PLAGL2 promotes epithelial-mesenchymal transition and mediates colorectal cancer metastasis via β-catenin-dependent regulation of ZEB1
PLAGL2 promotes epithelial-mesenchymal transition and mediates colorectal cancer metastasis via β-catenin-dependent regulation of ZEB1
复制标题
DOI：
10.1038/s41416-019-0679-z
复制
发表时间：
2020-02-01
影响因子：
8.8
通讯作者：
Shu, Xiaogang
中科院分区：
文献类型：
--
作者：
Wu, Liang;Zhou, Zili;Shu, Xiaogang
背景我们先前证实多形性腺瘤基因样蛋白2（PLAGL 2）参与了先天性巨结肠的发病机制。在几种恶性肿瘤中观察到PLAGL 2表达增强。然而，PLAGL 2的确切功能及其在结直肠癌（CRC）中的潜在机制在很大程度上仍然未知。方法采用免疫组织化学方法检测PLAGL 2的表达。进行了一系列体外和体内实验以揭示PLAGL 2在CRC进展中的作用。结果大肠癌组织中PLAGL 2的表达与EMT相关蛋白的表达显著相关。数据显示PLAGL 2在体外和体内均促进CRC细胞增殖、迁移、侵袭和EMT。PLAGL 2促进ZEB 1的表达。PLAGL 2通过降低β-连环蛋白的磷酸化水平来增强其表达和核转位。β-连环蛋白的缺失中和了由PLAGL 2表达增强引起的ZEB 1调节。小分子抑制剂PNU-74654也削弱了由修饰的PLAGL 2表达引起的ZEB 1的增强。ZEB 1的缺失可阻断大肠癌细胞中PLAGL 2的生物学功能。结论PLAGL 2通过β-catenin依赖性调节ZEB 1介导EMT促进结直肠癌转移。
Background We previously demonstrated that the pleomorphic adenoma gene like-2 (PLAGL2) is involved in the pathogenesis of Hirschsprung disease. Enhanced PLAGL2 expression was observed in several malignant tumours. However, the exact function of PLAGL2 and its underlying mechanism in colorectal cancer (CRC) remain largely unknown. Methods Immunohistochemical analysis of PLAGL2 was performed. A series of in vitro and in vivo experiments were conducted to reveal the role of PLAGL2 in the progression of CRC. Results Enhanced PLAGL2 expression was significantly associated with EMT-related proteins in CRC. The data revealed that PLAGL2 promotes CRC cell proliferation, migration, invasion and EMT both in vitro and in vivo. Mechanistically, PLAGL2 promoted the expression of ZEB1. PLAGL2 enhanced the expression and nuclear translocation of beta-catenin by decreasing its phosphorylation. The depletion of beta-catenin neutralised the regulation of ZEB1 that was caused by enhanced PLAGL2 expression. The small-molecule inhibitor PNU-74654, also impaired the enhancement of ZEB1 that resulted from the modified PLAGL2 expression. The depletion of ZEB1 could block the biological function of PLAGL2 in CRC cells. Conclusions Collectively, our findings suggest that PLAGL2 mediates EMT to promote colorectal cancer metastasis via beta-catenin-dependent regulation of ZEB1.