Areca nut extract upregulates vimentin by activating PI3K/AKT signaling in oral carcinoma
Areca nut extract upregulates vimentin by activating PI3K/AKT signaling in oral carcinoma
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DOI：
10.1111/j.1600-0714.2010.00978.x
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发表时间：
2011-02-01
影响因子：
3.3
通讯作者：
Chang, Kuo-Wei
中科院分区：
文献类型：
--
作者：
Tseng, Yu-Hsin;Yang, Cheng-Chieh;Chang, Kuo-Wei
背景：槟榔果是一类致癌物。已知槟榔提取物（ANE）可以激活口腔上皮细胞的信号通路。已知丝氨酸/苏氨酸蛋白激酶AKT/pKB （AKT）信号通路的激活在肿瘤过程中是重要的。静脉蛋白是一种间充质中间纤维，是肿瘤进展的调节因子。本研究探讨了ANE在vimentin表达过程中对PI3K/AKT活化的影响。材料和方法：用ANE处理口腔癌细胞，探讨波形蛋白表达的信号变化。对口腔癌组织进行免疫组织化学分析，以研究波形蛋白表达对患者生存的影响。结果：经ANE处理后，OECM-1和Fadu细胞呈成纤维样细胞形态，vimentin表达增加。该处理还诱导OECM-1细胞中AKT和糖原合成酶激酶3 β的磷酸化。阻断磷脂酰肌醇3-激酶(PI3K)/AKT信号通路可使ANE诱导的vimentin表达减弱。然而，它不影响ane介导的细胞外信号调节激酶（ERK）激活或环氧化酶2 （COX-2）上调。发现口腔癌组织样本中波形蛋白和pAKT的表达水平明显高于对照组。没有vimentin表达和AKT磷酸化较弱的肿瘤比高水平表达的肿瘤生存率更高。结论：PI3K/AKT的激活和vimentin的表达是槟槟酒相关口腔癌发生的重要致病级联。
Background:Areca nut is a group I carcinogen. Areca nut extract (ANE) is known to activate signaling pathways in oral epithelial cells. Activation of the serine/threonine protein kinase AKT/pKB (AKT) signaling pathway is known to be important during the neoplastic process. Vimentin is a mesenchymal intermediate filament and a regulator of tumor progression. This study investigated the impact of ANE on PI3K/AKT activation during vimentin expression.Materials and methods:Oral carcinoma cells were treated with ANE to explore the signaling changes underlying vimentin expression. Oral carcinoma tissues were subjected to immunohistochemical analysis to study the implications that vimentin expression has on patient survival.Results:After ANE treatment, the OECM-1 and Fadu cells developed a fibroblastoid morphology and there was an increase in vimentin expression. The treatment also induced the phosphorylation of AKT and glycogen synthase kinase 3 beta in OECM-1 cells. Blockage of phosphatidylinositol 3-kinase (PI3K)/AKT signaling attenuated vimentin expression when it was induced by ANE. However, it did not affect ANE-mediated extracellular signal-regulated kinase (ERK) activation or cyclooxygenase 2 (COX-2) upregulation. Oral carcinoma tissue samples were found to have significantly higher levels of vimentin and pAKT expression than their controls. Tumors exhibiting no vimentin expression and weak AKT phosphorylation were found to be associated with better survival than groups with high levels of expression.Conclusion:Our results imply that PI3K/AKT activation and vimentin expression are important pathogenic cascades in areca-associated oral carcinogenesis.