DJ-1 upregulates breast cancer cell invasion by repressing KLF17 expression.
DJ-1 upregulates breast cancer cell invasion by repressing KLF17 expression.
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DOI：
10.1038/bjc.2014.40
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发表时间：
2014-03-04
影响因子：
8.8
通讯作者：
Hong, S-H
中科院分区：
文献类型：
--
作者：
Ismail, I. A.;Kang, H. S.;Lee, H-J;Kim, J-K;Hong, S-H
DJ-1（PARK 7）被报道为Ras依赖性的癌基因。最近的研究表明，DJ-1刺激细胞增殖，细胞侵袭和癌症转移。然而，DJ-1诱导癌细胞侵袭和转移的分子机制尚不清楚。用DJ-1 siRNA或DJ-1过表达转染乳腺癌细胞，以研究DJ-1对KLF 17表达的影响。进行ID-1荧光素酶启动子测定以评价DJ-1依赖性KLF 17表达变化。此外，进行DJ-1和KLF 17的上位性分析以评估它们的调节相互作用。Ras抑制剂被预处理以确定DJ-1是否以Ras依赖性方式调节细胞侵袭。在本研究中，我们发现与非转移性细胞相比，DJ-1在高度侵袭性乳腺癌细胞中的表达增加。此外，DJ-1通过下调E-cadherin和增加Snail表达促进乳腺癌细胞侵袭。有趣的是，外源性DJ-1过表达显著降低了EMT负调控因子KLF 17的mRNA和蛋白表达。这些数据得到了ID-1启动子活性的证实，该启动子活性直接受DJ-1依赖性KLF 17转录因子的调节。上位性分析表明，KLF 17过表达克服了DJ-1增加的细胞侵袭，表明KLF 17可能是DJ-1的下游信号分子之一。Ras抑制剂可减轻DJ-1对细胞侵袭的加速作用，表明DJ-1与Ras协同作用增加细胞侵袭。总之，这些数据首次表明DJ-1通过调节KLF 17/ID-1通路在乳腺癌细胞中充当EMT阳性调节剂。
DJ-1 (PARK7) was reported as an oncogene in a Ras-dependent manner. Recent studies have shown that DJ-1 stimulates cell proliferation, cell invasion, and cancer metastasis. However, the molecular mehchanism by which DJ-1 induces cancer cell invasion and metastasis remains unclear. Breast cancer cells were transfected with DJ-1 siRNA or DJ-1 overexpression to investigate the effect of DJ-1 on KLF17 expression. ID-1 luciferase promoter assay was performed to evaluate DJ-1-dependent KLF17 expression changes. In addition, Epistasis analysis of DJ-1 and KLF17 was performed to evaluate their regulatory interactions. Ras inhibitors were pretreated to determine whether DJ-1 regulates cell invasion in a Ras-dependent manner. In the present study, we found increased DJ-1 expression in highly invasive breast cancer cells as compared with non-metastatic cells. Furthermore, DJ-1 promoted breast cancer cell invasion by downregulating E-cadherin and increasing Snail expression. Interestingly, exogenous DJ-1 overexpression markedly decreased mRNA and protein expression of KLF17, the EMT negative regulator. These data were confirmed by ID-1 promoter activity, which is directly regulated by DJ-1-dependent KLF17 transcription factor. Epistasis analysis showed that KLF17 overexpression overcomes increased cell invasion by DJ-1, suggesting that KLF17 might be one of the downstream signalling molecules of DJ-1. Acceleration of cell invasion by DJ-1 was alleviated by Ras inhibitors, suggesting that DJ-1 cooperates with Ras to increase cell invasion. Altogether, these data suggest for the first time that DJ-1 acts as an EMT-positive regulator in breast cancer cells via regulation of the KLF17/ID-1 pathway.
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影响因子：
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