AGR2 expression is regulated by HIF-1 and contributes to growth and angiogenesis of glioblastoma.

Glioblastoma multiforme (GBM) tumors are the most common type of brain tumors characterized by extensive angiogenesis that is mostly orchestrated by tumor hypoxia. The hypoxia induced factor-1 (HIF-1) transcriptional complex is the "master control switch" for hypoxia. Dysregulation of anterior gradient protein 2 (AGR2) expression is associated with tumor growth and metastasis. Whether AGR2 is a hypoxia-responsive factor and affects tumor progression via angiogenesis remains unknown. Here, we show that GBM cell lines, U87 and LN18, exhibited enhanced hypoxic responses compared with control normal human astrocytes, and a corresponding HIF-1-dependent increase in AGR2 mRNA and protein. Recombinant AGR2 and conditioned medium from GBM cells induced human umbilical vein endothelial cell (HUVEC) migration and tube formation, which were abrogated by anti-AGR2 neutralizing antibodies. Expression of the HIF-1α oxygen-dependent degradation domain mutant in cells resulted in elevated AGR2 levels and an increased ability to induce HUVEC migration and tube formation in vitro and enhanced growth and vascularity of tumor xenografts in vivo, which were prevented by AGR2 knockdown. Taken together, these results indicate that AGR2 expression is regulated by HIF-1 and plays an important role in control of glioblastoma growth and vascularity. Our findings suggest that inhibiting AGR2 may represent a new therapeutic target for anti-angiogenic cancer treatment.