Bcl2-associated athanogene 4 (BAG4) has been found to be aberrantly expressed in several types of human cancers. However, little is known about its expression, role, and clinical significance in gastric cancer (GC). In this study, we aimed to address these issues and to explore the underlying mechanisms. The expression level of BAG4, measured by immunohistochemistry, was significantly higher in GC tissues than in paired normal tissues. Elevated BAG4 expression was positively correlated with T stage, lymph node metastasis, and tumor size of GC and was associated with unfavorable outcomes of the patients. The overexpression of BAG4 promoted the in vitro invasion and in vivo metastasis of GC cells, and opposite results were observed after silencing of BAG4. Silencing of BAG4 significantly reduced the phosphorylation of PI3K, AKT, and p65, whereas overexpression of BAG4 markedly enhanced the phosphorylation of these molecules. At the same time, manipulating BAG4 expression resulted in the corresponding changes in p65 nuclear translocation and ZEB1 expression. Luciferase reporter and chromatin immunoprecipitation assays verified that p65 binds to the promoter of ZEB1 to upregulate its transcription. Our results demonstrate that BAG4 plays an oncogenic role in the invasion and metastasis of GC cells by activating the PI3K/AKT/NF-κB/ZEB1 axis to induce epithelial-mesenchymal transition.

已发现 Bcl2 相关的 athanogene 4 (BAG4) 在几种类型的人类癌症中异常表达。然而，人们对其在胃癌 (GC) 中的表达、作用和临床意义知之甚少。在这项研究中，我们旨在解决这些问题并探索潜在的机制。通过免疫组织化学测量，BAG4 的表达水平在 GC 组织中显着高于成对的正常组织。BAG4表达升高与GC的T分期、淋巴结转移和肿瘤大小呈正相关，并与患者的不良预后相关。BAG4的过表达促进了体外侵袭和体内GC 细胞的转移，在 BAG4 沉默后观察到相反的结果。BAG4 的沉默显着降低了 PI3K、AKT 和 p65 的磷酸化，而 BAG4 的过表达显着增强了这些分子的磷酸化。同时，操纵 BAG4 表达导致 p65 核易位和 ZEB1 表达的相应变化。荧光素酶报告基因和染色质免疫沉淀测定证实 p65 与ZEB1的启动子结合以上调其转录。我们的研究结果表明，BAG4 通过激活 PI3K/AKT/NF-κB/ZEB1 轴诱导上皮-间质转化，在 GC 细胞的侵袭和转移中发挥致癌作用。