SorCS3 Promotes the Internalization of p75NTR to Inhibit Glioma Progression

Abstract

Background: Glioma is a fatal malignancy caused by dysregulation of cellular signal transduction. Internalization plays a key role in maintaining signalling balance. SorCS3 is involved in nerve cell receptor internalization. However, the impact of SorCS3 on the biological processes involved in glioma has not yet been reported. Here, we highlight the potential of SorCS3-mediated regulation of signalling receptor internalization as a rational target for therapeutic intervention in glioma.Methods: SorCS3 expression was analysed in the TCGA and CGGA databases and in tissue microarrays. The effects of SorCS3 on the proliferation and metastasis of glioma cells were examined in vitro and in vivo with Transwell, wound healing, EdU incorporation and nude mouse tumorigenicity assays. Fluorescent 5-FAM, SE-labelled proteins were used to detect the internalization of SorCS3 in glioma cells. Immunofluorescence and Co-IP assays were conducted to investigate the downstream effector of SorCS3. Moreover, Dynasore and Ro 08-2750, inhibitors of internalization and NGF binding to p75NTR, respectively, were used to validate the biological functions of SorCS3 in glioma.Results: Our data demonstrated that SorCS3 was downregulated in glioma tissues and closely related to favourable prognosis. Overexpression of SorCS3 inhibited the proliferation and metastasis of glioma cells in vitro and in vivo, while silencing of SorCS3 exerted the opposite effects. Mechanistic investigations showed that SorCS3 bound to p75NTR, which subsequently increased the internalization of p75NTR, and then transported p75NTR to the lysosome for degradation, ultimately contributing to inhibition of glioma progression.Conclusions: Our work suggests that SorSC3 is a marker of promising prognosis in glioma patients and suggests that SorCS3 regulates internalization, which plays an important role in inhibiting glioma progression.