Claudin-3 expression increases the malignant potential of lung adenocarcinoma cells: role of epidermal growth factor receptor activation.
Claudin-3 expression increases the malignant potential of lung adenocarcinoma cells: role of epidermal growth factor receptor activation.
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Claudin-3表达增加肺腺癌细胞的恶性潜能：表皮生长因子受体激活的作用
DOI：
10.18632/oncotarget.14974
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发表时间：
2017-04-04
期刊：
影响因子：
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通讯作者：
Wang C
中科院分区：
文献类型：
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作者：
Zhang L;Wang Y;Zhang B;Zhang H;Zhou M;Wei M;Dong Q;Xu Y;Wang Z;Gao L;Qu Y;Shi B;Zhu J;Yin Y;Chen Y;Sun L;Zhang W;Xu S;Ying G;Wang C
claudin对于紧密连接（TJ）的形成和维持至关重要。claudin蛋白表达的改变已在多种恶性肿瘤中被描述。然而，这些蛋白在肺腺癌（ADC）中的改变尚不清楚。因此，我们报告，基于275例患者样本的蛋白表达分析，CLDN3在ADC组织中的表达显著升高，并与癌症进展相关，与ADC患者的不良生存率显著相关（p=0.041&0.029）。更重要的是，在没有内源性CLDN3表达的ADC细胞中，强迫CLDN3表达导致细胞增殖、锚定依赖性生长、迁移和耐药性显著增加。此外，表皮生长因子（EGF）信号通路调节了许多实体瘤中claudin的表达。然而，EGF在ADC中紧密结调控的机制尚不清楚。为了研究这种机制，我们用EGF及其抑制剂处理ADC细胞系。EGF通过MEK/ERK或PI3K/Akt信号通路调节CLDN3的表达，这是维持基线CLDN3表达所必需的。此外，在ADC细胞中发现下调CLDN3表达可阻止egf诱导的细胞增殖增加。总之，我们的研究结果证明了CLDN3过表达在促进肺腺癌恶性潜能中的新作用。该功能可能受到egf激活的MEK/ERK和PI3K-Akt通路的调控。
Claudins are essential for the formation and maintenance of tight junctions (TJ). The altered expression of claudin proteins has been described in a variety of malignancies. However, the alteration of these proteins in lung adenocarcinoma (ADC) are poorly understood. Therefore, we report, based on the protein expression analysis of a total of 275 patient samples, that claudin-3 (CLDN3) expression is significantly increased in ADC tissues and is associated with cancer progression, correlating significantly with the poor survival of ADC patients (p=0.041&0.029). More importantly, forcing CLDN3 expression in ADC cells without endogenous CLDN3 expression resulted in significant increases in the cell proliferation, anchorage-dependent growth, migration and drug-resistance. In addition, epidermal growth factor (EGF) signaling pathway modulates the expression of claudins in a number of solid tumors. However, the mechanism of tight junction regulation by EGF in ADC remains unclear. To investigate this mechanisms, ADC cell lines were treated with EGF and its inhibitor. EGF unregulated CLDN3 expression via the MEK/ERK or PI3K/Akt signaling pathways and was required for the maintenance of baseline CLDN3 expression. Furthermore, downregulation of CLDN3 expression in ADC cell was found to prevent the EGF-induced increase in cell proliferation. In conclusion, our results demonstrate a novel role of CLDN3 overexpression in promoting the malignant potential of lung adenocarcinoma. This function is potentially regulated by the EGF-activated MEK/ERK and PI3K-Akt pathways.