scholarly journals RBM23 Drives Hepatocellular Carcinoma by Activating NF-κB Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Hexu Han ◽  
Ting Lin ◽  
Ziyi Fang ◽  
Guoxiong Zhou
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Rna Binding ◽  
Vascular Endothelial Cells ◽  
Tube Formation ◽  
Nuclear Accumulation ◽  
Binding Motif ◽  
Strong Positive Correlation ◽  
Vascular Endothelial

Purpose. Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and angiogenesis has been proven to be significantly involved in its progression. However, the molecular mechanism underlying HCC angiogenesis has not been well researched. In this study, RNA Binding Motif Protein 23 (RBM23) was identified as a novel proangiogenic factor in HCC cell lines and tissues. Materials and Methods. Firstly, we analyzed the correlation of clinical specimens. In HCC tissues, the levels of RBM23 and microvessel density (MVD) showed a strong positive correlation. Furthermore, data from related cytology experiments showed that the knockdown of RBM23 expression in HCC cells significantly inhibited the tube formation by the human vascular endothelial cells in vitro. The mechanism of this phenomenon was found to be through increasing the mRNA of p65 and enhanced the nuclear accumulation of p65. Consequently, RBM23 activated the NF-κB signaling pathway and promoted expression of the proangiogenic cytokines selectively. Results and Conclusion. In summary, this study revealed that RBM23 promotes the angiogenesis properties of HCC via the NF-κB signaling pathway. It may, therefore, be a potential therapeutic target for the treatment of hepatocellular carcinoma.

scholarly journals DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

2018 ◽  
Vol 46 (2) ◽  
pp. 520-531 ◽  
Author(s):  
Yan Ding ◽  
Lanlan Shan ◽  
Wenqing Nai ◽  
Xiaojun Lin ◽  
Ling Zhou ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Gene Knockout ◽  
Umbilical Vein ◽  
Vascular Endothelial Cell ◽  
Tube Formation ◽  
Vascular Endothelial

Background/Aims: The mechanistic target of rapamycin (mTOR) signaling pathway is essential for angiogenesis and embryonic development. DEP domain-containing mTOR-interacting protein (DEPTOR) is an mTOR binding protein that functions to inhibit the mTOR pathway In vitro experiments suggest that DEPTOR is crucial for vascular endothelial cell (EC) activation and angiogenic responses. However, knowledge of the effects of DEPTOR on angiogenesis in vivo is limited. This study aimed to determine the role of DEPTOR in tissue angiogenesis and to elucidate the molecular mechanisms. Methods: Cre/loxP conditional gene knockout strategy was used to delete the Deptor gene in mouse vascular ECs. The expression or distribution of cluster of differentiation 31 (CD31), vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 alpha (HIF-1α) were detected by immunohistochemical staining or western blot. Tube formation assay was used to measure angiogenesis in vitro. Results: Deptor knockdown led to increased expression of CD31, VEGF and HIF-1α in heart, liver, kidney and aorta. After treatment with rapamycin, their expression was significantly down regulated. In vitro, human umbilical vein endothelial cells (HUVECs) were transfected with DEPTOR-specific small interfering RNA (siRNA), which resulted in a significant increase in endothelial tube formation and migration rates. In contrast, DEPTOR overexpression markedly reduced the expression of CD31, VEGF and HIF-1α. Conclusions: Our findings demonstrated that deletion of the Deptor gene in vascular ECs resulted in upregulated expression of CD31 and HIF-1α, and further stimulated the expression of VEGF which promoted angiogenesis, indicating that disruption of normal angiogenic pathways may occur through hyperactivation of the mTORC1/HIF-1α/VEGF signaling pathway.

CYLD regulates angiogenesis by mediating vascular endothelial cell migration

Blood ◽  
2010 ◽  
Vol 115 (20) ◽  
pp. 4130-4137 ◽  
Author(s):  
Jinmin Gao ◽  
Lei Sun ◽  
Lihong Huo ◽  
Min Liu ◽  
Dengwen Li ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Migration ◽  
Endothelial Cell ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial Cell ◽  
Tube Formation ◽  
Endothelial Cell Migration ◽  
Vascular Endothelial

Cylindromatosis (CYLD) is a deubiquitinase that was initially identified as a tumor suppressor and has recently been implicated in diverse normal physiologic processes. In this study, we have investigated the involvement of CYLD in angiogenesis, the formation of new blood vessels from preexisting ones. We find that knockdown of CYLD expression significantly impairs angiogenesis in vitro in both matrigel-based tube formation assay and collagen-based 3-dimensional capillary sprouting assay. Disruption of CYLD also remarkably inhibits angiogenic response in vivo, as evidenced by diminished blood vessel growth into the angioreactors implanted in mice. Mechanistic studies show that CYLD regulates angiogenesis by mediating the spreading and migration of vascular endothelial cells. Silencing of CYLD dramatically decreases microtubule dynamics in endothelial cells and inhibits endothelial cell migration by blocking the polarization process. Furthermore, we identify Rac1 activation as an important factor contributing to the action of CYLD in regulating endothelial cell migration and angiogenesis. Our findings thus uncover a previously unrecognized role for CYLD in the angiogenic process and provide a novel mechanism for Rac1 activation during endothelial cell migration and angiogenesis.

scholarly journals Effects of nicardipine on tube formation of bovine vascular endothelial cells in vitro.

