MUC1 and MUC4 expression are inversely correlated and trigger immunological response and transport pathways in gliomas

Diffuse gliomas are tumors that arise from glial or glial progenitor cells. They are currently classified as astrocytoma isocitrate dehydrogenase (IDH)-mutant or oligodendroglioma IDH-mutant, and chromosome arms 1p/19q-codeleted, both slower-growing tumors, or glioblastoma (GBM), a more aggressive tumor. Despite advances in the diagnosis and treatment of gliomas, the median survival time after diagnosis of GBM remains low, approximately 15 months, with a 5-year overall survival rate of only 6.8%. Therefore, new biomarkers and therapy targets that could support better prognosis of these tumors would be of great value. MUC1 and MUC4, membrane-bound mucins, has been identified as a potential biomarker in several tumors. However, the role of these mucins in adult gliomas has not yet been well explored. Here, we show for the first time, in a retrospective study and by in silico analysis, the relevance and correlation of these genes in adult gliomas. Analysis of adult diffuse glioma patient cohorts revealed differential methylation and expression patterns of MUC1 and MUC4 across GBM and non-GBM subtypes. GBM patients exhibited decreased MUC1 methylation and elevated expression (r-0.25, p < 0.0001) whereas increased MUC4 methylation and its lower expression (r-0.13, p = 0.1344). Conversely, in non-GBM patients, MUC1 showed higher methylation levels and low expression (r-0.27, p < 0.0001) whereas MUC4 showed lower methylation levels and high expression (r-0.32, p < 0.0001). The expression levels of these genes influenced overall survival (OS) in gliomas patients (p = 0.0344), with high MUC1 and low MUC4 expression associated with worse OS. MUC1 and MUC4 correlated with MUC20 in both GBM (r = 0.54) and non-GBM (r = 0.53) patients (p < 0.0001). Functional enrichment analysis revealed distinct biological roles for co-expressed genes with MUC1 involvement in innate immunity, antigen processing, pro-inflammatory responses in both non-GBM and GBM cohorts, and integrin-based signaling pathways in GBM patients. MUC4 co-expressed genes were involved in ion transport in GBM patients. Using molecular docking, we observed that MUC1 has domains that are physically capable of interacting with immune response-related proteins such as Receptor for Advanced Glycation End-products (RAGE), Major Histocompatibility Complex II (MHCII), and extracellular matrix receptor integrin alpha 2 (ITGA2). These findings shed light on the molecular mechanisms underlying glioma progression and highlight MUC1 and MUC4 as potential prognostic markers and therapeutic targets in glioma management.