TWIST1 a new determinant of epithelial to mesenchymal transition in EGFR mutated lung adenocarcinoma.
TWIST1 a new determinant of epithelial to mesenchymal transition in EGFR mutated lung adenocarcinoma.
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DOI：
10.1371/journal.pone.0029954
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Blons H
中科院分区：
文献类型：
--
作者：
Pallier K;Cessot A;Côté JF;Just PA;Cazes A;Fabre E;Danel C;Riquet M;Devouassoux-Shisheboran M;Ansieau S;Puisieux A;Laurent-Puig P;Blons H
转移是一个多步骤的过程，是肺癌患者死亡的主要原因。我们以前的研究表明，EGFR突变与7号染色体上TWIST 1基因位点的拷贝数增加相关。TWIST 1是一种参与胚胎发生的高度保守的发育基因，可在癌症中重新激活，通过上皮向间充质转化（EMT）促进恶性转化和癌症进展。本研究的目的是探讨TWIST 1再激活对EGFR突变肺癌间充质表型获得的可能影响。我们研究了一系列来自高加索非吸烟者的连续肺腺癌，其中手术冷冻样本可用（n = 33），并显示TWIST 1表达与EGFR突变（P<0.001），低CDH1表达（P<0.05）和低无病生存率（P = 0.044）相关。 为了验证TWIST 1是EGFR突变肺癌中EMT的驱动因素，我们使用了五种人肺癌细胞系，并证明EMT和相关细胞迁移率依赖于EGFR突变细胞中TWIST 1的表达。此外，通过EGF修复或通过小RNA技术抑制TWIST 1表达来减少EGFR途径刺激逆转了这种现象。总的来说，我们的体内和体外研究结果支持TWIST 1与EGF通路合作促进EGFR突变肺腺癌的EMT，并且需要大量EGFR突变肺癌患者来进一步确定TWIST 1再激活在该亚组中的预后作用。
Metastasis is a multistep process and the main cause of mortality in lung cancer patients. We previously showed that EGFR mutations were associated with a copy number gain at a locus encompassing the TWIST1 gene on chromosome 7. TWIST1 is a highly conserved developmental gene involved in embryogenesis that may be reactivated in cancers promoting both malignant conversion and cancer progression through an epithelial to mesenchymal transition (EMT). The aim of this study was to investigate the possible implication of TWIST1 reactivation on the acquisition of a mesenchymal phenotype in EGFR mutated lung cancer. We studied a series of consecutive lung adenocarcinoma from Caucasian non-smokers for which surgical frozen samples were available (n = 33) and showed that TWIST1 expression was linked to EGFR mutations (P<0.001), to low CDH1 expression (P<0.05) and low disease free survival (P = 0.044). To validate that TWIST1 is a driver of EMT in EGFR mutated lung cancer, we used five human lung cancer cell lines and demonstrated that EMT and the associated cell mobility were dependent upon TWIST1 expression in cells with EGFR mutation. Moreover a decrease of EGFR pathway stimulation through EGF retrieval or an inhibition of TWIST1 expression by small RNA technology reversed the phenomenon. Collectively, our in vivo and in vitro findings support that TWIST1 collaborates with the EGF pathway in promoting EMT in EGFR mutated lung adenocarcinoma and that large series of EGFR mutated lung cancer patients are needed to further define the prognostic role of TWIST1 reactivation in this subgroup.
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158.5
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