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.
Keywords: FMS related receptor tyrosine kinase 1; autocrine signaling; chondroitin sulfate; glioblastoma; neuropilin‑1.