FoxM1 is Overexpressed in <i>Helicobacter pylori</i> –Induced Gastric Carcinogenesis and Is Negatively Regulated by miR-370

Abstract

UNLABELLED: 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. IMPLICATIONS: These findings delineate the mechanisms governing FoxM1 regulation and the role of H. pylori in the process of gastric carcinogenesis.