Priming the seed: Helicobacter pylori alters epithelial cell invasiveness in early gastric carcinogenesis

Figure 2 Role of Helicobacter pylori in the reprograming of cellular and molecular programs related to invasive behavior. Upon infection, H. pylori induces a number of intracellular processes in gastric epithelial cells, some of them can result in the reprogramming of cellular and molecular mechanisms underlying the invasive cell behavior. Several of these events take place after phosphorylation of CagA, others may be independent of the translocation and phosphorylation of CagA, and a portion are not connected to the Cag-PAI at all. Although not exclusively, CagA plays an important role in the activation of transcription factors, such as β-catenin, Snail, ZEB1/2, NF-κB, and AP-1. Some of these transcriptional regulators (e.g., β-catenin, Snail, ZEB1/2) modify the expression of genes encoding for key effectors of the EMT and stem cell programs, including up-regulation of TGFβ and CD44 and down-regulation of E-cadherin. Changing of the gastric epithelial cell polarity is another downstream intracellular event connected to H. pylori, which is primarily attributed to the physical interaction of components of the T4SS (especially CagL) and β1 integrins. In addition to this translocation-independent mechanism, alteration of the cell polarity can also result from CagA translocation and phosphorylation. Another consequence of the manipulation of the invasive properties by H. pylori is the induction of the expression of ECM remodeling effectors, namely uPAR, uPA, MMP7, MMP2, MMP3, and MMP9. This is presumably linked to the activation of the MAPK signaling pathway, which in turn leads to the activation of NF-κB and AP-1. It is not yet clear whether plasminogen and MMP activation (dashed arrows) takes place, or what are the functional implications of the enhanced expression of these ECM-related molecules in this particular context. Cag-PAI: Cag pathogenicity island; ECM: Extracellular matrix; EMT: Epithelial-to-mesenchymal transition; H. pylori: Helicobacter pylori; MMP: Matrix metalloproteinase; NF-κB: Nuclear factor-kappa B; T4SS: Type IV secretion system; uPA: Plasminogen activator; uPAR: Plasminogen activator receptor.