Differential dependency of human glioblastoma cells on vascular endothelial growth factor‑A signaling via neuropilin‑1

Lee,Jungwhoi; Chong,Kyuha; Lee,Jungsul; Kim,Chungyeul; Kim,Jae-Hoon; Choi,Kyungsun; Choi,Chulhee

doi:10.3892/ijo.2022.5412

Differential dependency of human glioblastoma cells on vascular endothelial growth factor‑A signaling via neuropilin‑1

Authors:
- Jungwhoi Lee
- Kyuha Chong
- Jungsul Lee
- Chungyeul Kim
- Jae-Hoon Kim
- Kyungsun Choi
- Chulhee Choi
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Affiliations: Department of Applied Life Science, Sustainable Agriculture Research Institute (SARI), Jeju National University, Jeju‑do 63243, Republic of Korea, Department of Neurosurgery, Korea University Guro Hospital, Korea University Medicine, Korea University College of Medicine, Guro‑gu, Seoul 08308, Republic of Korea, Department of Bio and Brain Engineering, KAIST, Yuseong‑gu, Daejeon 34141, Republic of Korea, Department of Pathology, Korea University Guro Hospital, Korea University Medicine, Korea University College of Medicine, Guro‑gu, Seoul 08308, Republic of Korea, ILIAS Biologics Inc., Yuseong‑gu, Daejeon 34014 34014, Republic of Korea
Published online on: August 29, 2022 https://doi.org/10.3892/ijo.2022.5412
Article Number: 122
Copyright: © Lee et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Despite the high expression of neuropilin‑1 (NRP‑1) in human glioblastoma (GB), the understanding of its function as a co‑receptor of vascular endothelial growth factor receptors (VEGFRs) in angiogenesis is currently limited. Therefore, the aim of the present study was to elucidate the non‑classical function of NRP‑1 expression in human GB. Expression patterns of NRP‑1 and VEGF‑A were determined by sandwich ELISA, western blot analysis, or immunohistochemistry. Differential dependency of GB cells following ablation of VEGF‑A signaling was validated in vitro and in vivo. Cellular mechanism responsible for distinct response to VEGF‑A signaling was evaluated by western blotting and immunoprecipitation analysis. Prognostic implications were assessed using IHC analysis. GB cells exhibited differing sensitivity to silencing of vascular endothelial growth factor (VEGF)‑A signaling, which resulted in a distinct expression pattern of wild‑type or chondroitin‑sulfated NRP‑1. VEGF‑A‑sensitive GB exhibited the physical interaction between wild‑type NRP‑1 and FMS related receptor tyrosine kinase 1 (Flt‑1) whereas VEGF‑A‑resistant GB exhibited chondroitin‑sulfated NRP‑1 without interaction with Flt‑1. Eliminating the chondroitin sulfate modification in NRP‑1 led to re‑sensitization to VEGF‑A signaling, and chondroitin sulfate modification was found to be associated with an adverse prognosis in patients with GB. The present study identified the distinct functions of NRP‑1 in VEGF‑A signaling in accordance with its unique expression type and interaction with Flt‑1. The present research is expected to provide a strong basis for targeting VEGF‑A signaling in patients with GB, with variable responses.

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