Secreted phosphoprotein 1 promotes angiogenesis of glioblastoma through upregulating PSMA expression via transcription factor HIF1 alpha

Glioblastoma multiforme (GBM) is a highly vascularized malignant brain tumor. Our previous study showed that prostate-specific membrane antigen (PSMA) promotes angiogenesis of GBM. However, the specific mechanism underlying GBM-induced PSMA upregulation remains unclear. In this study, we demonstrate that the GBM-secreted cytokine phosphoprotein 1 (SPP1) can regulate the expression of PSMA in human umbilical vein endothelial cells (HUVECs). Our mechanistic study further reveals that SPP1 regulates the expression of PSMA through the transcription factor HIF1 alpha. Moreover, SPP1 promotes HUVEC migration and tube formation. In addition, HIF1 alpha knockdown reduces the expression of PSMA in HUVECs and blocks the ability of SPP1 to promote HUVEC migration and tube formation. We further confirm that SPP1 is abundantly expressed in GBM, is associated with poor prognosis, and has high clinical diagnostic value with considerable sensitivity and specificity. Collectively, our findings identify that the GBM-secreted cytokine SPP1 upregulates PSMA expression in endothelial cells via the transcription factor HIF1 alpha, providing insight into the angiogenic process and promising candidates for targeted GBM therapy.