Arsenic activates EGFR pathway signaling in the lung.
Arsenic activates EGFR pathway signaling in the lung.
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DOI：
10.1093/toxsci/kfp015
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发表时间：
2009-06
期刊：
影响因子：
--
通讯作者：
Duell EJ
中科院分区：
文献类型：
--
作者：
Andrew AS;Mason RA;Memoli V;Duell EJ
砷是一种公认的肺癌致癌物，但其致癌机制目前仍在研究中。据报道，在砷暴露的情况下，膀胱细胞中的表皮生长因子受体(EGFR)发生了磷酸化。EGFR是一种酪氨酸激酶跨膜受体，调节肿瘤发生过程中的重要过程，包括细胞存活、细胞周期进展、肿瘤侵袭和血管生成。我们利用体外培养的肺上皮细胞和新英格兰肺癌研究参与者的肺癌样本，研究了与人类暴露场景相关的砷水平对EGFR途径激活的机制。趾甲砷水平被用作砷暴露的内部生物标志物。我们的体外数据表明，砷增加了EGFR配体，即肝素结合EGF的水平，并激活了肺中EGFR的磷酸化。在EGFR下游，砷暴露增加了PERK和细胞周期蛋白D1的水平。用EGFR酪氨酸激酶抑制剂Tarceva(Erlotinib)处理培养细胞可抑制这些作用。在一系列连续的人类肺癌标本中，趾甲砷水平升高的受试者与低暴露水平受试者相比，pEGFR蛋白水平更高(经其他因素调整的优势比OR 4.1(95%可信区间1.1-15.6)(p=0.04)。这些数据表明，砷暴露可能会刺激肺中EGFR途径的激活。此外，暴露于砷的个体中出现的肿瘤也显示出EGFR途径失调的迹象。需要进一步的工作来评估靶向EGFR途径在暴露于高水平砷的肺癌患者亚组中的临床有效性。
Arsenic is an established lung carcinogen, however, the carcinogenic mechanisms are currently under investigation. Phosphorylation of the epidermal growth factor receptor (EGFR) has been reported with arsenic exposure in bladder cells. EGFR is a tyrosine kinase transmembrane receptor that regulates important processes in carcinogenesis, including cell survival, cell cycle progression, tumor invasion, and angiogenesis. We investigated the mechanisms of EGFR pathway activation by levels of arsenic relevant to human exposure scenarios both in vitro using cultured lung epithelial cells, and in lung tumors samples from New England Lung Cancer Study participants. Toenail arsenic levels were used as an internal biomarker of arsenic exposure. Our in vitro data suggest that arsenic increases levels of the EGFR ligand, heparin binding-EGF, and activate EGFR phosphorylation in the lung. Downstream of EGFR, arsenic exposure increased pERK and cyclin D1 levels. These effects were inhibited by treatment of cultured cells with the EGFR tyrosine kinase inhibitor, Tarceva (erlotinib). In a consecutive series of human lung tumor specimens, pEGFR protein levels were higher in subjects with elevated toenail arsenic levels compared to those with low exposure (odds ratio adjusted for other factors, OR 4.1 (95% confidence interval 1.1–15.6) (p = 0.04). These data suggest that arsenic exposure may stimulate EGFR pathway activation in the lung. Moreover, the tumors that arise in arsenic-exposed individuals also exhibit signs of EGFR pathway dysregulation. Further work is needed to assess the clinical utility of targeting the EGFR pathway in subgroups of lung cancer patients who have been exposed to elevated levels of arsenic.
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影响因子：
21.3
作者：
Lin, SY;Makino, K;Hung, MC
通讯作者：
Hung, MC
影响因子：
5
作者：
Karagas, MR;Tosteson, TD;Morris, JS
通讯作者：
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DOI：
10.1007/bf02036470
发表时间：
1995-08-01
期刊：
JOURNAL OF RADIOANALYTICAL AND NUCLEAR CHEMISTRY-ARTICLES
影响因子：
--
作者：
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通讯作者：
BASKETT, CK
影响因子：
254.7
作者：
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通讯作者：
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影响因子：
4.8
作者：
Liu, ZM;Huang, HS
通讯作者：
Huang, HS