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Fork head box M1 is overexpressed in Helicobacter pylori-induced gastric carcinogenesis and is negatively regulated by hsa-miR-370.


Mol Cancer Res. 2013 Apr 10;


Authors: Feng Y, Wang L, Zeng J, Shen L, Liang X, Yu H, Liu S, Liu Z, Sun Y, Li W, Chen C, Jihui J


Abstract

Helicobacter pylori (H. pylori) is implicated in human gastric mucosa. Fork head box M1 (FoxM1), the key positive regulator of cell proliferation is overexpressed in gastric cancer. MicroRNAs are important post-transcriptional regulators of gene expression. In this study, we explored the effect of H. pylori infection on FoxM1 expression and possible mechanisms. The expression of FoxM1 was gradually increased in human gastric specimens from inflammation to cancer. FoxM1 was time- and concentration-dependently upregulated in gastric epithelial-derived cell lines infected with H. pylori. CagA, the key virulence factor of H. pylori, was associated with increasing FoxM1 expression. H. pylori and CagA inhibited the expression of P27Kip1 (cylcin-dependent kinase inhibitor 1B, CDKN1B) and promoted cell proliferation by upregulating FoxM1. The expression of hsa-miR-370 was decreased in human gastritis and gastric cancer. FoxM1 was directly downregulated by hsa-miR-370 in gastric cell lines. H. pylori and CagA inhibited hsa-miR-370 expression, which led to overexpression of FoxM1 and cell proliferation. Furthermore, the overexpression of FoxM1 and reduced expression of hsa-miR-370 were confirmed in H. pylori-infected C57BL/6J mice. H. pylori and its key virulence factor CagA can upregulate the expression of FoxM1 in a hsa-miR-370-dependent manner, which affects the expression of P27Kip1 and promotes proliferation of gastric cells. These findings may provide further information for better understanding the mechanism of H. pylori carcinogenesis.

PMID: 23576572 [PubMed - as supplied by publisher]