The role of the c-Jun N-terminal kinase 2-α-isoform in non-small cell lung carcinoma tumorigenesis.
The role of the c-Jun N-terminal kinase 2-α-isoform in non-small cell lung carcinoma tumorigenesis.
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DOI：
10.1038/onc.2010.414
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发表时间：
2011-01-13
期刊：
影响因子：
8
通讯作者：
Wong AJ
中科院分区：
文献类型：
--
作者：
Nitta RT;Del Vecchio CA;Chu AH;Mitra SS;Godwin AK;Wong AJ
c-Jun N-末端激酶（JNK）是丝裂原活化蛋白激酶家族的成员，并且与肿瘤发生有关。特别是一种亚型JNK 2 α，已被证明在原发性脑肿瘤中经常被激活，以增强几种致瘤表型并增加小鼠中的肿瘤形成。由于JNK在非小细胞肺癌（NSCLC）中经常被激活，我们通过检测JNK 2 α亚型在原发性肿瘤中的表达和调节其在培养细胞系中的表达来研究JNK 2 α亚型在NSCLC形成中的作用。我们发现，60%的受试原发性NSCLC肿瘤的JNK 2蛋白表达是正常肺对照组织的3倍，JNK 2 α mRNA表达是正常肺对照组织的2 - 3倍。为了确定JNK 2 α在NSCLC进展中的重要性，我们使用短发夹RNA降低了多种NSCLC细胞系中JNK 2 α的表达。缺乏JNK 2 α的细胞系细胞生长和锚定非依赖性生长减少，肿瘤质量减少4倍。为了阐明JNK 2 α诱导NSCLC生长的机制，我们分析了JNK底物、信号转导子和转录激活子3（STAT 3）。我们的数据首次证明JNK 2 α可以通过磷酸化Ser 727残基来调节STAT 3的转录活性，从而调节致癌基因如c-Myc的表达。此外，重新引入JNK 2 α2或STAT 3可以恢复NSCLC细胞的致瘤性，这表明JNK 2 α对NSCLC进展很重要。我们的研究揭示了一种新的机制，其中STAT 3的磷酸化是由组成型活性JNK 2亚型JNK 2 α介导的。
The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase family and have been implicated in tumorigenesis. One isoform in particular, JNK2α, has been shown to be frequently activated in primary brain tumors, to enhance several tumorigenic phenotypes and to increase tumor formation in mice. As JNK is frequently activated in non-small cell lung carcinoma (NSCLC), we investigated the role of the JNK2α isoform in NSCLC formation by examining its expression in primary tumors and by modulating its expression in cultured cell lines. We discovered that 60% of the tested primary NSCLC tumors had three-fold higher JNK2 protein and two- to three-fold higher JNK2α mRNA expression than normal lung control tissue. To determine the importance of JNK2α in NSCLC progression, we reduced JNK2α expression in multiple NSCLC cell lines using short hairpin RNA. Cell lines deficient in JNK2α had decreased cellular growth and anchorage-independent growth, and the tumors were four-fold smaller in mass. To elucidate the mechanism by which JNK2α induces NSCLC growth, we analyzed the JNK substrate, signal transducer and activator of transcription 3 (STAT3). Our data demonstrates for the first time that JNK2α can regulate the transcriptional activity of STAT3 by phosphorylating the Ser727 residue, thereby regulating the expression of oncogenic genes, such as c-Myc. Furthermore, reintroduction of JNK2α2 or STAT3 restored the tumorigenicity of the NSCLC cells, demonstrating that JNK2α is important for NSCLC progression. Our studies reveal a novel mechanism in which phosphorylation of STAT3 is mediated by a constitutively active JNK2 isoform, JNK2α.
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