remodelingmentioning

confidence: 99%

Remodeling of the Microvasculature: May the Blood Flow Be With You

et al. 2020

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“…However, a recent study has shown that VEGF-A also induced vascular degeneration, which was regulated by phosphatidylinositol metabolic cycle controlled by CDP diacylglycerol synthase-2 (CDS2). ECs with mutant CDS2 suppressed vascular degeneration through reverse migration and apoptosis after being stimulated by VEGF-A ( 39 ).…”

Section: Vegf-amentioning

confidence: 99%

The Role of the VEGF Family in Coronary Heart Disease

Zhou

Zhu

Cui

et al. 2021

Front. Cardiovasc. Med.

105

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The vascular endothelial growth factor (VEGF) family, the regulator of blood and lymphatic vessels, is mostly investigated in the tumor and ophthalmic field. However, the functions it enjoys can also interfere with the development of atherosclerosis (AS) and further diseases like coronary heart disease (CHD). The source, regulating mechanisms including upregulation and downregulation, target cells/tissues, and known functions about VEGF-A, VEGF-B, VEGF-C, and VEGF-D are covered in the review. VEGF-A can regulate angiogenesis, vascular permeability, and inflammation by binding with VEGFR-1 and VEGFR-2. VEGF-B can regulate angiogenesis, redox, and apoptosis by binding with VEGFR-1. VEGF-C can regulate inflammation, lymphangiogenesis, angiogenesis, apoptosis, and fibrogenesis by binding with VEGFR-2 and VEGFR-3. VEGF-D can regulate lymphangiogenesis, angiogenesis, fibrogenesis, and apoptosis by binding with VEGFR-2 and VEGFR-3. These functions present great potential of applying the VEGF family for treating CHD. For instance, angiogenesis can compensate for hypoxia and ischemia by growing novel blood vessels. Lymphangiogenesis can degrade inflammation by providing exits for accumulated inflammatory cytokines. Anti-apoptosis can protect myocardium from impairment after myocardial infarction (MI). Fibrogenesis can promote myocardial fibrosis after MI to benefit cardiac recovery. In addition, all these factors have been confirmed to keep a link with lipid metabolism, the research about which is still in the early stage and exact mechanisms are relatively obscure. Because few reviews have been published about the summarized role of the VEGF family for treating CHD, the aim of this review article is to present an overview of the available evidence supporting it and give hints for further research.

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Endothelial CDS2 deficiency causes VEGFA-mediated vascular regression and tumor inhibition

Cited by 43 publications

References 93 publications

RETRACTED: CRISPR/Cas9-Mediated OC-2 Editing Inhibits the Tumor Growth and Angiogenesis of Ovarian Cancer

RETRACTED: CRISPR/Cas9-Mediated OC-2 Editing Inhibits the Tumor Growth and Angiogenesis of Ovarian Cancer

Remodeling of the Microvasculature: May the Blood Flow Be With You

The Role of the VEGF Family in Coronary Heart Disease

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