Uncovering the role of microRNA671-5p/CDCA7L/monoamine oxidase-A signaling in Helicobacter pylori mediated apoptosis in gastric epithelial cells.

Helicobacter pylori is a gram-negative microaerophilic bacterium and is associated with gastrointestinal diseases ranging from peptic ulcer and gastritis to gastric cancer and mucosa-associated lymphoid tissue lymphoma. In our laboratory, the transcriptomes and miRnomes of AGS cells infected with H. pylori have been profiled, and an miRNA-mRNA network has been constructed. MicroRNA 671-5p is upregulated during H. pylori infection of AGS cells or of mice. In this study, the role of miR-671-5p during infection has been investigated. It has been validated that miR-671-5p targets the transcriptional repressor CDCA7L, which is downregulated during infection (in vitro and in vivo) concomitant with miR-671-5p upregulation. Further, it has been established that the expression of monoamine oxidase A (MAO-A) is repressed by CDCA7L, and that MAO-A triggers the generation of reactive oxygen species (ROS). Consequently, miR-671-5p/CDCA7L signaling is linked to the generation of ROS during H. pylori infection. Finally, it has been demonstrated that ROS-mediated caspase 3 activation and apoptosis that occurs during H. pylori infection, is dependent on the miR-671-5p/CDCA7L/MAO-A axis. Based on the above reports, it is suggested that targeting miR-671-5p could offer a means of regulating the course and consequences of H. pylori infection.

Genome-wide mRNA-miRNA profiling uncovers a role of the microRNA miR-29b-1-5p/PHLPP1 signalling pathway in Helicobacter pylori-driven matrix metalloproteinase production in gastric epithelial cells.

Aberrant expression of microRNAs (miRNAs) is associated with tumour progression, extracellular matrix remodelling, and cell proliferation. miRNAs modulate host gene expression during infection by pathogens such as Helicobacter pylori, which is associated with varying degrees of gastric pathology. In order to gain insight into the regulation of gene expression by miRNAs during H. pylori infection of gastric epithelial cells and its likely downstream consequences, we analysed the transcriptomes and miRnomes of AGS cells infected with H. pylori. In silico analysis of miRNA-mRNA interactions suggested that miR-29b-1-5p was a likely regulator of pathways associated with gastric epithelial cell pathology. We validated PH domain leucine rich phosphatase 1 (PHLPP1), a negative regulator of the Akt signalling pathway, as a target of miR-29b-1-5p. In an in vivo mouse model, we observed that infection with H. pylori was associated with upregulation of miR-29b-1-5p and downregulation of PHLPP1. Transfection with either a mimic or an inhibitor of miR-29b-1-5p confirmed that downregulation of PHLPP1 upregulates Akt-dependent NF-κB signalling leading to activation of matrix metalloproteinases 2 and 9, players in the degradation of extracellular matrix during H. pylori infection. The secreted antigen HP0175 was associated with upregulation of miR-29b-1-5p, regulation of metalloproteinase activity, and migration of AGS cells. Our study suggests that targeting the miR-29b-1-5p/PHLPP1 signalling axis could be a potential host-directed approach for regulating the outcome of H. pylori infection.