This study evaluated expression of the endoplasmic reticulum resident protein ERP44 in lower‑grade glioma (LGG) using public genomics resources, including TCGA, GTEx, and CGGA datasets. The investigators found that ERP44 was markedly upregulated in LGG compared with reference tissues. Elevated ERP44 expression was associated with established adverse clinicopathological features: higher World Health Organization (WHO) grade, IDH wildtype status, and 1p/19q non‑codeletion. Those associations position ERP44 as correlated with molecular and histologic indicators of more aggressive LGG biology.
Survival analyses across TCGA and CGGA cohorts demonstrated that high ERP44 expression correlated with worse overall survival. The authors assessed prognostic discrimination with time‑dependent receiver operating characteristic (ROC) curves and integrated ERP44 into multivariable models. A prognostic nomogram that included ERP44 improved risk stratification relative to models without ERP44, indicating that ERP44 adds independent prognostic information in LGG. Specific hazard ratios, confidence intervals, and numerical performance metrics were not provided in the abstract and therefore are not reproduced here.
To explore potential biological mechanisms, the investigators performed differential expression analyses and Gene Set Enrichment Analysis (GSEA) along with Gene Ontology (GO) enrichment. High ERP44 expression was linked to enrichment of immune and inflammatory pathways and to a relative reduction in neuronal functional signatures. Correlation analyses showed that ERP44 positively associated with markers of immune infiltration as well as proliferation and stemness markers. These findings suggest ERP44 may be connected to tumor microenvironment modulation and proliferative or stem‑like phenotypes in LGG.
Using drug sensitivity analyses in the genomic datasets, ERP44 expression was predictive of resistance to temozolomide (TMZ), the frontline alkylating agent commonly used in glioma treatment. The in silico prediction provided the rationale for experimental validation testing whether ERP44 modulates TMZ responsiveness in cellular and animal models.
Functional experiments were performed in two lower‑grade glioma cell lines, SW1088 and SW1783. ERP44 expression was reduced using shRNA knockdown, and knockdown efficiency was assessed by RT‑qPCR and western blotting. Phenotypic assays demonstrated that ERP44 depletion inhibited cell proliferation in CCK‑8 assays and reduced colony formation capacity. ERP44 knockdown also lowered the half‑maximal inhibitory concentration (IC50) for TMZ in these cell lines, indicating increased sensitivity to the drug after ERP44 suppression. Together, the in vitro results support a role for ERP44 in promoting proliferation and contributing to TMZ resistance in LGG cells.
Subcutaneous xenograft models in mice were used to validate the in vitro findings. Tumors derived from ERP44‑depleted cells exhibited slower growth compared with controls. When combined with TMZ treatment, ERP44 knockdown enhanced the antitumor effect of TMZ, producing greater suppression of xenograft growth than TMZ alone. Immunohistochemical assessment showed decreased Ki67 positivity in tumors with ERP44 knockdown, consistent with reduced proliferative activity. The animal experiments corroborate the cell line data and support the conclusion that ERP44 promotes tumor proliferation and mediates resistance to TMZ in vivo.
Across public genomic datasets, cellular models, and mouse xenografts, the evidence presented indicates that ERP44 is upregulated in LGG, associated with adverse clinicopathological features, and predicts poorer survival. Mechanistically, ERP44 expression correlates with immune/inflammatory pathway activation and with markers of proliferation and stemness. Functional perturbation using shRNA reduced tumor cell proliferation, lowered TMZ IC50, suppressed xenograft growth, decreased Ki67 staining, and potentiated TMZ efficacy. The authors conclude that ERP44 is a prognostic biomarker that promotes LGG proliferation and temozolomide resistance, and they suggest ERP44 may represent a potential therapeutic target for improving outcomes in LGG.
Note: The abstract did not report detailed numerical results such as sample sizes, hazard ratios, exact p values, effect sizes, or specifics about immune cell subtypes; those detailed metrics are not included here because they were not reported in the source abstract.