Figure 2.

Porphyromonas gingivalis promoting the development and progression of OSCC.

Infection: Intracellular Porphyromonas gingivalis infection promotes survival and proliferation of the epithelial cell by increasing PI3K/Akt signaling shortly after infection, resulting in the inhibition of intrinsic apoptosis. Additionally, through secretion of its effector protein, nucleoside diphosphate kinase (NDK), P. gingivalis blocks extracellular ATP/P2X7 danger signaling, protecting itself and the host epithelial cell from damaging mitochondrial and NOX2 generated ROS. EMT: The epithelial-mesenchymal transition (EMT) is promoted through the inactivation of GSK3-β, which facilitates a switch from E-cadherin to Vimentin via increased expression and availability of Snail, Slug and β-catenin transcription factors. β-catenin also upregulates cyclins, ZEB1, and MMPs, resulting in increased epithelial cell proliferation and migration. Porphyromonas gingivalis continues to promote EMT through direct phosphorylation of HSP27 via its effector protein NDK, leading to increased levels of pro-MMP9. Furthermore, P. gingivalis increases the expression of cancer stem cell markers CD44 and CD133. OSCC Progression: P. gingivalis further maintains a pro-survival and proliferative phenotype in cancer cells by blocking p53. An invasive phenotype is promoted through gingipains – key virulence factors of P. gingivalis – which bind and process pro-MMP9 to MMP9. Moreover, P. gingivalis modulates the immune environment through cytokine and chemokine secretion and the increased expression of B7-H1 and B7-DC receptors which cause T-cell anergy and apoptosis of activated T cells.