Loss of NDRG2 promotes epithelial-mesenchymal transition of gallbladder carcinoma cells through MMP-19-mediated Slug expression
Loss of NDRG2 promotes epithelial-mesenchymal transition of gallbladder carcinoma cells through MMP-19-mediated Slug expression
复制标题
DOI：
10.1016/j.jhep.2015.08.007
复制
发表时间：
2015-12-01
影响因子：
25.7
通讯作者：
Min, Jeong-Ki
中科院分区：
文献类型：
--
作者：
Lee, Dong Gwang;Lee, Sang-Hyun;Min, Jeong-Ki
背景与目的：胆囊癌（GBC）是最常见的胆道恶性肿瘤，也是人类最致命的癌症之一。然而，关于GBC的分子发病机制的信息有限。在这里，我们研究了肿瘤抑制因子N-myc下游调控基因2 （NDRG2）的功能作用以及GBC疾病进展的潜在分子机制。方法：对86例GBC患者肿瘤组织进行免疫组化分析，检测NDRG2表达与临床病理因素的相关性。在NDRG2敲除或过表达的GBC细胞系中，研究了NDRG2和NDRG2介导的信号通路的生物学功能。结果：NDRG2表达缺失是GBC患者生存期降低的独立预测因子，并且与更晚期的T期、更高的细胞分级和淋巴浸润显著相关。NDRG2表达缺失的GBC细胞在体外增殖、迁移和侵袭性以及体内肿瘤生长和转移均显著增强。NDRG2缺失诱导基质金属蛋白酶-19 （matrix metalloproteinase-19, MMP-19）的表达，MMP-19在转录水平调控Slug的表达。此外，mmp -19诱导的Slug增加了受体酪氨酸激酶Axl的表达，通过正反馈回路维持Slug的表达，稳定了GBC细胞的上皮-间质转化。结论：我们的研究结果有助于解释为什么NDRG2表达缺失与GBC恶性肿瘤密切相关。这些结果强烈表明，NDRG2可能是一个良好的预后指标和治疗GBC药物的有希望的靶点。(C) 2015欧洲肝脏研究协会。Elsevier B.V.版权所有。
Background & Aims: Gallbladder carcinoma (GBC) is the most common malignancy of the biliary tract and one of the most lethal forms of human cancer. However, there is limited information about the molecular pathogenesis of GBC. Here, we examined the functional role of the tumor suppressor N-myc downstream-regulated gene 2 (NDRG2) and the underlying molecular mechanisms of disease progression in GBC.Methods: Clinical correlations between NDRG2 expression and clinicopathological factors were determined by immunohistochemical analysis of tumor tissues from 86 GBC patients. Biological functions of NDRG2 and NDRG2-mediated signaling pathways were determined in GBC cell lines with NDRG2 knock-down or overexpression.Results: Loss of NDRG2 expression was an independent predictor of decreased survival and was significantly associated with a more advanced T stage, higher cellular grade, and lymphatic invasion in patients with GBC. GBC cells with loss of NDRG2 expression showed significantly enhanced proliferation, migration, and invasiveness in vitro, and tumor growth and metastasis in vivo. Loss of NDRG2 induced the expression of matrix metalloproteinase-19 (MMP-19), which regulated the expression of Slug at the transcriptional level. In addition, MMP-19-induced Slug, increased the expression of a receptor tyrosine kinase, Axl, which maintained Slug expression through a positive feedback loop, and stabilized epithelial-mesenchymal transition of GBC cells.Conclusions: The results of our study help to explain why the loss of NDRG2 expression is closely correlated with malignancy of GBC. These results strongly suggest that NDRG2 could be a favorable prognostic indicator and promising target for therapeutic agents against GBC. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.