AGR2 Expression is Regulated by HIF-1 and Contributes to Growth and Angiogenesis of Glioblastoma

Abstract

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.

Agr2 Mediates Paracrine Effects on Stromal Fibroblasts That Promote Invasion by Gastric Signet-Ring Carcinoma Cells

“…Agr2 acts as a disulfide isomerase and contains a thioredoxinlike motif, which suggests that it has redox activity (6). Furthermore, expression of Agr2 is regulated by the hypoxiainduced factor-1 (HIF1) transcriptional complex, and Agr2 mRNA levels are elevated in hypoxic condition (23). Therefore, we next investigated whether Agr2 affects the ability of cells to survive oxidative stress or hypoxia.…”

“…In some types of cancer, however, Agr2 is also present in the extracellular space, serum, and urine (21,22). Although Agr2 is known to exert angiogenic effect (23), the functions of extracellular Agr2 are not as well characterized as the protein's roles in the ER.…”

Conjugation of gold nanoparticles and recombinant human endostatin modulates vascular normalization via interruption of anterior gradient 2–mediated angiogenesis

“…[21][22][23][24][25]31 In this study, the effect of rhES-AuNPs on mCRC tumor growth in vivo was firstly evaluated. The results suggested that rhES-AuNPs experimental group could modulate vascular morphology in mCRC tumor and improve tumor hypoxia.…”

Knockdown of anterior gradient 2 expression extenuates tumor-associated phenotypes of SNU-478 ampulla of Vater cancer cells

“…Both AGR2-mediated inhibition of p53 tumor suppressor activity and AGR2-associated expression of genes that regulate cell growth and survival may directly contribute to the tumor-promoting activity of AGR2 through augmented cell proliferation and survival. Meanwhile, increased invasiveness and metastasis associated with AGR2 expression might be the result of regulation of cathepsins B and D expression, enhanced angiogenesis and modulation of extracellular matrix by AGR2 [30, 32, 33]. It is plausible that changes in the AGR2-associated gene expression regulate the tumor phenotypes of the biliary cancer cells including viability, anchorage-independent growth and invasiveness.…”