title: FoxM1 is overexpressed in Helicobacter pylori-induced gastric carcinogenesis and is negatively regulated by miR-370.
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.
  
  
  CONCLUSIONS
  These findings delineate the mechanisms governing FoxM1 regulation and the role of H. pylori in the process of gastric carcinogenesis.
authors.affiliation: Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan 250012, PR China.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Feng
authors.forename: Lixiang
authors.initials: L
authors.lastname: Wang
authors.forename: Jiping
authors.initials: J
authors.lastname: Zeng
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.forename: Xiuming
authors.initials: X
authors.lastname: Liang
authors.forename: Han
authors.initials: H
authors.lastname: Yu
authors.forename: Shili
authors.initials: S
authors.lastname: Liu
authors.forename: Zhifang
authors.initials: Z
authors.lastname: Liu
authors.forename: Yundong
authors.initials: Y
authors.lastname: Sun
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Li
authors.forename: Chunyan
authors.initials: C
authors.lastname: Chen
authors.forename: Jihui
authors.initials: J
authors.lastname: Jia
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism / Q000382:microbiology; D005756:Gastritis / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D005786:Gene Expression Regulation; D016481:Helicobacter Infections / Q000150:complications / Q000382:microbiology*; D016480:Helicobacter pylori / Q000235:genetics / Q000472:pathogenicity*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; C526503:MIRN370 microRNA, human; C551449:MIRN370 microRNA, mouse; D035683:MicroRNAs; D037521:Virulence Factors; C080866:cagA protein, Helicobacter pylori; D050760:Cyclin-Dependent Kinase Inhibitor p27