Department of Pharmaceutical Sciences, College of Health Professions, North Dakota State University, Fargo, ND 58105, USA.
Int J Mol Sci. 2020 Oct 19;21(20):7723. doi: 10.3390/ijms21207723.
The receptor for advanced glycation end products (RAGE) contributes to many cellular aspects of pancreatic cancer including cell proliferation, migration, and survival. Studies have shown that RAGE activation by its ligands promotes pancreatic tumor growth by stimulating both cell proliferation and migration. In this study, we investigated the effect of RAGE up-regulation on the proliferation and migration of the human pancreatic cancer Panc-1 cell-line. We show that moderate overexpression of RAGE in Panc-1 cells results in increased cell proliferation, but decreased cell migration. The observed cellular changes were confirmed to be RAGE-specific and reversible by using RAGE-specific siRNAs and the small molecule RAGE inhibitor FPS-ZM1. At the molecular level, we show that RAGE up-regulation was associated with decreased activity of FAK, Akt, Erk1/2, and NF-κB signaling pathways and greatly reduced levels of α2 and β1 integrin expression, which is in agreement with the observed decreases in cell migration. We also demonstrate that RAGE up-regulation changes the expression of key molecular markers of epithelial-to-mesenchymal transition (EMT). Our results suggest that in the absence of stimulation by external ligands, RAGE up-regulation can differently modulate cell proliferation and migration in pancreatic cancer cells and regulates partly EMT.
晚期糖基化终产物受体（RAGE）有助于胰腺癌的许多细胞方面，包括细胞增殖、迁移和存活。研究表明，RAGE 与其配体的激活通过刺激细胞增殖和迁移来促进胰腺肿瘤的生长。在这项研究中，我们研究了 RAGE 上调对人胰腺癌细胞系 Panc-1 的增殖和迁移的影响。我们发现，RAGE 在 Panc-1 细胞中的适度过表达导致细胞增殖增加，但细胞迁移减少。通过使用 RAGE 特异性 siRNA 和小分子 RAGE 抑制剂 FPS-ZM1，证实了观察到的细胞变化是 RAGE 特异性和可逆的。在分子水平上，我们表明 RAGE 上调与 FAK、Akt、Erk1/2 和 NF-κB 信号通路活性降低以及 α2 和 β1 整合素表达水平大大降低有关，这与观察到的细胞迁移减少一致。我们还证明 RAGE 上调改变了上皮-间充质转化（EMT）的关键分子标志物的表达。我们的结果表明，在没有外部配体刺激的情况下，RAGE 上调可以不同地调节胰腺癌细胞中的细胞增殖和迁移，并调节部分 EMT。