Stroke ◽  
1992 ◽  
Vol 23 (11) ◽  
pp. 1637-1642 ◽  
Author(s):  
T Kaneko ◽  
I Nagata ◽  
S Miyamoto ◽  
H Kubo ◽  
H Kikuchi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Tube Formation ◽  
Vascular Endothelial

scholarly journals An In Vitro Model of Diabetic Retinal Vascular Endothelial Dysfunction and Neuroretinal Degeneration

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Qiyun Wang ◽  
Xinyuan Zhang ◽  
Kaiyue Wang ◽  
Ling Zhu ◽  
Bingjie Qiu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endothelial Dysfunction ◽  
Vascular Endothelial Cells ◽  
Tube Formation ◽  
Cell Counting ◽  
Vascular Endothelial ◽  
Migration Assay ◽  
Tube Formation Assay ◽  
Wide Range

Background. Diabetic retinopathy (DR) is a leading cause of blindness in working-age populations. Proper in vitro DR models are crucial for exploring pathophysiology and identifying novel therapeutic targets. This study establishes a rational in vitro diabetic retinal neuronal-endothelial dysfunction model and a comprehensive downstream validation system. Methods. Human retinal vascular endothelial cells (HRMECs) and retinal ganglion cells (RGCs) were treated with different glucose concentrations with mannitol as matched osmotic controls. Cell proliferation and viability were evaluated by the Cell Counting Kit-8. Cell migration was measured using a transwell migration assay. Cell sprouting was assessed by a tube formation assay. The VEGF expression was assessed by ELISA. RGCs were labeled by neurons and RGC markers TUJ1 and BRN3A for quantitative and morphological analysis. Apoptosis was detected using PI/Hoechst staining and TUNEL assay and quantified by ImageJ. Results. Cell proliferation and migration in HRMECs were significantly higher in the 25 mM glucose-treated group ( p < 0.001 ) but lower in the 50 mM and 100 mM groups ( p < 0.001 ). The permeability and the apoptotic index in HRMECs were statistically higher in the 25 mM, 50 mM, and 100 mM groups ( p < 0.05 ). The tube formation assay found that all the parameters were significantly higher in the 25 mM and 50 mM groups ( p < 0.001 ) concomitant with the elevated VEGFA expression in HRMECs ( p = 0.016 ). Cell viability was significantly lower in the 50 mM, 100 mM, and 150 mM groups in RGCs ( p 50 mM = 0.013 , p 100 mM = 0.019 , and p 150 mM = 0.002 ). Apoptosis was significantly elevated, but the proportion of RGCs with neurite extension was significantly lower in the 50 mM, 100 mM, and 150 mM groups ( p 50 mM < 0.001 , p 100 m M < 0.001 , and p 150 mM < 0.001 ). Conclusions. We have optimized glucose concentrations to model diabetic retinal endothelial (25-50 mM) or neuronal (50-100 mM) dysfunction in vitro, which have a wide range of downstream applications.

scholarly journals Mechanism and Molecular Network of RBM8A-Mediated Regulation of Oxaliplatin Resistance in Hepatocellular Carcinoma

2021 ◽  
Vol 10 ◽  
Author(s):  
Rong Liang ◽  
Jinyan Zhang ◽  
Zhihui Liu ◽  
Ziyu Liu ◽  
Qian Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Rna Binding ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Binding Motif ◽  
Mesenchymal Transition ◽  
Regulatory Pathways ◽  
Wide Range

RNA-binding motif protein 8A (RBM8A) is abnormally overexpressed in hepatocellular carcinoma (HCC) and involved in the epithelial-mesenchymal transition (EMT). The EMT plays an important role in the development of drug resistance, suggesting that RBM8A may be involved in the regulation of oxaliplatin (OXA) resistance in HCC. Here we examined the potential involvement of RBM8A and its downstream pathways in OXA resistance using in vitro and in vivo models. RBM8A overexpression induced the EMT in OXA-resistant HCC cells, altering cell proliferation, apoptosis, migration, and invasion. Moreover, whole-genome microarrays combined with bioinformatics analysis revealed that RBM8A has a wide range of transcriptional regulatory capabilities in OXA-resistant HCC, including the ability to regulate several important tumor-related signaling pathways. In particular, histone deacetylase 9 (HDAC9) emerged as an important mediator of RBM8A activity related to OXA resistance. These data suggest that RBM8A and its related regulatory pathways represent potential markers of OXA resistance and therapeutic targets in HCC.

