Evidence for the epidermal growth factor receptor as a target for lung cancer prevention.
Evidence for the epidermal growth factor receptor as a target for lung cancer prevention.
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发表时间：
2002
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通讯作者：
F. Lonardo;K. Dragnev;S. Freemantle;Yan Ma;N. Memoli;David J. Sekula;Elisabeth A Knauth;J. Beebe;E. Dmitrovsky
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作者：
F. Lonardo;K. Dragnev;S. Freemantle;Yan Ma;N. Memoli;David J. Sekula;Elisabeth A Knauth;J. Beebe;E. Dmitrovsky
目的：有必要确定肺癌的预防机制。先前报道了全反式视黄酸（RA）抑制BEAS-2B人支气管上皮细胞的N-亚硝胺-4-（甲基亚硝胺基）-1-（3吡啶基）-1-丁酮（NNK）致癌转化（J. Langenfeld等人，Oncogene，13：1983-1990，1996）。这项研究是为了确定在这种化学预防过程中靶向的途径。实验设计由于表皮生长因子受体（EGFR）过表达在非小细胞肺癌（NSCLC）和支气管癌前病变中常见，因此分别检测BEAS-2B细胞、致癌物转化的BEAS-2B（NNK）细胞和类维生素A化学预防的BEAS-2B（NNK RA）细胞的EGFR表达。研究RA治疗是否直接调节EGFR表达或报告质粒活性。在BEAS-2B细胞中检测了RA对表皮生长因子（EGF）诱导的EGFR-磷酸酪氨酸水平、细胞周期蛋白D1表达和有丝分裂的影响。结果NNK介导的BEAS-2B细胞转化增加了EGFR的表达。RA治疗抑制EGFR表达和报告质粒活性在这些细胞。这种治疗降低了EGF依赖的有丝分裂以及EGFR相关的磷酸酪氨酸水平和细胞周期蛋白D1的表达。这些发现通过突出EGFR作为肺中的化学预防靶点扩展了先前的工作。值得注意的是，尽管暴露于NNK，但RA治疗阻止了EGFR过表达支气管上皮细胞的转化以及生长。在急性NNK暴露后，在观察到EGFR表达增加之前，DNA损伤或氧化应激后出现的p53诱导的物质是明显的。结论：这些发现表明，当基因组损伤的修复不选择EGFR过表达细胞时，有效的化学预防是如何防止支气管上皮细胞的致癌性转化的。这暗示EGFR是暴露于致癌物的支气管上皮细胞的化学预防靶点。
PURPOSE There is a need to identify lung cancer prevention mechanisms. All-trans-retinoic acid (RA) was reported previously to inhibit N-nitrosamine-4-(methylnitrosamino)-1-(3 pyridyl)-1-butanone (NNK) carcinogenic transformation of BEAS-2B human bronchial epithelial cells (J. Langenfeld et al., Oncogene, 13: 1983-1990, 1996). This study was undertaken to identify pathways targeted during this chemoprevention. EXPERIMENTAL DESIGN Because epidermal growth factor receptor (EGFR) overexpression is frequent in non-small cell lung cancers (NSCLC) and bronchial preneoplasia, BEAS-2B cells, carcinogen-transformed BEAS-2B(NNK) cells, and retinoid chemoprevented BEAS-2B(NNK RA) cells were each examined for EGFR expression. Whether RA treatment regulated directly EGFR expression or reporter plasmid activity was studied. RA effects on epidermal growth factor (EGF) induction of EGFR-phosphotyrosine levels, cyclin D1 expression and mitogenesis were examined in BEAS-2B cells. RESULTS Findings reveal that NNK-mediated transformation of BEAS-2B cells increased EGFR expression. RA treatment repressed EGFR expression and reporter plasmid activity in these cells. This treatment reduced EGF-dependent mitogenesis as well as EGFR-associated phosphotyrosine levels and cyclin D1 expression. These findings extend prior work by highlighting EGFR as a chemoprevention target in the lung. Notably, RA treatment prevented transformation as well as outgrowth of EGFR overexpressing bronchial epithelial cells, despite NNK exposure. After acute NNK exposure, p53-induced species that appear after DNA damage or oxidative stress were evident before an observed increase in EGFR expression. CONCLUSIONS These findings indicate how effective chemoprevention prevents carcinogenic transformation of bronchial epithelial cells when repair of genomic damage does not select against EGFR overexpressing cells. This implicates EGFR as a chemoprevention target in the carcinogen-exposed bronchial epithelium.