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,Hongwei; Peng,Huifang; Zhuo,Huiqin

doi:10.3892/ijmm.2020.4692

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

Authors:
- Zhi Lyu
- Hongwei Jin
- Zhijian Yan
- Keyan Hu
- Hongwei Jiang
- Huifang Peng
- Huiqin Zhuo
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Affiliations: Respiratory Department, The Affiliated Zhongshan Hospital, Xiamen University, Xiamen, Fujian 361004, P.R. China, Medical Laboratory Center, The Affiliated Xiamen Humanity Hospital, Fujian Medical University, Xiamen, Fujian 361000, P.R. China, Department of Urology, The Affiliated Zhongshan Hospital, Xiamen University, Xiamen, Fujian 361004, P.R. China, Department of Endocrinology, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan 471000, P.R. China , Department of Gastrointestinal Surgery, The Affiliated Zhongshan Hospital, Xiamen University, Xiamen, Fujian 361004, P.R. China
Published online on: August 3, 2020 https://doi.org/10.3892/ijmm.2020.4692
Pages: 1321-1334
Copyright: © Lyu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Angiogenesis and vascular maturation play important roles in tumorigenesis and tumor development. The expression of neuropilin 1 (NRP1) is closely associated with angiogenesis in tumors; however, the molecular mechanisms of action in angiogenesis and tumor maturation, as well as the potential clinical value of NRP1 remain unclear. The importance of NRP1 expression in tumor progression was determined using The Cancer Genome Atlas (TCGA) database analysis. Gain‑ and loss‑of‑function experiments of NRP1 were performed in vascular endothelial cells (ECs) to investigate the functions in angiogenesis. CCK‑8, flow cytometry, Transwell experiments and a series of in vitro experiments were used to detect cell functions. A combination of angiogenesis antibody arrays and RNA‑Seq analyses were performed to reveal the proangiogenic mechanisms of action. The function of semaphorin 4D (SEMA4D) was also investigated separately. NRP1 mRNA levels were significantly increased in primary tumors compared with normal tissues based on TCGA data (P<0.01) and were associated with tumor development in patients. Gain‑ and loss‑of‑function experiments highlighted the function of NRP1 in promoting EC proliferation, motility and capillary‑like tube formation and in reducing apoptosis. NRP1 overexpression led to significantly decreased EC markers (PECAM‑1, angiogenin, PIGF and MMP‑9) expression levels and reduced the vascular maturity. MAPK7, TPM1, RRBP1, PTPRK, HSP90A, PRKD2, PFKFB3, RGS4 and SPARC were revealed to play important roles in this process. SEMA4D was revealed to be a key protein associated with NRP1 in ECs. These data indicated that NRP1‑promoted angiogenesis may be induced at the cost of reducing maturity of the ECs. NRP1 may also be a therapeutic target for antiangiogenic strategies and a candidate prognostic marker for tumors.

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