Annexin A2 regulates angiogenesis and invasion phenotypes of malignant glioma

Onishi, Manabu; Ichikawa, Tomotsugu; Kurozumi, Kazuhiko; Inoue, Satoshi; Maruo, Tomoko; Otani, Yoshihiro; Fujii, Kentaro; Ishida, Joji; Shimazu, Yosuke; Yoshida, Kôichi; Michiue, Hiroyuki; Chiocca, E. Antonio; Date, Isao

doi:10.1007/s10014-015-0216-6

Cited by 35 publications

(36 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…VEGF-related drugs have been used in clinical applications [8]. Over the past several decades, work from several laboratories has shown that annexin A2 plays an important role in NV by interacting with VEGF [9, 10]. Furthermore, work on annexin A2/AX2R in regulation of NV has been reported.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Annexin A2 Receptor Inhibits Neovascularization via the Promotion of Krüppel-Like Transcription Factor 2

Guo

Song

Zhao

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Annexin A2 receptor (AX2R) can mediate annexin A2 signalling and induce apoptosis in a variety of cells, but its role in neovascularization (NV) remains unclear. Krüppel-like transcription factor 2 (KLF2) is known to be expressed in a range of cell types and to participate in a number of processes during development and disease, such as endothelial homeostasis, vasoregulation and vascular growth/remodelling. The aim of our study was to investigate the role of AX2R in NV and the plausible molecular mechanism. Methods: We constructed a eukaryotic overexpression plasmid for AX2R (Lenti-AX2R) by using polymerase chain reaction (PCR). The full-length human AX2R gene was transfected into human retinal endothelial cells (HRECs) and human umbilical vein endothelial cells (HUVECs) using lentivirus vectors to overexpress AX2R. All experiments were divided into three groups: control, negative control (Lenti-EGFP), and Lenti-AX2R.Cell proliferation, cell migration, tube formation, mouse aortic ring assays and mouse matrigel plug assay were applied to analyse the effect of AX2R in NV. Furthermore, we conducted flow cytometry to evaluate whether AX2R could influence the cell cycle. A series of cell cycle-related proteins including cyclin A1, cyclin B1, cyclin D1, cyclin E1, CDK1, and p-CDC2 were detected by WB. The mRNA and protein levels of KLF2, vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) were further quantified by RT-PCR and WB to reveal the possible mechanism. Results: Overexpression of AX2R significantly inhibited cell proliferation, migration and tube formation in both types of endothelial cells (ECs), HRECs and HUVECs. It also suppressed vessel sprouting in the mouse aortic ring assay and NV in mouse matrigel plug assay. Furthermore, infection with Lenti-AX2R lentivirus arrested the cell cycle in S/G2 and influenced the expression of a series of cell cycle-related proteins. We also found that the overexpression of AX2R increased the expression of KLF2, mediating VEGF and VEGFR2. Conclusions: Overexpression of AX2R contributes to the inhibition of NV via suppressing KLF2 ubiquitin-dependent protein degradation, which might therefore be a therapeutic option for NV. It could be considered more broadly as an anti-angiogenic agent in the treatment of neovascular-related diseases in the future.

show abstract

Section: Introductionmentioning

confidence: 99%

Overexpression of Annexin A2 Receptor Inhibits Neovascularization via the Promotion of Krüppel-Like Transcription Factor 2

Guo

Song

Zhao

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…Immunohistochemical and qRT-PCR studies showed high expression of AnxA2, VEGF and PDGF in glioblastoma cells. Moreover, staining intensity of VEGF and PDGF positively correlated with AnxA2 overexpression hence suggesting AnxA2 role in regulating angiogenesis (Onishi et al, 2015).…”

Section: Annexin A2 In Gbmmentioning

confidence: 96%

“…AnxA2 mediates glioma cell adhesion to endothelial cells and promotes production of angiogenic factors such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) thus promotes neovascularization and invasion (Maule et al, 2016). In glioblastoma specimen, multiple satellites of tumour cells containing dilated blood vessels were found in brain parenchyma near brain tumour centre (Onishi et al, 2015). Immunohistochemical and qRT-PCR studies showed high expression of AnxA2, VEGF and PDGF in glioblastoma cells.…”

Section: Annexin A2 In Gbmmentioning

confidence: 99%

“…AnxA2 is overexpressed in many cancers including glioma, pancreatic cancer, colorectal and breast cancer (Kesavan et al, 2010). AnxA2 is involved in angiogenesis and more highly expressed in high-grade glioma than in low-grade glioma (Onishi et al, 2015). AnxA2 is involved in migration of the vascular endothelial cells and formation of the abnormal tumour vasculature in high-grade glioma (Kesavan et al, 2010).…”

