Abstract
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.
Highlights
Gastric cancer is the fourth diagnosed cancer and the second most common cause of cancer-related death worldwide, especially in developing countries [1, 2]
We previously reported that Forkhead box M1 (FoxM1) is upregulated in gastric cancer, and its inhibition leads to cellular senescence [18], but the relevance of H. pylori infection and FoxM1 expression associated with the pathogenesis of gastric cancer remains undefined
We investigated the expression of FoxM1 in gastric specimens at different disease stages, including 20 normal, 12 superficial gastritis, 12 atrophic gastritis associated with intestinal metaplasia (AG/IM), and 20 primary gastric cancer tissues (Supplementary Table S1)
Summary
Gastric cancer is the fourth diagnosed cancer and the second most common cause of cancer-related death worldwide, especially in developing countries [1, 2]. Most patients are diagnosed at an advantaged stage because of lack of early specific symptoms, so prognosis remains poor even after extensive surgery and adjuvant therapy. Gastric carcinogenesis is a complex, multistep, and multifactorial event. Helicobacter pylori (H. pylori) infection is involved in the early stage of gastric cancer pathogenesis by Authors' Affiliations: 1Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education; and Departments of 2Pharmacology and 3Biochemistry, School of Medicine, Shandong University, Jinan, PR China. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).
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