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

Abstract

<div>Abstract<p><i>Helicobacter pylori</i> (<i>H. pylori</i>) 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 <i>H. pylori</i> 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 <i>H. pylori</i>. CagA, a key virulence factor of <i>H. pylori</i>, was associated with increased FoxM1 expression. <i>H. pylori</i> and CagA inhibited the expression of p27<sup>Kip1</sup> (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. <i>H. pylori</i> 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 <i>H. pylori</i>–infected C57BL/6J mice. <i>H. pylori</i> infection and CagA upregulated FoxM1 expression, dependent on miR-370, altered the expression of p27<sup>Kip1</sup>, and promoted proliferation in gastric cells.</p><p><b>Implications:</b> These findings delineate the mechanisms governing FoxM1 regulation and the role of <i>H. pylori</i> in the process of gastric carcinogenesis. <i>Mol Cancer Res; 11(8); 834–44. ©2013 AACR</i>.</p></div>