SDF2 promotes glioma progression via GRP78‑mediated ERAD and copper homeostasis disruption.

Stromal cell‑derived factor 2 (SDF2) is an endoplasmic reticulum chaperone protein crucial for protein folding. Its role in gliomas is poorly understood. The present study investigated SDF2 expression and function in glioma progression. Our data revealed that the expression of SDF2 was upregulated in glioma tissues. In glioma cell lines, SDF2 promoted cell proliferation and migration, whereas the knockdown of SDF2 (Ad‑shSDF2) induced cell death. Further investigations revealed that the copper chelator tetrathiomolybdate (TTM) could reverse the reduction in cell viability caused by Ad‑shSDF2. Upon SDF2 knockdown, the expression of ATP7A and ATP7B was decreased in glioma cells, whereas the expression of glucose‑regulated protein 78 (GRP78) was increased. Moreover, the proteasome inhibitor MG132 and the silencing of GRP78 effectively blocked the Ad‑shSDF2‑mediated decrease in ATP7A and ATP7B expression, as well as the accumulation of dihydrolipoamide S‑acetyltransferase in mitochondria. In vivo, SDF2 promoted subcutaneous tumor growth in nude mice, an effect that could be reversed by overexpression of GRP78. This reversal was accompanied by an increase in the intra‑tumoral copper ion concentration. In gliomas, SDF2 promotes tumor growth by inhibiting the GRP78‑mediated endoplasmic reticulum‑associated degradation pathway, thereby increasing the expression of ATP7A and ATP7B. This results in reduced intracellular accumulation of copper ions, facilitating tumor progression.