scholarly journals MicroRNA-183 inhibition exerts suppressive effects on diabetic retinopathy by inactivating BTG1-mediated PI3K/Akt/VEGF signaling pathway

2019 ◽  
Vol 316 (6) ◽  
pp. E1050-E1060 ◽  
Author(s):  
Zhen-Zhen Zhang ◽  
Xiu-Hong Qin ◽  
Jing Zhang
Keyword(s):  
Endothelial Cells ◽  
Diabetic Retinopathy ◽  
Cell Growth ◽  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Vascular Endothelial Cells ◽  
Tube Formation ◽  
Vascular Endothelial ◽  
Vegf Signaling ◽  
Vegf Signaling Pathway

Diabetic retinopathy (DR) is a serious diabetic complication caused by both environmental and genetic factors. Molecular mechanisms of DR may lead to the discovery of reliable prognostic indicators. The current study aimed to clarify the mechanism of microRNA-183 (miR-183) in DR in relation to the PI3K/Akt/VEGF signaling pathway. Microarray-based gene expression profiling of DR was used to identify the differentially expressed genes. Sprague-Dawley rats were used for the establishment of DR models, and then miR-183 was altered by mimic or inhibitor or BTG1 was downregulated by siRNA to explore the regulatory mechanism of miR-183 in DR. Furthermore, the expression of miR-183, CD34, endothelial nitric oxide synthase (eNOS), BTG1 and the PI3K/Akt/VEGF signaling pathway-related genes as well as reactive oxygen species (ROS) level was determined, and the relationship between miR-183 and BTG1 was also verified. Cell growth, cell apoptosis, and angiogenesis were determined. Microarray analysis revealed the involvement of miR-183 in DR via the PI3K/Akt/VEGF signaling pathway by targeting BTG1. Upregulated miR-183 and downregulated BTG1 were observed in retinal tissues of DR rats. miR-183 overexpression activated the PI3K/Akt/VEGF signaling pathway, upregulated CD34, eNOS, and ROS, and inhibited BTG1. BTG1 was confirmed as a target gene of miR-183. miR-183 overexpression or BTG1 knockdown promoted cell growth and tube formation while it suppressed cell apoptosis of vascular endothelial cells in DR rats. In this study, we demonstrated that miR-183 silencing inhibiting cell growth and tube formation in vascular endothelial cells of DR rats via the PI3K/Akt/VEGF signaling pathway by upregulating BTG1.

scholarly journals Synergistic Anti-Proliferation and Anti-Angiogenesis Effects of Sevacizumab on Hepatocellular Carcinoma Cells in Combination with Chemotherapy

2021 ◽  
Author(s):  
Lin Liu ◽  
Shukui Qin ◽  
Zhengcao Liu ◽  
Yinghui Zheng ◽  
Li Han ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Endothelial Cell ◽  
Combination Therapy ◽  
Blood Vessels ◽  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Tube Formation ◽  
Hcc Cells

Abstract Background We previously found that (via inhibition of the VEGF/VEGFR signaling pathway) ckgroundSevacizumab (Sev), an anti-VEGF monoclonal antibody, was proven to have a superior inhibitory effect than bevacizumab (Bev) on the growth of hepatocellular carcinoma (HCC) cells. This study aimed to explore the anti-proliferation and anti-angiogenic effects of Sev on HCC cells in combination with oxaliplatin (OXA) or 5-fluorouracil (5-Fu). Methods In vitro HCC/endothelial cell growth in different concentration drug was analyzed by MTT assay, DAPI and flow cytometry assay. Cell scratch test, transwell assay, tube formation assay, zebrafish assay, and CAM assay were used to investigate anti-angiogenesis effect of drugs. VEGF mRNA relative expression changes of zebrafish embryos were detected by RT-PCR.A fluorescence imaging system was applied to observe the growth of transplantation tumor and blood vessels in HCC mouse xenografts. Tissue H-E staining and TEM detection were used to detect the tumor cell apoptosis. MVD was detected by immunohistochemical analysis of CD31. ELISA and western-blots were used to detect the cell VEGF/VEGFR pathway and its downstream target activity both in vitro and in vivo. Results In vitro results showed that the combination of Sev with OXA/5-Fu can synergistically inhibit the proliferation of HCC and endothelial cells. Compared with the corresponding monotherapy group, combination therapy showed a stronger effect on inducing apoptosis and cell cycle arrest. In vivo findings revealed that Sev in combination with chemotherapy can synergistically inhibit tumor growth by inducing cell apoptosis in nude mice with HCC xenografts. In addition, the wound healing and transwell migration assays demonstrated that Sev can inhibit the migration of endothelial cell lines in combination with chemotherapy. In vitro tube formation test, zebrafish and chicken embryonic-angiogenic assay, immunohistochemistry, and in vivo fluorescence imaging consistently verified that Sev and OXA/5-Fu can synergistically inhibit the growth of blood vessels, and the underlying mechanism may be associated with inhibition of the VEGF/VEGFR signaling pathway. Conclusions The combination of Sev and chemotherapy is associated with the inhibition of HCC growth and tumor angiogenesis, which may provide a significant biological rationale for evaluating the efficacy of Sev and OXA/5-Fu combination therapy on HCC.

