Anterior gradient 2 promotes tumorigenesis through upregulation of CCAAT‐enhancer binding protein beta and hypoxia‐inducible factor‐2α and subsequent secretion of interleukin‐6, interleukin‐8, and vascular endothelial growth factor in the Caki‐1 clear cell renal cell carcinoma cell line

Abstract

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.

<p>CircPVT1 Promoted the Progression of Breast Cancer by Regulating MiR-29a-3p-Mediated AGR2-HIF-1α Pathway</p>

“…Previous studies have proved that AGR2 promoting cancer progression via enhancing HIF-1α or HIF-2α expression. [37][38][39] Even HIF-1A upregulation led to higher level of AGR2. 40 As for HIF-1α, it is a vital transcription factor that regulates cellular and systemic homeostatic response to hypoxia by activating transcription of many genes.…”

High Expression of DNTTIP1 Predicts Poor Prognosis in Clear Cell Renal Cell Carcinoma

“…9 HIF2α is believed to be the most important driver for the development of the ccRCC. 27 HIF1α and HIF2α could induce angiogenesis 37,38 and lipid accumulation in renal cancer tissues. 27,39 DNTTIP1 was predicted to play a certain role in cellular response to hypoxia and angiogenesis.…”

Fatty acid metabolism-related signature predicts survival in patients with clear cell renal carcinoma

“…Consistent with these results, HAO2 was reported to inhibit malignancy of clear cell renal cell carcinoma by promoting lipid catabolic process [ 21 ]. In addition, AGR2 and IGF2BP1 promoted tumorigenesis by accelerating hypoxia state in renal cell carcinoma cell line [ 22 – 23 ].…”