Department of Pathology, University of Sydney, Sydney, New South Wales, Australia.
Antioxid Redox Signal. 2013 Mar 10;18(8):874-87. doi: 10.1089/ars.2011.4273. Epub 2012 May 8.
The metastasis suppressor gene, N-myc downstream regulated gene-1 (NDRG1), is negatively correlated with tumor progression in multiple neoplasms, including pancreatic cancer. Moreover, NDRG1 is an iron-regulated gene that is markedly upregulated by cellular iron-depletion using novel antitumor agents such as the chelator, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), in pancreatic cancer cells. However, the exact function(s) of NDRG1 remain to be established and are important to elucidate.
In the current study, using gene-array analysis along with NDRG1 overexpression and silencing, we identified the molecular targets of NDRG1 in three pancreatic cancer cell lines. We demonstrate that NDRG1 upregulates neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) and GLI-similar-3 (GLIS3). Further studies examining the downstream effects of NEDD4L led to the discovery that NDRG1 affects the transforming growth factor-β (TGF-β) pathway, leading to the upregulation of two key tumor suppressor proteins, namely phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and mothers against decapentaplegic homolog-4 (SMAD4). Moreover, NDRG1 inhibited the phosphatidylinositol 3-kinase (PI3K) and Ras oncogenic pathways.
This study provides significant insights into the mechanisms underlying the antitumor activity of NDRG1. For the first time, a role for NDRG1 is established in regulating the key signaling pathways involved in oncogenesis (TGF-β, PI3K, and Ras pathways).
The identified target genes of NDRG1 and their effect on the TGF-β signaling pathway reveal its molecular function in pancreatic cancer and a novel therapeutic avenue.
N- MYC 下游调节基因 1（NDRG1）是一种转移抑制基因，与多种肿瘤包括胰腺癌的肿瘤进展呈负相关。此外，NDRG1 是一种铁调节基因，在用新型抗肿瘤剂如螯合剂二吡啶酮 4,4-二甲基-3-硫代缩氨基甲酸盐（Dp44mT）耗尽细胞铁时，其表达在胰腺癌细胞中明显上调。然而，NDRG1的确切功能仍有待确定，这一点很重要。
在本研究中，我们通过基因芯片分析以及 NDRG1 的过表达和沉默，鉴定了 NDRG1 在三种胰腺癌细胞系中的分子靶标。我们证明 NDRG1 上调神经前体细胞表达的发育下调 4 样（NEDD4L）和 GLI 样-3（GLIS3）。进一步研究检查 NEDD4L 的下游效应导致发现 NDRG1 影响转化生长因子-β（TGF-β）途径，导致两个关键肿瘤抑制蛋白磷酸酶和张力蛋白同源物缺失 10 号染色体（PTEN）和母亲抗 Decapentaplegic 同源物-4（SMAD4）的上调。此外，NDRG1 抑制了磷脂酰肌醇 3-激酶（PI3K）和 Ras 致癌途径。
本研究为 NDRG1 的抗肿瘤活性的机制提供了重要的见解。首次建立了 NDRG1 在调节参与致癌作用的关键信号通路（TGF-β、PI3K 和 Ras 通路）中的作用。
NDRG1 的鉴定靶基因及其对 TGF-β信号通路的影响揭示了其在胰腺癌中的分子功能和新的治疗途径。
