Department of Vascular Surgery, China-Japan Union Hospital Affiliated to Jilin University, Changchun, 130031, China.
Cell Biochem Biophys. 2013;67(3):1487-95. doi: 10.1007/s12013-013-9650-4.
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.
多形性胶质母细胞瘤（GBM）肿瘤是最常见的脑肿瘤类型，其特征为广泛的血管生成，主要由肿瘤缺氧所调控。缺氧诱导因子-1（HIF-1）转录复合物是缺氧的“主控制开关”。前梯度蛋白 2（AGR2）表达的失调与肿瘤生长和转移有关。AGR2 是否是一种缺氧反应因子，并通过血管生成影响肿瘤进展尚不清楚。在这里，我们表明，与对照正常人类星形胶质细胞相比，GBM 细胞系 U87 和 LN18 表现出增强的缺氧反应，并且相应地 HIF-1 依赖性 AGR2 mRNA 和蛋白增加。重组 AGR2 和 GBM 细胞的条件培养基诱导人脐静脉内皮细胞（HUVEC）迁移和管形成，而抗 AGR2 中和抗体则使其消失。细胞中 HIF-1α 氧依赖性降解结构域突变体的表达导致 AGR2 水平升高，并在体外增强诱导 HUVEC 迁移和管形成的能力，以及体内肿瘤异种移植物的生长和血管生成，而 AGR2 敲低则可防止这些作用。总之，这些结果表明 AGR2 的表达受 HIF-1 调控，并在控制胶质母细胞瘤生长和血管生成中发挥重要作用。我们的研究结果表明，抑制 AGR2 可能代表抗血管生成癌症治疗的新治疗靶点。
