Keith Wilson
Faculty Member
Last active: 11/2/2019

Strain-specific suppression of microRNA-320 by carcinogenic Helicobacter pylori promotes expression of the antiapoptotic protein Mcl-1.

Noto JM, Piazuelo MB, Chaturvedi R, Bartel CA, Thatcher EJ, Delgado A, Romero-Gallo J, Wilson KT, Correa P, Patton JG, Peek RM
Am J Physiol Gastrointest Liver Physiol. 2013 305 (11): G786-96

PMID: 24136787 · PMCID: PMC3882435 · DOI:10.1152/ajpgi.00279.2013

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.

MeSH Terms (20)

Adenocarcinoma Animals Antigens, Bacterial Apoptosis Bacterial Proteins Carcinogenesis Cell Line, Tumor Down-Regulation Female Gastric Mucosa Gene Expression Regulation, Neoplastic Helicobacter pylori Humans Mice MicroRNAs Middle Aged Myeloid Cell Leukemia Sequence 1 Protein Species Specificity Stomach Neoplasms Transcription, Genetic

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