Integrated analysis reveals prognostic value and mesenchymal identity suppression by glycoprotein M6B in glioma

Glioblastoma (GBM) stem cells (GSCs) possess multilineage differentiation potential, which is responsible for cancer progression. Glycoprotein M6B (GPM6B) is a pivotal enzyme in regulating intracranial cell differentiation and neuronal myelination, and is widely studied in several cancers. However, research on GPM6B in glioma is limited. In this study, we analyzed the clinical and molecular characteristics of GPM6B using RNA sequencing data of glioma samples from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) datasets. Quantitative real-time PCR (qRT-PCR), western blot (WB), and immunohistochemistry (IHC) were performed for further validation. Moreover, a neurosphere formation assay, extreme limiting dilution assay, and bioluminescent imaging were employed to validate the therapeutic effects targeted on GPM6B in vitro and in vivo. We found lower expression of GPM6B in aggressive glioma. Receiver operating characteristic (ROC) analysis suggested that GPM6B is an indicator of mesenchymal subtype. Kaplan-Meier analysis also revealed that patients with glioma with high GPM6B expression levels had a tendency toward prolonged survival. The GPM6B expression level could predict favorable prognosis of patients independent of age, grade, IDH status, and 1p/19q status. Additionally, targeting GPM6B impaired the self-renewal and tumorgenicity of mesenchymal GSCs by inhibiting the activation of the Wnt pathway in vitro and in vivo. Our results demonstrated that GPM6B is a crucial predictor in glioma prognosis and represents an underlying therapeutic target in GSC therapy.