Identification and validation of dysregulated MAPK7 (ERK5) as a novel oncogenic target in squamous cell lung and esophageal carcinoma.
Identification and validation of dysregulated MAPK7 (ERK5) as a novel oncogenic target in squamous cell lung and esophageal carcinoma.
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DOI：
10.1186/s12885-015-1455-y
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发表时间：
2015-06-04
期刊：
影响因子：
3.8
通讯作者：
Ji Q
中科院分区：
文献类型：
--
作者：
Gavine PR;Wang M;Yu D;Hu E;Huang C;Xia J;Su X;Fan J;Zhang T;Ye Q;Zheng L;Zhu G;Qian Z;Luo Q;Hou YY;Ji Q
MAPK 7/ERK 5（细胞外信号调节激酶5）在包括MEK（MAPK/ERK激酶）5、MEKK（MEK激酶）2/3和ERK 5本身的典型三层MAPK（促分裂原活化蛋白激酶）信号级联中起作用。尽管是MAPK模块中研究最少的，但证据支持MAPK 7信号传导在几种癌症类型的病理学中的作用。荧光原位杂交（FISH）分析在4%（3/74）的非小细胞肺癌（NSCLC）（在鳞状细胞癌中富集至6%（3/49））和2%（2/95）的鳞状食管癌（sqEC）中鉴定出MAPK 7基因扩增。免疫组化（IHC）分析显示MAPK 7基因扩增和蛋白表达之间有良好的相关性。通过在肿瘤细胞系中进行MAPK 7的体外siRNA敲低来验证MAPK 7作为增殖致癌驱动剂。最后，开发了一种新的MEK 5/MAPK 7共转染的HEK 293细胞系，并用于常规的基于细胞的药效学筛选。磷酸化抗体微阵列分析还鉴定了肿瘤细胞中MAPK 7激酶抑制的新型下游药效学（PD）生物标志物（pMEF 2A和pMEF 2D）。总之，这些数据突出了失调的MAPK 7在高度流行的肿瘤类型的小生境人群中驱动肿瘤发生的更广泛的作用，并描述了目前在建立强大的药物发现筛选级联方面的努力。本文的在线版本（doi：10.1186/s12885-015-1455-y）包含补充材料，可供授权用户使用。
MAPK7/ERK5 (extracellular-signal-regulated kinase 5) functions within a canonical three-tiered MAPK (mitogen activated protein kinase) signaling cascade comprising MEK (MAPK/ERK kinase) 5, MEKK(MEK kinase) 2/3 and ERK5 itself. Despite being the least well studied of the MAPK-modules, evidence supports a role for MAPK7-signaling in the pathology of several cancer types. Fluorescence in situ hybridization (FISH) analysis identified MAPK7 gene amplification in 4 % (3/74) of non-small cell lung cancers (NSCLC) (enriched to 6 % (3/49) in squamous cell carcinoma) and 2 % (2/95) of squamous esophageal cancers (sqEC). Immunohistochemical (IHC) analysis revealed a good correlation between MAPK7 gene amplification and protein expression. MAPK7 was validated as a proliferative oncogenic driver by performing in vitro siRNA knockdown of MAPK7 in tumor cell lines. Finally, a novel MEK5/MAPK7 co-transfected HEK293 cell line was developed and used for routine cell-based pharmacodynamic screening. Phosphorylation antibody microarray analysis also identified novel downstream pharmacodynamic (PD) biomarkers of MAPK7 kinase inhibition in tumor cells (pMEF2A and pMEF2D). Together, these data highlight a broader role for dysregulated MAPK7 in driving tumorigenesis within niche populations of highly prevalent tumor types, and describe current efforts in establishing a robust drug discovery screening cascade. The online version of this article (doi:10.1186/s12885-015-1455-y) contains supplementary material, which is available to authorized users.
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