Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan 250012, PR China.
Mol Cancer Res. 2013 Aug;11(8):834-44. doi: 10.1158/1541-7786.MCR-13-0007. Epub 2013 Apr 10.
Helicobacter pylori (H. pylori) infections are strongly implicated in human gastric mucosa-associated diseases. Forkhead box M1 (FoxM1), a key positive regulator of cell proliferation, is overexpressed in gastric cancer. MicroRNAs are important post-transcriptional regulators of gene expression. In this study, the effects of H. pylori infection on FoxM1 expression and possible mechanisms of carcinogenesis were explored. The expression of FoxM1 was gradually increased in human gastric specimens from inflammation to cancer. FoxM1 upregulation was time- and concentration-dependent in gastric epithelial-derived cell lines infected with H. pylori. CagA, a key virulence factor of H. pylori, was associated with increased FoxM1 expression. H. pylori and CagA inhibited the expression of p27(Kip1) (CDKN1B) and promoted cell proliferation by upregulating FoxM1. The expression of miR-370 was decreased in human gastritis and gastric cancer. FoxM1 was directly downregulated by miR-370 in gastric cell lines. H. pylori and CagA inhibited miR-370 expression, which led to overexpression of FoxM1 and cell proliferation. Furthermore, the overexpression of FoxM1 and reduced expression of miR-370 was confirmed in H. pylori-infected C57BL/6J mice. H. pylori infection and CagA upregulated FoxM1 expression, dependent on miR-370, altered the expression of p27(Kip1), and promoted proliferation in gastric cells.
These findings delineate the mechanisms governing FoxM1 regulation and the role of H. pylori in the process of gastric carcinogenesis.
幽门螺杆菌（H. pylori）感染与人胃黏膜相关疾病密切相关。叉头框 M1（FoxM1）是细胞增殖的关键正调控因子，在胃癌中过度表达。microRNAs 是基因表达的重要转录后调控因子。在这项研究中，探讨了 H. pylori 感染对 FoxM1 表达的影响及其致癌作用的可能机制。FoxM1 的表达在人胃组织从炎症到癌症的过程中逐渐增加。感染 H. pylori 的胃上皮细胞系中 FoxM1 的上调呈时间和浓度依赖性。H. pylori 的关键毒力因子 CagA 与 FoxM1 表达的增加有关。H. pylori 和 CagA 通过上调 FoxM1 抑制 p27（Kip1）（CDKN1B）的表达并促进细胞增殖。miR-370 在人类胃炎和胃癌中的表达降低。FoxM1 在胃细胞系中直接受 miR-370 下调。H. pylori 和 CagA 抑制 miR-370 的表达，导致 FoxM1 过表达和细胞增殖。此外，在 H. pylori 感染的 C57BL/6J 小鼠中证实了 FoxM1 的过表达和 miR-370 的表达降低。H. pylori 感染和 CagA 上调 FoxM1 表达，依赖于 miR-370，改变了 p27（Kip1）的表达，并促进了胃细胞的增殖。
这些发现描绘了调节 FoxM1 的机制以及 H. pylori 在胃癌发生过程中的作用。
