JMJD2B Promotes Epithelial-Mesenchymal Transition by Cooperating with β-Catenin and Enhances Gastric Cancer Metastasis
JMJD2B Promotes Epithelial-Mesenchymal Transition by Cooperating with β-Catenin and Enhances Gastric Cancer Metastasis
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DOI：
10.1158/1078-0432.ccr-13-0254
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发表时间：
2013-12-01
影响因子：
11.5
通讯作者：
Jia, Jihui
中科院分区：
文献类型：
--
作者：
Zhao, Li;Li, Wenjuan;Jia, Jihui
目的：本研究探讨组蛋白去甲基化酶Jumonji结构域蛋白2B（JMJD 2B）在促进上皮间质转化（EMT）中的作用及其在胃癌发生发展中的分子机制。实验设计：通过一系列实验研究JMJD 2B对胃癌细胞EMT的诱导作用及其机制。进行体内和体外测定以阐明JMJD 2B在胃癌细胞中的侵袭潜力。结果：特异性siRNA抑制JMJD 2B表达可抑制胃癌细胞的EMT，而异位表达可诱导EMT。重要的是，JMJD 2B与β-连环蛋白物理相关，并增强其核定位和转录活性。JMJD 2B与b-连环蛋白一起结合到b-连环蛋白靶基因波形蛋白的启动子上，通过局部诱导H3 K9去甲基化来增加其转录。JMJD 2B抑制剂在体外减弱胃癌细胞的迁移和侵袭以及在体内减弱转移。JMJD 2B的表达与肿瘤大小呈正相关（P = 0.017），分化状态（P = 0.002），肿瘤浸润（P = 0.045），淋巴结转移（P = 0.000），远处转移（P = 0.024）和肿瘤淋巴结转移（TNM）分期胃癌患者中，P0.002。结论：这些数据揭示了JMJD 2B在促进EMT和胃癌侵袭和转移中的新功能，暗示JMJD 2B作为逆转EMT和干预胃癌进展的潜在靶点。Clin Cancer Res; 19（23）; 6419-29. (C)2013年AACR。
Purpose: This study investigated the role of histone demethylase Jumonji domain-containing protein 2B (JMJD2B) in promoting epithelial-mesenchymal transition (EMT) and underlying molecular mechanisms in the progression of gastric cancer.Experimental Design: The induction of EMT by JMJD2B in gastric cancer cells and its underlying mechanisms were examined by a series of assays. In vivo and in vitro assays were performed to clarify invasive potential of JMJD2B in gastric cancer cells. The expression dynamics of JMJD2B were detected using immunohistochemistry in 101 cases of primary gastric cancer tissues.Results: Inhibition of JMJD2B by specific siRNA suppresses EMT of gastric cancer cells, whereas ectopic expression of JMJD2B induces EMT. Importantly, JMJD2B is physically associated with beta-catenin and enhances its nuclear localization and transcriptional activity. JMJD2B, together with b-catenin, binds to the promoter of the b-catenin target gene vimentin to increase its transcription by inducing H3K9 demethylation locally. JMJD2B inhibition attenuates migration and invasion of gastric cancer cells in vitro and metastasis in vivo. The expression of JMJD2B was positively correlated with tumor size (P = 0.017), differentiation status (P = 0.002), tumor invasion (P = 0.045), lymph node metastasis (P = 0.000), distant metastasis (P = 0.024), and tumor-node-metastasis (TNM) stage (P 0.002) in patients with gastric cancer.Conclusions: The data reveal a novel function of JMJD2B in promoting EMT and gastric cancer invasion and metastasis, implicating JMJD2B as a potential target for reversing EMT and intervention of the progression of gastric cancer. Clin Cancer Res; 19(23); 6419-29. (C) 2013 AACR.