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.

中文翻译：

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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。

EMT 调节因子 Twist1 的上调与人类三阴性乳腺癌 (TNBC) 的血管生成拟态 (VM) 形成有关。Twist1 靶向肝细胞癌细胞中的 Claudin15 启动子。克劳丁家族成员与TNBC有关系。然而，Claudin15与VM形成之间的关系尚不清楚。在本研究中，我们首先发现Claudin15表达在人类TNBC中频繁下调，并且Claudin15下调与VM和Twist1核表达显着相关。与高水平相比，Claudin15 下调与较短的生存期相关。Claudin15 沉默显着增强非 TNBC MCF-7 细胞中的细胞运动性、侵袭性和 VM 形成。相反，Claudin15 的上调显着减少了 TNBC MDA-MB-231 细胞迁移、侵袭和 VM 形成。我们还表明，Claudin15 的下调是 Twist1 依赖性的，并且 Twist1 抑制了 Claudin15 启动子活性。此外，对 Claudin15 缺陷小鼠乳腺的 GeneChip 分析表明，Claudin18 和 Jun 可能是 Twist1-Claudin15 的下游因子。我们的结果表明，Twist1 通过抑制 TNBC 中的 Claudin15 诱导 VM，而 Twist1 对 Claudin15 的抑制可能涉及 Claudin18 和 Jun 的表达。