Zhao Rongrong, Liu Zhengxia, Xu Wenting, Song Le, Ren Haifeng, Ou Yang, Liu Yakun, Wang Siying
Department of Physiopathology, Anhui Medical University, Hefei, Anhui, China.
Department of Pathology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
Cancer Med. 2020 Apr;9(7):2551-2563. doi: 10.1002/cam4.2892. Epub 2020 Feb 4.
Krüppel-like factor 4 (KLF4) has a tumor suppressor role in the progression of gastric cancer (GC), and inhibition or loss of KLF4 expression was identified in GC. The aim of this study was to explore the new molecular mechanism of KLF4 inactivation in gastric cancer. Herein, we report that Helicobacter pylori infection or Cag pathogenicity island protein A (CagA) gene transduction resulted in KLF4 expression downregulation and promoted gastric epithelial cell and gastric cancel cell proliferation, migration, and colony formation. Mechanistically, we found that CagA gene transduction led to DNA methylation of the KLF4 promoter, an effect that was relevant to the significant downregulation of TET1 expression. Causally, knockdown of TET1 expression decreased KLF4 expression, whereas overexpression of TET1 had the opposite effect. Clinically, we found that KLF4 expression and the 5-hmC levels were lower in GC cells with H pylori infection than in GC cells without H pylori infection. Thus, our study not only sheds new light on how H pylori infection promotes the progression of GC but also elucidates a novel mechanism of KLF4 inactivation in GC pathogenesis. During pathogenesis, an alteration in the H pylori/CagA-TET1-KLF4 signaling pathway plays a critical role, suggesting that this pathway may be a prospective target for gastric carcinoma intervention and therapy.
Krüppel样因子4（KLF4）在胃癌（GC）进展中具有肿瘤抑制作用，且在GC中发现KLF4表达受到抑制或缺失。本研究旨在探索胃癌中KLF4失活的新分子机制。在此，我们报道幽门螺杆菌感染或空泡毒素相关蛋白A（CagA）基因转导导致KLF4表达下调，并促进胃上皮细胞和胃癌细胞的增殖、迁移及集落形成。机制上，我们发现CagA基因转导导致KLF4启动子DNA甲基化，这一效应与TET1表达的显著下调相关。因果关系上，敲低TET1表达降低KLF4表达，而TET1过表达则产生相反作用。临床上，我们发现幽门螺杆菌感染的GC细胞中KLF4表达和5-羟甲基胞嘧啶（5-hmC）水平低于未感染幽门螺杆菌的GC细胞。因此，我们的研究不仅揭示了幽门螺杆菌感染如何促进GC进展，还阐明了GC发病机制中KLF4失活的新机制。在发病过程中，幽门螺杆菌/CagA-TET1-KLF4信号通路的改变起关键作用，提示该通路可能是胃癌干预和治疗的潜在靶点。
