Ouyang Yaobin, Liu Gongmeizi, Xu Wenting, Yang Zhen, Li Nianshuang, Xie Chuan, Zhou Chun, Chen Jiang, Zhu Yin, Hong Junbo, Lu Nonghua
Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
Department of Endocrinology, The First Affiliated Hospital of Tsinghua University, Beijing 100700, P.R. China.
Oncol Lett. 2021 Feb;21(2):165. doi: 10.3892/ol.2021.12426. Epub 2021 Jan 4.
() is a main risk factor for gastric cancer (GC). Epithelial-mesenchymal transition (EMT) is involved in the development and progression of -associated GC. However, the exact molecular mechanism of this process remains unclear. The AKT/GSK3β signaling pathway has been demonstrated to promote EMT in several types of cancer. The present study investigated whether infection induced EMT, and promoted the development and metastasis of cancer in the normal gastric mucosa, and whether this process was dependent on AKT activation. The expression levels of the EMT-associated proteins, including E-cadherin and N-cadherin, were determined in 165 gastric mucosal samples of different disease stages by immunohistochemical analysis. The expression levels of E-cadherin, N-cadherin, AKT, phosphorylated (p-)AKT (Ser473), GSK3β and p-GSK3β (Ser9) were further determined in -infected Mongolian gerbil gastric tissues and cells co-cultured with by immunohistochemical analysis and western blotting. The results indicated that the expression levels of the epithelial marker E-cadherin were decreased, whereas the expression levels of the mesenchymal marker N-cadherin were increased during gastric carcinogenesis. Their expression levels were associated with infection. Furthermore, infection resulted in downregulation of E-cadherin expression and upregulation of N-cadherin expression in Mongolian gerbils and GES-1 cells. In addition, an investigation of the associated mechanism of action revealed that p-AKT (Ser473) and p-GSK3β (Ser9) were activated in GES-1 cells following co-culture with . Furthermore, following pretreatment of the cells with the AKT inhibitor VIII, the expression levels of E-cadherin, N-cadherin, p-AKT and p-GSK3β did not show significant differences between GES-1 cells that were co-cultured with or without . The levels of p-AKT and p-GSK3β were increased in -infected Mongolian gerbils. In conclusion, the present study demonstrated that infection activated AKT and resulted in the phosphorylation and inactivation of GSK3β, which in turn promoted early stage EMT. These effects were AKT-dependent. This mechanism may serve as a prerequisite for GC development.
（）是胃癌（GC）的主要危险因素。上皮-间质转化（EMT）参与了与-相关的GC的发生和发展。然而，这一过程的确切分子机制仍不清楚。AKT/GSK3β信号通路已被证明在几种类型的癌症中促进EMT。本研究调查了感染是否诱导EMT，并促进正常胃黏膜中癌症的发生和转移，以及这一过程是否依赖于AKT激活。通过免疫组织化学分析在165份不同疾病阶段的胃黏膜样本中测定了包括E-钙黏蛋白和N-钙黏蛋白在内的EMT相关蛋白的表达水平。通过免疫组织化学分析和蛋白质印迹法进一步测定了感染的蒙古沙鼠胃组织和与共培养的细胞中E-钙黏蛋白、N-钙黏蛋白、AKT、磷酸化（p-）AKT（Ser473）、GSK3β和p-GSK3β（Ser9）的表达水平。结果表明，在胃癌发生过程中，上皮标志物E-钙黏蛋白的表达水平降低，而间质标志物N-钙黏蛋白的表达水平升高。它们的表达水平与感染有关。此外，感染导致蒙古沙鼠和GES-1细胞中E-钙黏蛋白表达下调和N-钙黏蛋白表达上调。另外，对相关作用机制的研究表明，与共培养后，GES-1细胞中的p-AKT（Ser473）和p-GSK3β（Ser9）被激活。此外，在用AKT抑制剂VIII预处理细胞后，与共培养或未共培养的GES-1细胞之间，E-钙黏蛋白、N-钙黏蛋白、p-AKT和p-GSK3β的表达水平没有显著差异。感染的蒙古沙鼠中p-AKT和p-GSK3β的水平升高。总之，本研究表明感染激活了AKT，并导致GSK3β的磷酸化和失活，进而促进早期EMT。这些作用是依赖于AKT的。这一机制可能是GC发生的前提条件。
