DLK1 promotes lung cancer cell invasion through upregulation of MMP9 expression depending on Notch signaling.
DLK1 promotes lung cancer cell invasion through upregulation of MMP9 expression depending on Notch signaling.
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DOI：
10.1371/journal.pone.0091509
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Li L;Tan J;Zhang Y;Han N;Di X;Xiao T;Cheng S;Gao Y;Liu Y
跨膜和分泌蛋白δ样1同源物（DLK 1）属于EGF样家族。DLK 1在调节细胞分化，如脂肪形成和骨形成中起重要作用已被广泛接受。DLK 1的异常表达已在包括肺癌在内的各种类型的人类癌症中发现。该实验室以前的一项研究表明，DLK 1与肿瘤侵袭有关，尽管其机制仍不清楚。为了探索DLK 1可能对侵袭的潜在影响，DLK 1在人肺癌细胞系中过表达或敲低。随后评估了蛋白质对细胞侵袭的影响。transwell分析显示DLK 1过表达显著促进癌细胞侵袭。Western blotting和明胶酶谱分析表明DLK 1可以影响基质金属蛋白酶9（MMP 9）的表达及其细胞外活性。对DLK 1刺激或耗竭期间NOTCH 1和HES 1基因表达以及Notch胞内结构域（NICD）核转位的分析表明，DLK 1可以激活肺癌细胞中的Notch信号传导。此外，通过γ-分泌酶抑制剂（GSI）抑制Notch信号，DLK 1刺激诱导的MMP 9表达升高可显著降低。本研究中提供的数据表明，DLK 1可以通过上调MMP 9的表达来促进肺癌细胞的侵袭，这取决于Notch信号传导。
The transmembrane and secreted protein delta-like 1 homolog (DLK1) belongs to the EGF-like family. It is widely accepted that DLK1 plays important roles in regulating cell differentiation, such as adipogenesis and osteogenesis. Aberrant expression of DLK1 has been found in various types of human cancers, including lung cancer. A previous study in this lab has revealed that DLK1 is associated with tumor invasion, although the mechanism is still unknown. To explore the potential effects that DLK1 might have on invasion, DLK1 was overexpressed or knocked down in the human lung cancer cell lines. The protein's influences on cell invasion were subsequently evaluated. A transwell assay showed that DLK1 overexpression significantly promoted cancer cell invasion. Western blotting and gelatin zymography analysis indicated that DLK1 could affect both matrix metalloproteinase-9 (MMP9) expression and its extracellular activity. An analysis of NOTCH1 and HES1 gene expression and Notch intracellular domain (NICD) nuclear translocation during DLK1 stimulation or depletion demonstrated that DLK1 could activate Notch signaling in lung cancer cells. Additionally, the elevated expression of MMP9 induced by DLK1 stimulation could be significantly decreased by inhibiting Notch signaling using γ-secretase inhibitor (GSI). The data presented in this study suggest that DLK1 can promote the invasion of lung cancer cells by upregulating MMP9 expression, which depends on Notch signaling.
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