It has been previously established that hypoxia leads to tumor development, treatment resistance, and a poor prognosis. Under oxygen deprivation, hypoxia‐inducible factors (HIFs) are stimulated to activate the genes necessary for tumor development in a low‐oxygen environment. These genes encode regulators of angiogenesis, epithelial‐mesenchymal transition, and cellular metabolism. A disulfide isomerase, anterior gradient 2 (AGR2), has been shown to increase hypoxia‐inducible factor 1, alpha subunit (HIF‐1α) stability in breast cancer. Our goal was to determine if AGR2 affects the level of transcription factor hypoxia‐inducible factor 2, alpha subunit (HIF‐2α). As a model, we used the clear cell renal cell carcinoma (ccRCC) cell line Caki‐1. The cells were transduced with lentiviral vector (Tet‐On) encoding AGR2. After induction of AGR2 expression, cells were grown under either hypoxic (0.5% O2) or normoxic (21% O2) conditions. Our data showed that AGR2 upregulated both HIF‐1α and HIF‐2α expression in Caki‐1 cells increasing the expression of HIF‐activated genes (glucose transporter 1, phosphoglycerate kinase 1, vascular endothelial growth factor A, and transforming growth factor‐alpha) under the hypoxic conditions. Under the normoxic conditions, AGR2 strongly activated CCAAT‐enhancer binding protein beta (C/EBPβ). Upregulation of C/EBPβ correlated with increased expression and secretion of the interleukin‐6 and interleukin‐8, inducing angiogenesis and inflammation in Caki‐1 cells. In summary, our studies revealed that AGR2 has essential functions in ccRCC progression through upregulation of C/EBPβ and HIF‐2α expressions, which affects cell signaling and metabolism.

中文翻译：

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前梯度 2 通过上调 CCAAT 增强子结合蛋白 β 和缺氧诱导因子 2α 以及随后在 Caki-1 透明细胞肾细胞癌细胞系中分泌白细胞介素 6、白细胞介素 8 和血管内皮生长因子来促进肿瘤发生

先前已经确定缺氧会导致肿瘤发展、治疗抵抗和不良预后。在缺氧条件下，缺氧诱导因子 (HIF) 被刺激以激活低氧环境中肿瘤发展所必需的基因。这些基因编码血管生成、上皮间质转化和细胞代谢的调节因子。一种二硫化物异构酶，前梯度 2 (AGR2)，已被证明可以增加缺氧诱导因子 1，α 亚基 (HIF-1α) 在乳腺癌中的稳定性。我们的目标是确定 AGR2 是否影响转录因子缺氧诱导因子 2 α 亚基 (HIF-2α) 的水平。我们使用透明细胞肾细胞癌 (ccRCC) 细胞系 Caki-1 作为模型。用编码 AGR2 的慢病毒载体 (Tet-On) 转导细胞。诱导 AGR2 表达后，细胞在缺氧 (0.5% O2) 或常氧 (21% O2) 条件下生长。我们的数据显示，AGR2 上调 Caki-1 细胞中 HIF-1α 和 HIF-2α 的表达，增加了 HIF 激活基因（葡萄糖转运蛋白 1、磷酸甘油酸激酶 1、血管内皮生长因子 A 和转化生长因子-α）的表达缺氧条件下。在常氧条件下，AGR2 强烈激活 CCAAT 增强子结合蛋白β（C/EBPβ）。C/EBPβ 的上调与白细胞介素 6 和白细胞介素 8 的表达和分泌增加相关，诱导 Caki-1 细胞的血管生成和炎症。总之，我们的研究表明，AGR2 通过上调 C/EBPβ 和 HIF-2α 表达在 ccRCC 进展中具有重要功能，这会影响细胞信号传导和代谢。