title: Strain-specific suppression of microRNA-320 by carcinogenic Helicobacter pylori promotes expression of the antiapoptotic protein Mcl-1.
abstract: Helicobacter pylori is the strongest risk factor for gastric cancer, and strains harboring the cag pathogenicity island, which translocates the oncoprotein CagA into host cells, further augment cancer risk. We previously reported that in vivo adaptation of a noncarcinogenic H. pylori strain (B128) generated a derivative strain (7.13) with the ability to induce adenocarcinoma, providing a unique opportunity to define mechanisms that mediate gastric carcinogenesis. MicroRNAs (miRNAs) are small noncoding RNAs that regulate expression of oncogenes or tumor suppressors and are frequently dysregulated in carcinogenesis. To identify miRNAs and their targets involved in H. pylori-mediated carcinogenesis, miRNA microarrays were performed on RNA isolated from gastric epithelial cells cocultured with H. pylori strains B128, 7.13, or a 7.13 cagA(-) isogenic mutant. Among 61 miRNAs differentially expressed in a cagA-dependent manner, the tumor suppressor miR-320 was significantly downregulated by strain 7.13. Since miR-320 negatively regulates the antiapoptotic protein Mcl-1, we demonstrated that H. pylori significantly induced Mcl-1 expression in a cagA-dependent manner and that suppression of Mcl-1 results in increased apoptosis. To extend these results, mice were challenged with H. pylori strain 7.13 or its cagA(-) mutant; consistent with cell culture data, H. pylori induced Mcl-1 expression in a cagA-dependent manner. In human subjects, cag(+) strains induced significantly higher levels of Mcl-1 than cag(-) strains, and Mcl-1 expression levels paralleled the severity of neoplastic lesions. Collectively, these results indicate that H. pylori suppresses miR-320, upregulates Mcl-1, and decreases apoptosis in a cagA-dependent manner, which likely confers an increased risk for gastric carcinogenesis.
authors.affiliation: Jr., 2215 Garland Ave., Medical Research Bldg. IV 1030C, Nashville, TN 37232. richard.peek@vanderbilt.edu.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Noto
authors.forename: M Blanca
authors.initials: MB
authors.lastname: Piazuelo
authors.forename: Rupesh
authors.initials: R
authors.lastname: Chaturvedi
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Bartel
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Thatcher
authors.forename: Alberto
authors.initials: A
authors.lastname: Delgado
authors.forename: Judith
authors.initials: J
authors.lastname: Romero-Gallo
authors.forename: Keith T
authors.initials: KT
authors.lastname: Wilson
authors.forename: Pelayo
authors.initials: P
authors.lastname: Correa
authors.forename: James G
authors.initials: JG
authors.lastname: Patton
authors.forename: Richard M
authors.initials: RM
authors.lastname: Peek
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000382:microbiology; D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism / Q000382:microbiology; D015972:Gene Expression Regulation, Neoplastic; D016480:Helicobacter pylori / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity; D013274:Stomach Neoplasms / Q000378:metabolism / Q000382:microbiology; D014158:Transcription, Genetic
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C579095:MCL1 protein, human; C572916:MIRN320 microRNA, human; D035683:MicroRNAs; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C080866:cagA protein, Helicobacter pylori
keywords: Helicobacter pylori; Mcl-1; apoptosis; gastric cancer; microRNA