ZLM-7 exhibits anti-angiogenic effects via impaired endothelial cell function and blockade of VEGF/VEGFR-2 signaling

Su, Min; Huang, Jingjia; Li, Jijia; Qin, Xiyuan; Tang, Xiaoning; Jin, Fang; Chen, Shali; Jiang, Changjin; Zou, Zizheng; Peng, Kunjian; Nuruzzaman, Mohammed; Zhang, Jianting; Luo, Jun-Li; Liu, Suyou; Luo, Zhitian

doi:10.18632/oncotarget.7968

Cited by 9 publications

(15 citation statements)

References 49 publications

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“…Although publication on ZLM-7 was limited, there were publications about other microtubule inhibitors which could inhibit angiogenesis, such as SP-6-27 and MT189 (which also functions through VEGF signal) (Kulshrestha et al 2017 ; Xu et al 2018 ), however, their regulating mechanism was never addressed. The anti-angiogenetic effect of ZLM-7 was previously validated by chicken chorioallantoic membrane (CAM) model and MCF-7 xenograft model, presumably through inhibiting VEGF/VEGFR2 pathway (Su et al 2016 ). Our findings here were much in consistence with this study.…”

Section: Discussionmentioning

confidence: 99%

“…All mice were housed in a specific-pathogen-free facility with a 12 h light: dark cycle at a temperature of 21 ℃ ± 2 ℃ and a relative air humidity of 55% ± 10%. ZLM-7 was administrated 15 mg/kg/day by intraperitoneal injection based on previous reports (Su et al 2016 ). MiR-212-3p inhibitor dissolved in Entranster-in vivo (Engreen Biosystem, China) was injected through caudal vein 1 mg/kg weekly (Zhang et al 2019 ).…”

Section: Methodsmentioning

confidence: 99%

“…It has a strong affinity for microtubule proteins, leading to the instability of cytoskeleton (Ma et al 2016 ). ZLM-7 is a cis restricted sulfide derivative of CA-4, which has the same antitumor activity as CA-4, but its toxicity is lower than CA-4 (Su et al 2016 ). Previous studies had shown that ZLM-7 treatment could reduce the proliferation and angiogenesis of BC cells (Su et al 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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ZLM-7 inhibits the occurrence and angiogenesis of breast cancer through miR-212-3p/Sp1/VEGFA signal axis

Zou

Wen

et al. 2020

Mol Med

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Background Breast cancer (BC) is a common malignant tumor with poor prognosis. Angiogenesis is related to the growth and progression of solid tumors and associated with prognosis. ZLM-7, SP1, VEGFA and miR-212-3p were associated with BC angiogenesis and proliferation, however the detailed mechanism was not clear. This study aimed to reveal the regulatory mechanism of angiogenesis of BC. Methods BC cell lines were treated with 10 nM ZLM-7 for 8 h. We detected protein expression level by western blot and RNA expression level by qRT-PCR. Overexpression or inhibition of miR-212-3p is performed using miR-212-3p mimics or miR-212-3p inhibitor, Sp1 overexpression using pcDNA3.1 vector. Angiogenesis was analyzed by co-culturing BC cell lines and HUVEC cells. To evaluate regulatory relationship between miR-212-3p and Sp1, dual luciferase assay was performed. Besides, the direct interaction between Sp1 and VEGFA was analyzed by ChIP. Migration and invasion were analyzed by transwell assay and proliferation was detected by clone formation assay. In mice xenograft model developed using BC cells, we also detected angiogenesis marker CD31 through immunohistochemistry. Results ZLM-7 up-regulated miR-212-3p and inhibited invasion, migration, proliferation and angiogenesis of BC, while miR-212-3p inhibitor antagonized such effects. Binding sequence was revealed between miR-212-3p and Sp1, and expression of Sp1 was inhibited by miR-212-3p on both protein and mRNA level. Sp1 could interact with VEGFA and promoted its expression. Overexpression of miR-212-3p inhibited migration, invasion, proliferation and angiogenesis of BC cell lines, while Sp1 overexpression showed the opposite effect and could antagonize these effects of miR-212-3p overexpression. ZLM-7 decreased VEGFA expression, which was rescued by co-transfection with miR-212-3p inhibitor. Similar, ZLM-7 could inhibit tumor growth and angiogenesis through the miR-212-3p/Sp1/VEGFA axis in vivo. Conclusions ZLM-7 could directly up-regulate miR-212-3p in BC. MiR-212-3p could inhibit VEGFA expression through Sp1, thereby inhibiting angiogenesis and progression of BC.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ZLM-7 inhibits the occurrence and angiogenesis of breast cancer through miR-212-3p/Sp1/VEGFA signal axis

