Effects of NRP1 on angiogenesis and vascular maturity in�endothelial cells are dependent on the expression of SEMA4D

Lyu, Zhi; Jin, Hongwei; Yan, Zhijian; Hu, Keyan; Jiang, Hong; Peng, Huifang; Zhuo, Huiqin

doi:10.3892/ijmm.2020.4692

Cited by 18 publications

(21 citation statements)

References 46 publications

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“…We hypothesized that BM-MSC EVs would contain angiogenesis-related cargo. Donor 1 and donor 2 shared three angiogenesis-related proteins in common: Neuropilin-1 (NRP1) [ 44 – 50 ], tumor necrosis factor alpha-induced protein 2 (TNFAIP2) [ 51 ], and Sushi repeat-containing protein (SRPX2) [ 52 ] (Fig. 5 A), which have all been demonstrated to be modulators of angiogenesis.…”

Section: Resultsmentioning

confidence: 99%

Proteomic analysis of bone marrow-derived mesenchymal stem cell extracellular vesicles from healthy donors: implications for proliferation, angiogenesis, Wnt signaling, and the basement membrane

et al. 2021

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Background Bone marrow-derived mesenchymal stem cells (BM-MSCs) have shown therapeutic potential in various in vitro and in vivo studies in cutaneous wound healing. Furthermore, there are ubiquitous studies highlighting the pro-regenerative effects of BM-MSC extracellular vesicles (BM-MSC EVs). The similarities and differences in BM-MSC EV cargo among potential healthy donors are not well understood. Variation in EV protein cargo is important to understand, as it may be useful in identifying potential therapeutic applications in clinical trials. We hypothesized that the donors would share both important similarities and differences in cargo relating to cell proliferation, angiogenesis, Wnt signaling, and basement membrane formation—processes shown to be critical for effective cutaneous wound healing. Methods We harvested BM-MSC EVs from four healthy human donors who underwent strict screening for whole bone marrow donation and further Good Manufacturing Practices-grade cell culture expansion for candidate usage in clinical trials. BM-MSC EV protein cargo was determined via mass spectrometry and Proteome Discoverer software. Corresponding proteomic networks were analyzed via the UniProt Consortium and STRING consortium databases. Results More than 3000 proteins were identified in each of the donors, sharing > 600 proteins among all donors. Despite inter-donor variation in protein identities, there were striking similarities in numbers of proteins per biological functional category. In terms of biologic function, the proteins were most associated with transport of ions and proteins, transcription, and the cell cycle, relating to cell proliferation. The donors shared essential cargo relating to angiogenesis, Wnt signaling, and basement membrane formation—essential processes in modulating cutaneous wound repair. Conclusions Healthy donors of BM-MSC EVs contain important similarities and differences among protein cargo that may play important roles in their pro-regenerative functions. Further studies are needed to correlate proteomic signatures to functional outcomes in cutaneous repair.

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Section: Resultsmentioning

confidence: 99%

Proteomic analysis of bone marrow-derived mesenchymal stem cell extracellular vesicles from healthy donors: implications for proliferation, angiogenesis, Wnt signaling, and the basement membrane

et al. 2021

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“…NRP1 is a transmembrane cell surface coreceptor that serves as a receptor for the VEGF 165 isoform of vascular endothelial growth factor (VEGF) to enhance angiogenesis, vascular permeability, and arteriogenesis via interaction with VEGF receptor 2 (VEGFR2) 33 . In addition, NRP1 regulates angiogenesis by activating the intracellular kinase ABL1 independent of VEGF signaling 34 .…”

Section: Discussionmentioning

confidence: 99%

HIF-1α promoted vasculogenic mimicry formation in lung adenocarcinoma through NRP1 upregulation in the hypoxic tumor microenvironment

Ding

et al. 2021

Cell Death Dis

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Neovascularization is a key factor that contributes to tumor metastasis, and vasculogenic mimicry (VM) is an important form of neovascularization found in highly invasive tumors, including lung cancer. Despite the increasing number of studies focusing on VM, the mechanisms underlying VM formation remain unclear. Herein, our study explored the role of the HIF-1α/NRP1 axis in mediating lung adenocarcinoma metastasis and VM formation. HIF-1α, NRP1 expression, and VM in lung adenocarcinoma (LUAD) patient samples were examined by immunohistochemical staining. Quantitative real-time (qRT-PCR), western blot, transwell assay, wound healing assay, and tube formation assay were performed to verify the role of HIF-1α/NRP1 axis in LUAD metastasis and VM formation. ChIP and luciferase reporter assay were used to confirm whether NRP1 is a direct target of HIF-1α. In LUAD tissues, we confirmed a positive relationship between HIF-1α and NRP1 expression. Importantly, high HIF-1α and NRP1 expression and the presence of VM were correlated with poor prognosis. We also found that HIF-1α could induce LUAD cell migration, invasion, and VM formation by regulating NRP1. Moreover, we demonstrated that HIF-1α can directly bind to the NRP1 promoter located between −2009 and −2017 of the promoter. Mechanistically, MMP2, VE-cadherin, and Vimentin expression were affected. HIF-1α plays an important role in inducing lung adenocarcinoma cell metastasis and VM formation via upregulation of NRP1. This study highlights the potential therapeutic value of targeting NRP1 for suppressing lung adenocarcinoma metastasis and progression.

