Twist1 accelerates tumour vasculogenic mimicry by inhibiting Claudin15 expression in triple-negative breast cancer
Twist1 accelerates tumour vasculogenic mimicry by inhibiting Claudin15 expression in triple-negative breast cancer
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Twist1通过抑制三阴性乳腺癌中Claudin15的表达来加速肿瘤血管生成拟态
DOI：
10.1111/jcmm.15167
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发表时间：
2020
影响因子：
5.3
通讯作者：
Zheng Xu
中科院分区：
文献类型：
--
作者：
Zhang Danfang;Sun Baocun;Zhao Xiulan;Sun Huizhi;An Jindan;Lin Xian;Zhu Dongwang;Zhao Xueming;Wang Xudong;Liu Fang;Zhang Yanhui;Liu Jiameng;Gu Qiang;Dong Xueyi;Qiu Zhiqiang;Liu Zhiyong;Qi Hong;Che Na;Li Jing;Cheng Runfen;Zheng Xu
EMT调节因子Twist1的上调与人类三阴性乳腺癌血管生成拟态(Vm)的形成有关。Twist1靶向肝细胞癌细胞中的Claudin15启动子。Claudin家族成员与TNBC相关。然而，Claudin15与VM形成之间的关系尚不清楚。在这项研究中，我们首次发现Claudin15在人TNBC中的表达经常下调，并且Claudin15的下调与Vm和Twist1的核表达显著相关。与高水平相比，Claudin15表达下调与生存期缩短相关。Claudin15沉默显著增强了非TNBC MCF-7细胞的细胞运动、侵袭力和VM的形成。相反，Claudin15的上调显著减少了TNBC MDA-MB-231细胞的迁移、侵袭和VM的形成。我们还发现Claudin15的下调是Twist1依赖的，Twist1抑制了Claudin15启动子的活性。此外，对Claudin15缺陷小鼠乳腺的基因芯片分析表明，Claudin18和Jun可能是Twist1-Claudin15的下游因子。我们的结果提示Twist1通过抑制Claudin15诱导TNBC的VM，Twist1抑制Claudin15可能与Claudin18和Jun的表达有关。
The up‐regulation of EMT regulator Twist1 has been implicated in vasculogenic mimicry (VM) formation in human triple‐negative breast cancer (TNBC). Twist1 targets the Claudin15 promoter in hepatocellular carcinoma cells. Claudin family members are related with TNBC. However, the relationship between Claudin15 and VM formation is not clear. In this study, we first found that Claudin15 expression was frequently down‐regulated in human TNBC, and Claudin15 down‐regulation was significantly associated with VM and Twist1 nuclear expression. Claudin15 down‐regulation correlated with shorter survival compared with high levels. Claudin15 silence significantly enhanced cell motility, invasiveness and VM formation in the non‐TNBC MCF‐7 cells. Conversely, an up‐regulation of Claudin15 remarkably reduced TNBC MDA‐MB‐231 cell migration, invasion and VM formation. We also showed that down‐regulation of Claudin15 was Twist1‐dependent, and Twist1 repressed Claudin15 promoter activity. Furthermore, GeneChip analyses of mammary glands of Claudin15‐deficient mice indicated that Claudin18 and Jun might be downstream factors of Twist1‐Claudin15. Our results suggest that Twist1 induced VM through Claudin15 suppression in TNBC, and Twist1 inhibition of Claudin15 might involve Claudin18 and Jun expression.