Lee Mei-Yi, Chou Cheng-Yang, Tang Ming-Jer, Shen Meng-Ru
Institute of Basic Medical Sciences, Department of Obstetrics and Gynecology, National Cheng Kung University, Tainan, Taiwan.
Clin Cancer Res. 2008 Aug 1;14(15):4743-50. doi: 10.1158/1078-0432.CCR-08-0234.
Acquisition of epithelial-mesenchymal transition (EMT) by primary carcinoma cells is associated with disrupted epithelial integrity, local invasion, and ultimately metastasis. Little is known about the existence and function of EMT in cervical cancer. This study aims to investigate the regulation of EMT in cervical squamous cell carcinoma.
We investigated the molecular events of EMT in surgical specimens, which present the progression of cervical carcinoma. Two cervical cancer cell lines and the primary culture of normal cervical epithelia were used to study the regulatory mechanisms of EMT.
The chronic epidermal growth factor (EGF) treatment induces the elongation of cell shape, increases cell scattering, and enhances cell invasion. EGF treatment down-regulates E-cadherin and up-regulates vimentin in cervical cancer cells. These characteristics are consistent with the morphologic changes, molecular events, and functional significance of EMT. EGF receptor (EGFR) signaling inactivates glycogen synthase kinase-3beta, which results in the nuclear accumulation of up-regulated Snail and then leads to EMT program. alpha(5)beta(1) integrin signaling and extracellular matrix fibronectin can modulate EGF-induced EMT. Importantly, the immunofluorescent stainings of surgical specimens indicate that cervical carcinoma progression is accompanied by EGFR overexpression, which is in parallel with decreased E-cadherin and increased vimentin. Up-regulation and nuclear accumulation of Snail correlate with EMT program in tumor tissues.
EGF cooperates with alpha(5)beta(1) integrin signaling to induce EMT in cervical cancer cells via up-regulated Snail. Blockade of EGFR activity or expression may provide a potential target for the treatment of cervical cancer progression.
原发性癌细胞发生上皮-间质转化（EMT）与上皮完整性破坏、局部侵袭及最终转移相关。关于EMT在宫颈癌中的存在及功能知之甚少。本研究旨在探讨宫颈癌中EMT的调控机制。
我们研究了手术标本中EMT的分子事件，这些标本呈现了宫颈癌的进展情况。使用两种宫颈癌细胞系及正常宫颈上皮的原代培养物来研究EMT的调控机制。
慢性表皮生长因子（EGF）处理可诱导细胞形态伸长、增加细胞散射并增强细胞侵袭。EGF处理可下调宫颈癌细胞中的E-钙黏蛋白并上调波形蛋白。这些特征与EMT的形态学变化、分子事件及功能意义一致。表皮生长因子受体（EGFR）信号通路使糖原合酶激酶-3β失活，导致上调的Snail核内积聚，进而引发EMT程序。α5β1整合素信号通路及细胞外基质纤连蛋白可调节EGF诱导的EMT。重要的是，手术标本的免疫荧光染色表明宫颈癌进展伴随着EGFR过表达，这与E-钙黏蛋白减少及波形蛋白增加平行。Snail的上调及核内积聚与肿瘤组织中的EMT程序相关。
EGF与α5β1整合素信号通路协同作用，通过上调Snail诱导宫颈癌细胞发生EMT。阻断EGFR活性或表达可能为治疗宫颈癌进展提供潜在靶点。
