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.

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