Hypoxia increases the motility of lung adenocarcinoma cell line A549 via activation of the epidermal growth factor receptor pathway
Hypoxia increases the motility of lung adenocarcinoma cell line A549 via activation of the epidermal growth factor receptor pathway
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DOI：
10.1111/j.1349-7006.2007.00428.x
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发表时间：
2007-04-01
期刊：
影响因子：
5.7
通讯作者：
Fukayama, Masashi
中科院分区：
文献类型：
--
作者：
Wang, Tao;Niki, Toshiro;Fukayama, Masashi
肿瘤缺氧与癌细胞的恶性表型和患者预后不良相关。为了研究缺氧在肿瘤进展中的作用，我们研究了缺氧对A549肺腺癌细胞系的影响。首先，我们发现低氧处理降低了细胞间的粘附，并诱导了癌细胞的分散。伴随着这些形态学变化，癌细胞的运动性增加，如Boyden室测定所示。然后，我们使用寡核苷酸阵列分析，以确定与缺氧诱导的运动表型的因果关系的基因。结果表明，约100个基因的表达诱导缺氧超过5倍。其中包括表皮生长因子受体（EGFR），以及其他众所周知的缺氧诱导基因，如血管内皮生长因子。原发性肺腺癌的免疫组织化学分析证实了EGFR在坏死区域附近的肿瘤细胞中的诱导，这是肿瘤缺氧的组织学指标。值得注意的是，EGFR抑制剂AG1478（10 μ M）完全阻断了缺氧诱导的细胞运动性增加。因此，本研究证明了EGFR途径在缺氧肿瘤环境中发生的癌细胞运动性增加中的重要性。
Tumor hypoxia is associated with a malignant phenotype of cancer cells and poor patient prognosis. To investigate the role of hypoxia in tumor progression, we studied the effects of hypoxia in the A549 lung adenocarcinoma cell line. First, we showed that hypoxic treatment decreased cell-cell adhesion and induced a scattering of cancer cells. Concomitant with these morphological changes, the motility of cancer cells was increased, as demonstrated by the Boyden chamber assay. Then, we used oligonucleotide array analyses to identify the genes causally related to the hypoxia-induced motile phenotype. The results showed that the expression of approximately 100 genes was induced more than 5-fold by hypoxia. These included (among others) epidermal growth factor receptor (EGFR), as well as other well-known hypoxia-induced genes, such as vascular endothelial growth factor. Immunohistochemical analyses of primary lung adenocarcinomas confirmed the induction of EGFR in tumor cells in the vicinity of necrotic areas, a histological indicator of tumor hypoxia. Remarkably, the EGFR inhibitor AG1478 (10 mu M) completely blocked the increased cell motility induced by hypoxia. Thus, the present study demonstrates the importance of the EGFR pathway in the increased motility of cancer cells that occurs in a hypoxic tumor environment.