Quantitative proteomic landscape reveals the role of CSPG5 in the recurrence of glioma

The high recurrence rate of glioma accounts for the majority of glioma-related deaths. Although numerous studies have investigated genomic and transcriptomic alterations, high-resolution quantitative proteomic profiling studies remain limited. A total of 63 pairs of primary and recurrent formalin-fixed paraffin-embedded glioma tissues (WHO grade II–IV) were collected. Proteomic profiles were generated by data-independent acquisition mass spectrometry (DIA-MS). Differentially expressed proteins were validated using publicly available databases, immunohistochemistry, and Western blotting. The effects of CSPG5 on glioma cell proliferation and invasion were assessed in vitro and in an orthotopic mouse model. Protein–protein interactions were examined by co-immunoprecipitation, and the influence of CSPG5 on ErbB2 degradation was evaluated by immunofluorescence and quantitative PCR. Two distinct proteomic clusters (Cluster 1 and Cluster 2) associated with glioma recurrence were identified. Chondroitin sulfate proteoglycan 5 (CSPG5) was markedly down-regulated in recurrent tumors. Overexpression of CSPG5 significantly inhibited glioma cell proliferation and invasion in vitro and reduced tumor burden in vivo. Mechanistically, CSPG5 interacted with ErbB2 and promoted its lysosomal degradation, leading to attenuated PI3K-AKT and ERK signaling. CSPG5 acts as a novel suppressor of ErbB2 signaling; its loss facilitates ErbB2 hyperactivation and thereby promotes glioma recurrence.