Han Ming, Xu Wanpeng
1 School of Clinical Medicine, Weifang Medical University, Weifang, China.
2 Department of Gastrointestinal and Anal Diseases Surgery, Affiliated Hospital of Weifang Medical University, Weifang, China.
Tumour Biol. 2017 Jul;39(7):1010428317718404. doi: 10.1177/1010428317718404.
In this study, we aimed to explore new downstream effectors of TWIST1/2 in inducing epithelial-to-mesenchymal transition in gastric cancer. Bioinformatic data mining was performed using data in The Cancer Genome Atlas Stomach Adenocarcinoma. Survival curves were generated using Kaplan-Meier plotter. Gastric cancer cell lines (AGS and SGC-7901) were used as in vitro cell model to investigate the regulative effect of TWIST1/2 on epithelial membrane protein 3 expression and the progression of epithelial-to-mesenchymal transition. Results showed that TWIST1 and TWIST2 are usually co-upregulated in patients with primary gastric cancer. High TWIST1 expression is associated with worse overall survival (hazard ratio = 1.26; 95% confidence interval = 1.06-1.49; p = 0.007) and also worse first progression-free survival (hazard ratio = 1.47; 95% confidence interval = 1.18-1.82; p < 0.0001). Similarly, high TWIST2 expression is associated with unfavorable overall survival (hazard ratio = 1.71; 95% confidence interval = 1.32-2.22; p < 0.0001) and progression-free survival (hazard ratio = 1.99; 95% confidence interval = 1.45-2.72; p < 0.0001). Epithelial membrane protein 3 is negatively correlated to CDH1 expression (Pearson's r = -0.46) but is positively correlated to VIM expression (Pearson's r = 0.83). Knockdown of epithelial membrane protein 3 significantly increased E-cadherin but significantly decreased Vimentin expression in AGS cells. Gastric cancer patients with metastasis have significantly higher epithelial membrane protein 3 expression than the cases without metastasis. In addition, high epithelial membrane protein 3 expression is associated with worse overall survival (hazard ratio = 2.59; 95% confidence interval = 2.06-3.26; p < 0.0001) and also worse progression-free survival (hazard ratio = 2.21; 95% confidence interval = 1.78-2.74; p < 0.0001). In conclusion, epithelial membrane protein 3 is a downstream effector of TWIST1/2 in inducing epithelial-to-mesenchymal transition in gastric cancer. Epithelial membrane protein 3 upregulation might be associated with gastric cancer metastasis and is a potential indicator of unfavorable overall survival and progression-free survival in gastric cancer patients.
在本研究中，我们旨在探索TWIST1/2在诱导胃癌上皮-间质转化过程中的新的下游效应分子。利用癌症基因组图谱胃腺癌数据库中的数据进行生物信息学数据挖掘。使用Kaplan-Meier绘图工具生成生存曲线。采用胃癌细胞系（AGS和SGC-7901）作为体外细胞模型，研究TWIST1/2对上皮膜蛋白3表达及上皮-间质转化进程的调控作用。结果显示，在原发性胃癌患者中，TWIST1和TWIST2通常共同上调。TWIST1高表达与较差的总生存期相关（风险比=1.26；95%置信区间=1.06-1.49；p=0.007），且与较差的首次无进展生存期也相关（风险比=1.47；95%置信区间=1.18-1.82；p<0.0001）。同样，TWIST2高表达与不良的总生存期（风险比=1.71；95%置信区间=1.32-2.22；p<0.0001）和无进展生存期（风险比=1.99；95%置信区间=1.45-2.72；p<0.0001）相关。上皮膜蛋白3与CDH1表达呈负相关（Pearson相关系数r=-0.46），但与VIM表达呈正相关（Pearson相关系数r=0.83）。敲低上皮膜蛋白3可显著增加AGS细胞中E-钙黏蛋白的表达，但显著降低波形蛋白的表达。发生转移的胃癌患者上皮膜蛋白3表达显著高于未发生转移的患者。此外，上皮膜蛋白3高表达与较差的总生存期（风险比=2.59；95%置信区间=2.06-3.26；p<0.0001）和较差的无进展生存期（风险比=2.21；95%置信区间=1.78-2.74；p<0.0001）相关。总之，上皮膜蛋白3是TWIST1/2在诱导胃癌上皮-间质转化过程中的下游效应分子。上皮膜蛋白3的上调可能与胃癌转移相关，并且是胃癌患者不良总生存期和无进展生存期的一个潜在指标。
