PDIA6 promotes glioma malignancy by activating the IRE1α- p-HSP27 signaling axis

Background: Protein disulfide isomerase A6 (PDIA6) is commonly overexpressed in multiple human cancers, but its functional significance in glioma is still not well defined. Methods: PDIA6 expression and its correlation with pathological grade was assessed in clinical glioma tissues using real-time quantitative polymerase chain reaction (qPCR), western blot, and immunohistochemistry (IHC), complemented by bioinformatic analysis from GEPIA (Gene Expression Profiling Interactive Analysis) and R2 platform. Lentiviral shRNA of stable PDIA6 knockdown was established in glioma cells lines. Functional assays-including Cell Counting Kit-8 assay, Scratch assay, and transwell invasion assay-were performed to assess the impact of PDIA6 on glioma cells in vitro. While, in vivo tumor growth was evaluated in mouse xenograft models using 7.0T magnetic resonance imaging (MRI). Downstream phosphor-signaling components were identified through phospho-kinase array. Results: PDIA6 was significantly upregulated in glioma, and its expression positively correlated with higher pathological grade and poor patient prognosis. PDIA6 Knockdown markedly suppressed proliferation, migration, and invasion of glioma cells. In xenograft models, PDIA6 depletion led reduce tumor volume and prolonged survival. Mechanistically, PDIA6 activated the unfolded protein response (UPR) through upregulation of IRE1α. The PDIA6- IRE1α axis further promoted malignancy by enhancing HSP27 phosphorylation. Conclusions: Our findings indicated that PDIA6 acts as an oncogenic in glioma and functions as a critical mediator within the IRE1α-p-HSP27 signaling pathway.