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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。

Twist1 accelerates tumour vasculogenic mimicry by inhibiting Claudin15 expression in triple-negative breast cancer.

机构信息

Department of Pathology, Tianjin Medical University, Tianjin, China.

Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China.

出版信息

J Cell Mol Med. 2020 Jul;24(13):7163-7174. doi: 10.1111/jcmm.15167. Epub 2020 May 29.

DOI:10.1111/jcmm.15167
PMID:32469152
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7339217/
Abstract

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.

摘要

EMT 调节因子 Twist1 的上调与人类三阴性乳腺癌(TNBC)中的血管生成拟态(VM)形成有关。Twist1 靶向肝癌细胞中的 Claudin15 启动子。Claudin 家族成员与 TNBC 有关。然而,Claudin15 与 VM 形成之间的关系尚不清楚。在这项研究中,我们首先发现 Claudin15 在人类 TNBC 中表达经常下调,Claudin15 的下调与 VM 和 Twist1 核表达显著相关。Claudin15 的下调与较短的生存期相关,与高水平相比。Claudin15 沉默显着增强了非 TNBC MCF-7 细胞的细胞迁移、侵袭和 VM 形成。相反,Claudin15 的上调显着降低了 TNBC MDA-MB-231 细胞的迁移、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 Claudin15 启动子活性。此外,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。我们的研究结果表明,Twist1 通过 TNBC 中 Claudin15 的抑制诱导 VM,而 Twist1 抑制 Claudin15 可能涉及 Claudin18 和 Jun 的表达。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/889d/7339217/a6f97bc3913e/JCMM-24-7163-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/889d/7339217/e9f678686b4c/JCMM-24-7163-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/889d/7339217/35b75927cfac/JCMM-24-7163-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/889d/7339217/ef86d7e30b77/JCMM-24-7163-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/889d/7339217/0b6ab7adcc5d/JCMM-24-7163-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/889d/7339217/a6f97bc3913e/JCMM-24-7163-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/889d/7339217/e9f678686b4c/JCMM-24-7163-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/889d/7339217/35b75927cfac/JCMM-24-7163-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/889d/7339217/ef86d7e30b77/JCMM-24-7163-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/889d/7339217/0b6ab7adcc5d/JCMM-24-7163-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/889d/7339217/a6f97bc3913e/JCMM-24-7163-g006.jpg

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