scholarly journals PNO1 regulates autophagy and apoptosis of hepatocellular carcinoma via the MAPK signaling pathway

2021 ◽  
Author(s):  
Zhiqiang Han ◽  
Dongming Liu ◽  
Lu Chen ◽  
Yuchao He ◽  
Xiangdong Tian ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Rna Seq ◽  
Hcc Cells

Abstract Background Some studies have reported that the activated ribosomes are positively associated with malignant tumors, especially in hepatocellular carcinoma (HCC). The RNA-binding protein PNO1, as a critical ribosome has been rarely reported in human tumors. Thus, the roles of PNO1 in HCC should be explored. Methods We collected 150 formalin-fixed and paraffin-embedded (FFPE) samples and 8 fresh samples to explore the expression and prognosis of PNO1 in HCC by immunohistochemistry, Western Blotting and RT-PCR. Public databases (TCGA and GEO) were used to verify the expression and prognosis. The functions of PNO1 in HCC was verified by in vitro and in vivo experiments. The underlying molecular mechanisms of PNO1 were examined by RNA-seq analysis and a series of functional experiments. Results PNO1 expression was considerably higher in HCC tissues and the higher expression of PNO1 was associated with poor prognosis of HCC patients. In vitro experiments indicated that PNO1 overexpression promoted proliferation and depressed apoptosis of HCC cells. In addition, high expression of PNO1 increased autophagy of HCC cells. Consistent results were also observed in vivo experiments. The results of the RNA-seq analysis indicted that PNO1 as an oncogene promoted HCC progression through the MAPK signaling pathway. The results were also verified by in vivo experiments. Conclusions PNO1 was overexpressed in HCC, promoted autophagy and inhibited apoptosis of HCC cells via the MAPK signaling pathway.

The regulation and mechanism of a dual PI3K/mTOR signaling inhibitor in hemangioma vascular endothelial cells in vitro

2020 ◽  
Author(s):  
wangshu liu ◽  
Yang Yu ◽  
Juan Li ◽  
Hui Huang ◽  
Hao Liu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Signaling Pathway ◽  
Vascular Endothelial Cells ◽  
Mtor Signaling ◽  
Control Group ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Mtor Signaling Pathway ◽  
Protein Levels

Abstract Objective To observe the influence of the dual PI3K/mTOR inhibitor NVP-BEZ235 on proliferation and apoptosis of hemangioma cells in vitro and key molecules of the PI3K/Akt/mTOR signaling pathway.Methods Hemangioma-derived endothelial cells (HeECs) were obtained by surgical resection and cultured after the explants with the trypsin-digestion method. Fourth generation cells were cultured with serum-free medium for 24 hours. Then, the intervention group cells were added to the culture medium with 0.50 μM or 1.00 μM NVP-BEZ235. Cell proliferation was detected with CCK-8 assays, apoptosis was detected by flow cytometry, and PI3K, Akt, mTOR, and p70s6k protein levels were detected by Western blots. Then, the relationship between the phenotype of hemangioma vascular endothelial cells and the four proteins was analyzed.Results the 0.50 μM and 1.00 μM NVP-BEZ235 groups were significantly lower (0.88±0.03 and 0.59±0.05, respectively) than the control group (1.10±0.02) (P<0.01). The rate of G0/G1 phase cells in the 0.50 μM and 1.00 μM NVP-BEZ235 group were higher than the control group (P<0.01). The total rates of apoptotic cells in the 0.50 μM and 1.00 μM NVP-BEZ235 groups were higher than the control group (2.77±1.23)% (P<0.01). The PI3K pathway related protein levels in the NVP-BEZ235 group were lower than control group (P<0.01).Conclusion The PI3K/Akt/mTOR signaling pathway participates in hemangioma development. NVP-BEZ235 affected hemangioma vascular endothelial cells in vitro by regulating the PI3K/Akt/mTOR signaling pathway in a dose-dependent manner.

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