Mitogen- and stress-activated Kinase 1 mediates Epstein-Barr virus latent membrane protein 1-promoted cell transformation in nasopharyngeal carcinoma through its induction of Fra-1 and c-Jun genes.
Mitogen- and stress-activated Kinase 1 mediates Epstein-Barr virus latent membrane protein 1-promoted cell transformation in nasopharyngeal carcinoma through its induction of Fra-1 and c-Jun genes.
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丝裂原和应激激活激酶 1 通过诱导 Fra-1 和 c-Jun 基因介导 Epstein-Barr 病毒潜伏膜蛋白 1 促进鼻咽癌细胞转化
DOI：
10.1186/s12885-015-1398-3
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发表时间：
2015-05-10
期刊：
影响因子：
3.8
通讯作者：
He Z
中科院分区：
文献类型：
--
作者：
Li B;Wan Z;Huang G;Huang Z;Zhang X;Liao D;Luo S;He Z
丝裂原和应激激活的激酶1(MSK1)是一种核蛋白，在细胞外信号和基因表达的初级反应之间起着活跃的连接作用。然而，MSK1在恶性转化和癌症发展中的作用还不是很清楚。本研究旨在探讨MSK1在EB病毒(EBV)潜伏膜蛋白1(LMP1)促鼻咽癌发生中的作用。采用免疫组织化学方法检测鼻咽癌组织和正常鼻咽组织中Thr581位MSK1的磷酸化水平，并分析其与鼻咽癌组织和鼻咽癌细胞系中LMP1的相关性。以MSK1抑制剂H89或小干扰RNA(SiRNA)-MSK1分别用CCK-8比色法、流式细胞仪和病灶形成实验检测MSK1对LMP1促进的CNE1细胞增殖和转化的影响。此外，通过报告基因分析和Western blotting分析，确定了MSK1介导组蛋白H3在Ser10处的磷酸化对Fra-1或c-jun启动子活性和表达的调节作用。免疫组织化学分析显示，低分化鼻咽癌组织中Thr581位MSK1的磷酸化水平显著高于正常鼻咽组织(P <； 0.001)。此外，在鼻咽癌组织和鼻咽癌细胞系中，高水平的磷酸化MSK1与LMP1的表达呈正相关(r = 0.393，P = 0.002)。MSK1抑制剂H89或siRNA阻断MSK1可显著抑制LMP1促进的CNE1细胞增殖，这与诱导细胞周期停滞于G0/G1期有关。此外，在MSK1基因敲除细胞中，LMP1促进的锚定非依赖性生长被阻断。当抑制MSK1的活性或表达时，LMP1诱导的Fra-1和c-jun的启动子活性及其蛋白水平显著降低。结果发现，与模型细胞相比，只有H3WT而不是突变体H3S10A显著增加LMP1对Fra-1和c-jun基因的诱导。MSK1活性的升高对LMP1促进鼻咽癌细胞增殖和转化具有重要意义，这可能与其通过Ser10位组蛋白H3的磷酸化而诱导Fra-1和c-jun的表达有关。
Mitogen- and Stress-Activated Kinase 1 (MSK1) is a nuclear kinase that serves as active link between extracellular signals and the primary response of gene expression. However, the involvement of MSK1 in malignant transformation and cancer development is not well understood. In this study, we aimed to explore the role of MSK1 in Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1)-promoted carcinogenesis of nasopharyngeal carcinoma (NPC). The level of MSK1 phosphorylation at Thr581 was detected by the immunohistochemical analysis in NPC tissues and normal nasopharynx tissues, and its correlation with LMP1 was analyzed in NPC tissues and cell lines. Using MSK1 inhibitor H89 or small interfering RNA (siRNA)-MSK1, the effects of MSK1 on LMP1-promoted CNE1 cell proliferation and transformation were evaluated by CCK-8 assay, flow cytometry and focus-forming assay respectively. Furthermore, the regulatory role of MSK1-mediated histone H3 phosphorylation at Ser10 on the promoter activity and expression of Fra-1 or c-Jun was determined by reporter gene assay and western blotting analysis. Immunohistochemical analysis revealed that the level of MSK1 phosphorylation at Thr581 was significantly higher in the poorly differentiated NPC tissues than that in normal nasopharynx tissues (P < 0.001). Moreover, high level of phosphorylated MSK1 was positively correlated with the expression of LMP1 in NPC tissues (r = 0.393, P = 0.002) and cell lines. MSK1 inhibitor H89 or knockdown of MSK1 by siRNA dramatically suppressed LMP1-promoted CNE1 cell proliferation, which was associated with the induction of cell cycle arrest at G0/G1 phase. In addition, the anchorage-independent growth promoted by LMP1 was blocked in MSK1 knockdown cells. When the activity or expression of MSK1 was inhibited, LMP1-induced promoter activities of Fra-1 and c-Jun as well as their protein levels were greatly reduced. It was found that only H3 WT, but not mutant H3 S10A, dramatically increased LMP1 induction of Fra-1 and c-Jun genes compared with mock cells. Increased MSK1 activity is critically important for LMP1-promoted cell proliferation and transformation in NPC, which may be correlated with its induction of Fra-1 and c-Jun through phosphorylation of histone H3 at Ser10.
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影响因子：
2.4
作者：
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通讯作者：
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