Abstract / Summary
Glioma is the most prevalent and aggressive primary brain malignancy, characterized by a grim clinical prognosis. Although an epithelial–mesenchymal transition (EMT)-like process is implicated in driving glioma invasiveness, therapeutic resistance, and recurrence, the precise molecular underpinnings remain largely elusive. Here, we elucidate the oncogenic role of ANTXR1 in glioma progression and define its mechanistic contribution to mesenchymal reprogramming. ANTXR1 expression profiles were evaluated across public clinico-genomic cohorts and validated in human glioma cellular models. Phenotypic alterations in proliferation and invasion were assessed in vitro using gain- and loss-of-function approaches. Subcutaneous xenograft models were utilized to evaluate in vivo tumor kinetics and biomarker alterations. Furthermore, protein stability assays and co-immunoprecipitation were employed to elucidate the ANTXR1–DKK2 interaction and its regulatory impact on ubiquitin-proteasomal degradation. ANTXR1 is robustly upregulated in glioma and actively fosters tumor proliferation and invasiveness both in vitro and in vivo. Mechanistically, ANTXR1 forms a protein complex with and stabilizes the DKK2 protein by preventing its proteasomal degradation, thereby activating mesenchymal transition during glioma pathogenesis. ANTXR1 acts as a crucial stabilizer of DKK2, driving the mesenchymal transition of glioma. The ANTXR1/DKK2 signaling axis represents a promising target that warrants further evaluation for its potential to suppress glioma invasion and improve patient outcomes.