Fhit Regulates EMT Targets through an EGFR/Src/ERK/Slug Signaling Axis in Human Bronchial Cells
Fhit Regulates EMT Targets through an EGFR/Src/ERK/Slug Signaling Axis in Human Bronchial Cells
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DOI：
10.1158/1541-7786.mcr-13-0386-t
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发表时间：
2014-05-01
影响因子：
5.2
通讯作者：
Nawrocki-Raby, Beatrice
中科院分区：
文献类型：
--
作者：
Joannes, Audrey;Grelet, Simon;Nawrocki-Raby, Beatrice
在许多癌症中，包括肺癌，脆性组氨酸三联体（Fhit）经常减少或丢失。Fhit状态最近被证明与肺癌的体外和体内侵袭性升高相关。上皮-间充质转化（EMT）促进肿瘤细胞侵袭，EMT是肿瘤细胞失去其上皮特征以获得间充质细胞样表型的过程。在这项研究中，Fhit调节EMT的机制被破译。使用Slug敲除、药理学抑制剂PD 98059、PP 1和吉非替尼以及抗EGFR抗体，证明了支气管细胞中的Fhit沉默诱导两个主要EMT相关靶标MMP-9和波形蛋白的过表达，以调节依赖于EGFR/Src/ERK/Slug信号传导途径的细胞侵袭。此外，在Fhit缺陷型肺癌细胞中Fhit的异位表达下调了该途径。最后，在一组人鳞状细胞肺癌标本中观察到Fhit和磷酸化EGFR水平之间呈负相关。这些结果证明了在EMT调节的EGFR信号传导的控制中的Fhit依赖性机制。（C）2014年AACR。
In many cancers, including lung carcinomas, Fragile histidine triad (Fhit) is frequently decreased or lost. Fhit status has recently been shown to be associated with elevated in vitro and in vivo invasiveness in lung cancer. Tumor cell invasion is facilitated by epithelial-mesenchymal transition (EMT), a process by which tumor cells lose their epithelial features to acquire a mesenchymal cell-like phenotype. In this study, the mechanism underlying Fhit-regulated EMT was deciphered. Using Slug knockdown, pharmacologic inhibitors PD98059, PP1, and gefitinib as well as an anti-EGFR antibody, it was demonstrated that Fhit silencing in bronchial cells induced overexpression of two primary EMT-associated targets, MMP-9 and vimentin, to regulate cell invasion dependent on an EGFR/Src/ERK/Slug signaling pathway. Moreover, ectopic expression of Fhit in Fhit-deficient lung cancer cells down-regulated this pathway. Finally, an inverse correlation was observed between Fhit and phospho-EGFR levels in a cohort of human squamous cell lung carcinoma specimens. These results demonstrate a Fhit-dependent mechanism in the control of EMT-regulated EGFR signaling. (C)2014 AACR.