MAPK/AP-1 signal pathway in tobacco smoke-induced cell proliferation and squamous metaplasia in the lungs of rats
MAPK/AP-1 signal pathway in tobacco smoke-induced cell proliferation and squamous metaplasia in the lungs of rats
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DOI：
10.1093/carcin/bgi189
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发表时间：
2005-12-01
期刊：
影响因子：
4.7
通讯作者：
Pinkerton, KE
中科院分区：
文献类型：
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作者：
Zhong, CY;Zhou, YM;Pinkerton, KE
大量证据表明，烟草烟雾(TS)与多种癌症，尤其是肺癌之间存在因果关系。持续性上皮细胞增生和鳞状化生被认为是肺癌形成过程中的癌前病变。TS导致肺癌的细胞和分子机制尚不清楚。丝裂原活化蛋白激酶(MAPK)/激活蛋白-1(AP-1)可被多种刺激激活，在调控细胞增殖和分化中发挥重要作用。到目前为止，关于MAPK/AP-1通路在TS诱导的增生和鳞状化生中的反应的信息还很缺乏。因此，我们研究了TS对大鼠肺上皮细胞增生和鳞状化生的发生、对MAPK/AP-1活性的调节以及AP-1调节的细胞周期蛋白和分化标志物的表达的影响。大鼠暴露于TS(30 mg/m(3)或80 mg/m(3)，每天6小时，每周3天，共14周)可剂量依赖性地诱导细胞增殖和鳞状化生，其作用与AP-1-DNA结合活性的激活平行。TS可使ERK1/2、JNK、p38和ERK5磷酸化水平显著升高，提示这些MAPK通路被激活。TS对Jun和Fos蛋白的表达具有差异性调控作用。TS上调AP-1依赖的细胞周期蛋白的表达，包括细胞周期蛋白D1和增殖细胞核抗原。在AP-1依赖的细胞分化标志物中，角蛋白5和角蛋白14在TS暴露后表达上调，而氯化蛋白、丝状蛋白和总蛋白表达下调。这些发现提示MAPK/AP-1通路在TS诱导的发病机制中具有重要作用，从而为研究TS相关肺部疾病包括肺癌的分子机制提供了新的思路。
Overwhelming evidence has demonstrated tobacco smoke (TS) is causally associated with various types of cancers, especially lung cancer. Sustained epithelial cell hyperplasia and squamous metaplasia are considered as preneoplastic lesions during the formation of lung cancer. The cellular and molecular mechanisms leading to lung cancer due to TS are not clear. Mitogen-activated protein kinases (MAPK)/activator protein-1 (AP-1) can be activated by various stimuli and play a critical role in the control of cell proliferation and differentiation. To date, information on the response of the MAPK/AP-1 pathway during hyperplasia and squamous metaplasia induced by TS is lacking. We therefore investigated the effects of TS on the development of epithelial hyperplasia and squamous metaplasia, regulation of MAPK/AP-1 activation, and expression of AP-1-regulated cell cycle proteins and differentiation markers in the lungs of rats. Exposure of rats to TS (30 mg/m(3) or 80 mg/m(3), 6 h/day, 3 days/week for 14 weeks) dramatically induced cell proliferation and squamous metaplasia in a dose-dependent manner, effects that paralleled the activation of AP-1-DNA binding activity. Phosphorylated ERK1/2, JNK, p38 and ERK5 were significantly increased by exposure to TS, indicating the activation of these MAPK pathways. Expression of Jun and Fos proteins were differentially regulated by TS. TS upregulated the expression of AP-1-dependent cell cycle proteins including cyclin D1 and proliferating cell nuclear antigen (PCNA). Among the AP-1-dependent cell differentiation markers, keratin 5 and 14 were upregulated, while loricrin, filaggrin and involucrin were downregulated following TS exposure. These findings suggest the important role of MAPK/AP-1 pathway in TS-induced pathogenesis, thus providing new insights into the molecular mechanisms of TS-associated lung diseases including lung cancers.