Section: High Expression Of Mmp2 Mmp9 and Annexin A2 In Gbmmentioning

confidence: 99%

“…Cltx was shown to have anti-angiogenic effects by binding to human umbilical vein endothelial cells (HUVECs) (Zhai et al, 2011). Cltx also binds to AnxA2 on glioma cells thus inhibiting migration and metastasis (Kesavan et al, 2010;Onishi et al, 2015). Small interfering RNA (SiRNA) knockout AnxA2 cells showed reduced Cltx binding as well as reduced migration (Kesavan et al, 2010).…”

Section: Chlorotoxinmentioning

confidence: 99%

See 2 more Smart Citations

The mechanism of action of the scorpion toxin, chlorotoxin, a bioinformatics approach

Sheikh¹

View full text Add to dashboard Cite

Glioblastoma is a very invasive and metastatic cancer with low patient survival-rate and high resistance to current treatment. Matrix metalloproteinase 2 (MMP2) is upregulated in glioblastoma multiforme (GBM) and its high expression is directly correlated with invasion and metastasis of GBM cells. Annexin A2 is involved in angiogenesis, and it is overexpressed in GBM. MMP2 and annexin A2 are potential targets for effective glioma therapy. Chlorotoxin is a promising toxin peptide for glioma targeted therapy. Chlorotoxin decreased migration and metastasis of GBM cells, although mechanism of action of the toxin is unclear due to the complicated nature of GBM, slow and costly experiments and challenging techniques. The relationship of chlorotoxin binding to both MMP2 and annexin A2 is controversial and further work is needed to clarify a complex situation. Chlorotoxin-like short toxins are homologous peptides that may also have potential therapeutic effects for glioma.In this study homology modelling was used to predict 3D models of chlorotoxin-like short toxins. Stereochemical quality estimation of 3D models was performed with QMEAN, Z-Score and Procheck server. ClusPro docking programme was used to dock 3D structures of chlorotoxin and chlorotoxin homologues with their putative binding partners MMP2 and annexin A2 to provide a first step to understand the mechanism of action of the toxin. Chlorotoxin shows binding interaction with both MMP2 and annexin A2. Chlorotoxin-like short toxins also showed stronger binding interaction with activated MMP2 than annexin A2. The positively charged surface of chlorotoxin is mainly involved in interaction with MMP2. All three chlorotoxin-like short toxins bind to a similar site on MMP2 but on separate sites on annexin A2hence suggesting the significance of observed interaction between chlorotoxin and MMP2.

show abstract

Annexin A2: The diversity of pathological effects in tumorigenesis and immune response

Huang

Jia

Yang

et al. 2022

Intl Journal of Cancer

View full text Add to dashboard Cite

Annexin A2 (ANXA2) is widely used as a marker in a variety of tumors. By regulating multiple signal pathways, ANXA2 promotes the epithelial‐mesenchymal transition, which can cause tumorigenesis and accelerate thymus degeneration. The elevated ANXA2 heterotetramer facilitates the production of plasmin, which participates in pathophysiologic processes such as tumor cell invasion and metastasis, bleeding diseases, angiogenesis, inducing the expression of inflammatory factors. In addition, the ANXA2 on the cell membrane mediates immune response via its interaction with surface proteins of pathogens, C1q, toll‐like receptor 2, anti‐dsDNA antibodies and immunoglobulins. Nuclear ANXA2 plays a role as part of a primer recognition protein complex that enhances DNA synthesis and cells proliferation by acting on the G1‐S phase of the cell. ANXA2 reduction leads to the inhibition of invasion and metastasis in multiple tumor cells, bleeding complications in acute promyelocytic leukemia, retinal angiogenesis, autoimmunity response and tumor drug resistance. In this review, we provide an update on the pathological effects of ANXA2 in both tumorigenesis and the immune response. We highlight ANXA2 as a critical protein in numerous malignancies and the immune host response.

show abstract

Annexin A2 regulates angiogenesis and invasion phenotypes of malignant glioma

Cited by 35 publications

References 27 publications

Overexpression of Annexin A2 Receptor Inhibits Neovascularization via the Promotion of Krüppel-Like Transcription Factor 2

Overexpression of Annexin A2 Receptor Inhibits Neovascularization via the Promotion of Krüppel-Like Transcription Factor 2

The mechanism of action of the scorpion toxin, chlorotoxin, a bioinformatics approach

Annexin A2: The diversity of pathological effects in tumorigenesis and immune response

Contact Info

Product

Resources

About