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“…In comparison the Tagln2 associated transcriptomic profiling with that of NRP1 in our previous study (22), 20 common DEGs (23%) were obtained with the similar change trends, including 11 upregulated genes (HIVEP2, SLC38A2, CASP10, ATP2C1, NSD2, PTPRK, ZNF462, SEMA4D, ELP5, NCOA4 and DNPEP), and 10 downregulated genes (SFXN3, NAGK, GPSM1, TNIP1, ATP6V0E2, ZNF839, NBPF14, PJA1, TUBGCP2 and PLEKHM1). Moreover, four genes (HIVEP2, CASP10, PTPRK and SEMA4D) were implicated in the mentioned network.…”

Section: The Most Critical Molecule and Signaling Pathway Identificationmentioning

confidence: 58%

“…NRP1 also acts as a receptor for class III/IV semaphorins (35) and several other growth factors, such as HGF, FGF, TGF-b, and PDGFB (36,37). NRP1 expression was upregulated in primary tumor tissue than normal tissue of stomach adenocarcinoma from TCGA data, which was related to tumor stage, and high expression of NRP1 was significantly related to a shorter overall survival (22). Recent studies have supported NRP1 as a potential tumor anti-angiogenesis therapeutic target, and NRP1-neutralizing antibodies or small-molecule antagonists have been shown to suppress tumor growth in an additive manner to VEGF neutralization (38).…”

Section: Discussionmentioning

confidence: 99%

An Essential NRP1-Mediated Role for Tagln2 in Gastric Cancer Angiogenesis

et al. 2021

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Knowledge about the precise biological role and underlying mechanism of Tagln2 in tumor progression is relatively limited, especially in angiogenesis focused on tumor derived endothelial cells (ECs) has rarely been reported. Here, the function, molecular mechanism and potential clinical value of Tagln2 in gastric cancer (GC) angiogenesis were investigated. GC tissue microarrays were used to assess the expression of Tagln2 in ECs. The relationships between expression and clinicopathological features were analyzed to evaluate the clinical value of Tagln2. Gain- and loss-of-function approaches were performed in ECs to investigate the functions of Tagln2 in angiogenesis. A combination of angiogenesis antibody array, RNA-Seq analyses and a series of in vitro experiments were performed to reveal the proangiogenic mechanism mediated by NRP1. Immunohistochemistry performed on an independent tissue chip (n=75) revealed significant upregulation of Tagln2 in tumor-derived ECs which were specifically immunolabeled with CD34. Additionally, high Tagln2 levels correlated significantly with the presence of lymph node as well as distant metastases. Gain- and loss-of-function approaches highlighted the function of Tagln2 in promoting EC proliferation, motility, and capillary-like tube formation and in reducing apoptosis. Tagln2 upregulation led to significantly increased mRNA and protein levels of NRP1 and subsequently activated the NRP1/VEGFR2 and downstream MAPK signaling pathways. These data indicate the importance of Tagln2 in angiogenesis, as a potential therapeutic target, and as a candidate prognostic marker in GC.

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Effects of NRP1 on angiogenesis and vascular maturity in�endothelial cells are dependent on the expression of SEMA4D

Cited by 18 publications

References 46 publications

Proteomic analysis of bone marrow-derived mesenchymal stem cell extracellular vesicles from healthy donors: implications for proliferation, angiogenesis, Wnt signaling, and the basement membrane

Proteomic analysis of bone marrow-derived mesenchymal stem cell extracellular vesicles from healthy donors: implications for proliferation, angiogenesis, Wnt signaling, and the basement membrane

HIF-1α promoted vasculogenic mimicry formation in lung adenocarcinoma through NRP1 upregulation in the hypoxic tumor microenvironment

An Essential NRP1-Mediated Role for Tagln2 in Gastric Cancer Angiogenesis

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