title: A MDM2-dependent positive-feedback loop is involved in inhibition of miR-375 and miR-106b induced by Helicobacter pylori lipopolysaccharide.
abstract: Dysregulation of microRNAs (miRNAs) has been linked to virulence factors of Helicobacter pylori and shown to contribute to the progression of gastric cancer. However, the mechanisms of these processes remain poorly understood. The aim of this study was to investigate the mechanisms by which lipopolysaccharide (LPS), a virulence factor of H. pylori, regulates miR-375 and miR-106b expression in gastric epithelial cells. The results show that LPS from H. pylori 26695 downregulated the expression of miR-375 and miR-106b in gastric epithelial cells, and low levels of Dicer were also observed. Downregulation of miR-375 was found to increase expression of MDM2 with SP1 activation. Overexpression of MDM2 inhibited Dicer by repressing p63 to create a positive-feedback loop involving SP1/MDM2/p63/Dicer that leads to inhibition of miR-375 and miR-106b expression. In addition, we demonstrated that JAK1 and STAT3 were downstream target genes of miR-106b. H. pylori LPS also enhanced the tyrosine phosphorylation of JAK1, JAK2 and STAT3. Together, these results provide insight into the regulatory mechanisms of MDM2 on H. pylori LPS-induced specific miRNAs, and furthermore, suggest that gastric epithelial cells treated with H. pylori LPS may be susceptible to JAK/STAT3 signal pathway activation via inhibition of miR-375 and miR-106b.
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Ye
authors.forename: Chunli
authors.initials: C
authors.lastname: Tang
authors.forename: Weijia
authors.initials: W
authors.lastname: Shi
authors.forename: Juan
authors.initials: J
authors.lastname: Qian
authors.forename: Shuping
authors.initials: S
authors.lastname: Xiao
authors.forename: Min
authors.initials: M
authors.lastname: Gu
authors.forename: Yini
authors.initials: Y
authors.lastname: Dang
authors.forename: Jianping
authors.initials: J
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Ruihua
authors.initials: R
authors.lastname: Shi
authors.forename: Guoxin
authors.initials: G
authors.lastname: Zhang
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism / Q000821:virology; D016481:Helicobacter Infections / Q000235:genetics; D016480:Helicobacter pylori / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics*; D008875:Middle Aged; D010766:Phosphorylation / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics / Q000821:virology; D037521:Virulence Factors / Q000235:genetics
chemical_list: D008070:Lipopolysaccharides; C542541:MIRN106 microRNA, human; C540933:MIRN375 microRNA, human; D035683:MicroRNAs; D037521:Virulence Factors; C442865:lipopolysaccharide, Helicobacter pylori; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Helicobacter pylori; gastric cancer; lipopolysaccharide; miR-106b; miR-375