Disruption of adherens junction and alterations in YAP-related proliferation behavior as part of the underlying cell transformation process of alcohol-induced oral carcinogenesis.
Disruption of adherens junction and alterations in YAP-related proliferation behavior as part of the underlying cell transformation process of alcohol-induced oral carcinogenesis.
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粘附连接的破坏和 YAP 相关增殖行为的改变是酒精诱导口腔癌发生的潜在细胞转化过程的一部分
DOI：
10.1016/j.bbamcr.2017.10.015
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Pascal Tomakidi
中科院分区：
文献类型：
--
作者：
Ayman Husari;Diana Hülter-Hassler;Thorsten Steinberg;Simon Daniel Schulz;Pascal Tomakidi
越来越多的证据表明，酒精可能是口腔癌的致病因素。不幸的是，在体外细胞系统中，揭示潜在的细胞转化过程的分子背景是罕见的。因此，进行本研究，以确定分子变化，并表征其假定的细胞行为后果上皮样（EPI）和成纤维细胞（FIB）的口腔角质形成细胞表型，所产生的长期酒精治疗。关于粘附连接（AJs），EPI和FIB均显示膜结合β-catenin，但E-cadherin和zyxin表现出差异。尽管EPI显示E-钙粘蛋白/β-连环蛋白膜共定位，其部分也适用于zyxin，但FIB膜缺乏E-钙粘蛋白并表现出边缘zyxin表达。胎牛血清（FCS）管理饥饿的细胞促进角质形成细胞表型，其中EPI和FIB产生了显着修改FCS的敏感性在时间尺度上的增殖。与EPI（> 45 h）相比，基于阻抗测量的细胞指数检测在FIB（< 20 h）中产生增殖刺激发生得更早。在FIB中增殖相关雅普共转录因子的核偏好性不依赖于FCS，而在EPI中需要FCS。总之，缺乏膜固有的E-钙粘蛋白/β-连环蛋白共定位以及低zyxin -揭示了FIB中AJ完整性的扰动。关于细胞行为，FIB中受干扰的AJs与对FCS的时间增殖敏感性相关。CYF为5.6，强烈提示染色质结合的雅普参与FIB的增殖温度敏感性。EPI和FIB检测到的这些分子差异是酒精诱导的口腔癌发生的潜在细胞转化过程的一部分，并表明FIB处于更高级的转化阶段。
Accumulating evidences indicate that alcohol might play a causative in oral cancer. Unfortunately,in vitrocell systems, uncovering the molecular background of the underlying cell transformation process, are rare. Therefore, this study was conducted, to identify molecular changes and characterize their putative cell behavioral consequences in epitheloid (EPI) and fibroblastoid (FIB) oral keratinocyte phenotypes, arising from chronical alcohol treatment. Concerning adherens junctions (AJs), both EPI and FIB showed membrane-bound β-catenin, but exhibited differences for E-cadherin and zyxin. While EPI revealed E-cadherin/β-catenin membrane co-localization, which in parts also applied for zyxin, FIB membranes were devoid of E-cadherin and exhibited marginal zyxin expression. Fetal calf serum (FCS) administration in starved cells promoted proliferation in both keratinocyte phenotypes, whereat EPI and FIB yielded a strikingly modified FCS sensitivity on the temporal scale. Impedance measurement-based cell index detection yielded proliferation stimulation occurring much earlier in FIB (< 20 h) compared to EPI (> 45 h). Nuclear preference of the proliferation-associated YAP co-transcription factor in FIB was FCS independent, while it required FCS in EPI. Taken together, the lack of membrane-inherent E-cadherin/β-catenin co-localization together with low zyxin - reveals perturbation of AJ integrity in FIB. Regarding cell behavior, perturbed AJs in FIB correlate with temporal proliferation sensitivity towards FCS. CYF of 5.6 strongly suggests involvement of chromatin-bound YAP in FIB's proliferation temperosensitivity. These molecular differences detected for EPI and FIB are part of the underlying cell transformation process of alcohol-induced oral carcinogenesis, and indicate FIB being in a more advanced transformation stage.
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