Zou

Wen

et al. 2020

Mol Med

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“…These modifications act as an important basis for a protein's structural as well as functional entity . For instance, several cellular signaling pathways like MAP kinase, JAK‐STAT, AKT, etc., are driven by specific phosphorylation events and have been implicated in many important diseases like cancer, different metabolic diseases, etc. Further to exemplify, glycosylation of basement membrane proteins such as collagen IV have been shown to be important in providing the scaffold for tissue‐structure maintenance .…”

Section: Integrative Analysis To Decipher Gene Expression and Regulationmentioning

confidence: 99%

Integrating transcriptome and proteome profiling: Strategies and applications

et al. 2016

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Discovering the gene expression signature associated with a cellular state is one of the basic quests in majority of biological studies. For most of the clinical and cellular manifestations, these molecular differences may be exhibited across multiple layers of gene regulation like genomic variations, gene expression, protein translation and post-translational modifications. These system wide variations are dynamic in nature and their crosstalk is overwhelmingly complex, thus analyzing them separately may not be very informative. This necessitates the integrative analysis of such multiple layers of information to understand the interplay of the individual components of the biological system. Recent developments in high throughput RNA sequencing and mass spectrometric (MS) technologies to probe transcripts and proteins made these as preferred methods for understanding global gene regulation. Subsequently, improvements in "big-data" analysis techniques enable novel conclusions to be drawn from integrative transcriptomic-proteomic analysis. The unified analyses of both these data types have been rewarding for several biological objectives like improving genome annotation, predicting RNA-protein quantities, deciphering gene regulations, discovering disease markers and drug targets. There are different ways in which transcriptomics and proteomics data can be integrated; each aiming for different research objectives. Here, we review various studies, approaches and computational tools targeted for integrative analysis of these two high-throughput omics methods.

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“…In this study, we found that quercetin administration not only downregulated the expression of pulmonary VEGF-A but also significantly decreased p-VEGFR-2 and p-Akt protein levels in the CBDL rats. Multiple reports ( 30 - 32 ) demonstrated that hypoxia or hypoxemia cause VEGFR-2 phosphorylation, and subsequently, neovascularization. Taken together, our findings indicate that quercetin exerts its anti-angiogenic effect through inhibition of the VEGF/VEGFR-2/Akt pathway in rats with HPS.…”

Section: Discussionmentioning

confidence: 99%

Quercetin alleviates pulmonary angiogenesis in a rat model of hepatopulmonary syndrome

Chen

Wang

et al. 2016

Braz J Med Biol Res

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Quercetin shows protective effects against hepatopulmonary syndrome (HPS), as demonstrated in a rat model. However, whether these effects involve pulmonary vascular angiogenesis in HPS remains unclear. Therefore, this study aimed to assess the effect of quercetin on pulmonary vascular angiogenesis and explore the underlying mechanisms. Male Sprague-Dawley rats weighing 200-250 g underwent sham operation or common bile duct ligation (CBDL). Two weeks after surgery, HIF-1α and NFκB levels were assessed in rat lung tissue by immunohistochemistry and western blot. Then, CBDL and sham-operated rats were further divided into 2 subgroups each to receive intraperitoneal administration of quercetin (50 mg/kg daily) or 0.2% Tween for two weeks: Sham (Sham+Tween; n=8), CBDL (CBDL+Tween; n=8), Q (Sham+quercetin; n=8), and CBDL+Q (CBDL+quercetin; n=8). After treatment, lung tissue specimens were assessed for protein (immunohistochemistry and western blot) and/or gene expression (quantitative real-time PCR) levels of relevant disease markers, including VEGFA, VEGFR2, Akt/p-Akt, HIF-1α, vWf, and IκB/p-IκB. Finally, arterial blood was analyzed for alveolar arterial oxygen pressure gradient (AaPO2). Two weeks after CBDL, HIF-1α expression in the lung decreased, but was gradually restored at four weeks. Treatment with quercetin did not significantly alter HIF-1α levels, but did reduce AaPO2 as well as lung tissue NF-κB activity, VEGFA gene and protein levels, Akt activity, and angiogenesis. Although hypoxia is an important feature in HPS, our findings suggest that HIF-1α was not the main cause for the VEGFA increase. Interestingly, quercetin inhibited pulmonary vascular angiogenesis in rats with HPS, with involvement of Akt/NF-κB and VEGFA/VEGFR-2 pathways.

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ZLM-7 exhibits anti-angiogenic effects via impaired endothelial cell function and blockade of VEGF/VEGFR-2 signaling

Cited by 9 publications

References 49 publications

ZLM-7 inhibits the occurrence and angiogenesis of breast cancer through miR-212-3p/Sp1/VEGFA signal axis

ZLM-7 inhibits the occurrence and angiogenesis of breast cancer through miR-212-3p/Sp1/VEGFA signal axis

Integrating transcriptome and proteome profiling: Strategies and applications

Quercetin alleviates pulmonary angiogenesis in a rat model of hepatopulmonary syndrome

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