Dual specificity phosphatase 6 (DUSP6) is an ETS-regulated negative feedback mediator of oncogenic ERK signaling in lung cancer cells
Dual specificity phosphatase 6 (DUSP6) is an ETS-regulated negative feedback mediator of oncogenic ERK signaling in lung cancer cells
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DOI：
10.1093/carcin/bgq020
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发表时间：
2010-04-01
期刊：
影响因子：
4.7
通讯作者：
Halmos, Balazs
中科院分区：
文献类型：
--
作者：
Zhang, Zhenfeng;Kobayashi, Susumu;Halmos, Balazs
丝裂原活化蛋白激酶（MAPK）信号通路在大多数非小细胞肺癌（NSCLC）中起重要作用。在NSCLC细胞系中表皮生长因子受体（EGFR）抑制的先前微阵列分析中，我们注意到几种双特异性磷酸酶（DUSPs）是最高度和最直接调节的基因之一。DUSPs作为MAPK信号转导的天然终止子，因此，我们假设通过反馈机制发挥肿瘤抑制作用。在目前的研究中，我们专注于DUSP 6的评估，DUSP 6是一种对细胞外信号调节激酶（ERK）具有高度特异性的细胞质DUSP。我们证明，DUSP 6的表达跟踪串联ERK抑制和DUSP 6的调节是介导的启动子水平的ETS 1，一个众所周知的核靶激活ERK。在DUSP 6-高H441肺癌细胞中的小干扰RNA敲低显著增加ERK活化和细胞增殖，而在DUSP 6-低H1975肺癌细胞中质粒驱动的过表达显著降低ERK活化和细胞增殖并促进凋亡。此外，在EGFR突变型HCC 827细胞中，DUSP 6过表达与EGFR抑制剂治疗协同作用。我们的研究结果表明，DUSP 6的表达受到ERK信号的调节，DUSP 6通过负反馈调节发挥抗肿瘤作用，这表明NSCLC中存在一个重要的反馈回路。评估DUSP 6的肿瘤抑制作用和旨在调节其活性的策略的进一步研究是必要的。
Mitogen-activated protein kinase (MAPK) pathway signaling plays an important role in the majority of non-small-cell lung cancers (NSCLCs). In a prior microarray analysis of epidermal growth factor receptor (EGFR) inhibition in NSCLC cell lines, we noted that several dual specificity phosphatases (DUSPs) were among the most highly and immediately regulated genes. DUSPs act as natural terminators of MAPK signal transduction and therefore, we hypothesized a tumor suppressive role via feedback mechanisms. In the current study, we focus on the assessment of DUSP6, a cytoplasmic DUSP with high specificity for extracellular signal-regulated kinase (ERK). We demonstrate that DUSP6 expression tracks in tandem with ERK inhibition and that regulation of DUSP6 is mediated at the promoter level by ETS1, a well-known nuclear target of activated ERK. Small interfering RNA knockdown in DUSP6-high H441 lung cancer cells significantly increased ERK activation and cellular proliferation, whereas plasmid-driven overexpression in DUSP6-low H1975 lung cancer cells significantly reduced ERK activation and cellular proliferation and promoted apoptosis. Also, DUSP6 overexpression synergized with EGFR inhibitor treatment in EGFR-mutant HCC827 cells. Our results indicate that DUSP6 expression is regulated by ERK signaling and that DUSP6 exerts antitumor effects via negative feedback regulation, pointing to an important feedback loop in NSCLC. Further studies assessing the tumor suppressive role of DUSP6 and strategies aimed at modulation of its activity are warranted.