DCLK1 Plays a Metastatic-Promoting Role in Human Breast Cancer Cells
DCLK1 Plays a Metastatic-Promoting Role in Human Breast Cancer Cells
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DCLK1 在人类乳腺癌细胞中发挥促进转移的作用。
DOI：
10.1155/2019/1061979
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发表时间：
2019-01-01
影响因子：
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通讯作者：
An, Guangyu
中科院分区：
文献类型：
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作者：
Liu, Heshu;Wen, Tao;An, Guangyu
背景双皮质素样激酶1（DCLK 1）已被普遍确定为癌症干细胞（CSC）标志物，并发现在包括乳腺癌在内的许多类型的癌症中过表达。然而，关于DCLK 1在乳腺癌转移中的功能作用的数据很少。在本研究中，我们试图研究DCLK 1是否以及如何在人类乳腺癌细胞中发挥转移促进作用。方法.我们使用Crispr/Cas9技术在乳腺癌细胞系BT474中敲除DCLK 1，该细胞系基本上以较高水平表达DCLK 1，并在另一种乳腺癌细胞系T47 D中稳定过表达DCLK 1，该细胞系基本上以较低水平表达DCLK 1。我们进一步分析了这些细胞转移特性的改变和潜在的机制。结果结果表明，与相应的对照细胞相比，DCLK 1过表达导致T47 D细胞的转移行为增加，包括增强的迁移和侵袭。相比之下，DCLK 1的强制耗竭显著抑制BT474细胞中的这些转移特性。从机制上讲，上皮-间充质转化（EMT）程序，这是癌症转移的关键，在DCLK 1过表达的癌细胞中被显著激活，这通过上皮标志物ZO-1的减少和几种间充质标志物（包括ZEB 1和波形蛋白）的增强来证明。此外，DCLK 1过表达诱导ERK MAPK通路，其结果是增强MT 1-MMP的表达，其也参与癌转移。敲除DCLK 1可以逆转这些事件，进一步支持DCLK 1的转移促进作用。结论.总的来说，我们的数据表明，DCLK 1过表达可能是乳腺癌细胞转移特征增加的原因。靶向DCLK 1可能成为乳腺癌转移的治疗选择。
Background. Doublecortin-like kinase 1 (DCLK1) has been universally identified as a cancer stem cell (CSC) marker and is found to be overexpressed in many types of cancers including breast cancer. However, there is little data regarding the functional role of DCLK1 in breast cancer metastasis. In the present study, we sought to investigate whether and how DCLK1 plays a metastatic-promoting role in human breast cancer cells. Methods. We used Crispr/Cas9 technology to knock out DCLK1 in breast cancer cell line BT474, which basically possesses DCLK1 at a higher level, and stably overexpressed DCLK1 in another breast cancer cell line, T47D, that basically expresses DCLK1 at a lower level. We further analyzed the alterations of metastatic characteristics and the underlying mechanisms in these cells. Results. It was shown that, compared with the corresponding control cells, DCLK1 overexpression led to an increase in metastatic behaviors including enhanced migration and invasion of T47D cells. By contrast, forced depletion of DCLK1 drastically inhibited these metastatic characteristics in BT474 cells. Mechanistically, the epithelial-mesenchymal transition (EMT) program, which is critical for cancer metastasis, was prominently activated in DCLK1-overexpressing cancer cells, evidenced by a decrease in an epithelial marker ZO-1 and an enhancement in several mesenchymal markers including ZEB1 and Vimentin. In addition, DCLK1 overexpression induced the ERK MAPK pathway, which resultantly enhanced the expression of MT1-MMP that is also involved in cancer metastasis. Knockout of DCLK1 could reverse these events, further supporting a metastatic-promoting role for DCLK1. Conclusions. Collectively, our data suggested that DCLK1 overexpression may be responsible for the increased metastatic features in breast cancer cells. Targeting DCLK1 may become a therapeutic option for breast cancer metastasis.