Porphyromonas gingivalis secretion leads to dysplasia of normal esophageal epithelial cells via the Sonic hedgehog pathway

Abstract

ObjectivesTo investigate the pathogenic effect of Porphyromonas gingivalis cultured media on the esophagus and the mechanism underlying the effect.BackgroundPeriodontitis is strongly associated with esophageal squamous cell carcinoma (ESCC). The cultured media of P. gingivalis may act on healthy esophagus to trigger a malignant transformation; however, this has not been confirmed.MethodsCell migration assays and cell cycle measurements were performed on normal human esophageal epithelial cells in the presence or absence of P. gingivalis cultured media. The esophagi of healthy adult C57BL/6J mice were isolated and cultured in-vitro. Hematoxylin-eosin and immunohistochemical staining using antibodies against proliferating cell nuclear antigen (PCNA), Claudin 1 and Claudin 4 were performed to detect dysplasia in specific tissues. Total mRNA was extracted to determine transcriptional dysregulation. A specific inhibitor of Sonic hedgehog signaling, cyclopamine, was used to confirm the underlying molecular mechanism.ResultsIn the presence of P. gingivalis cultured media, proliferation and migration of normal human esophageal epithelial cells were up-regulated, and aneuploid cells appeared. Compared with control cells, the arrangement of mouse esophageal epithelial cells became disordered, the percentage of PCNA-positive cells increased, and the positive staining of Claudin 1 and Claudin 4 became weak. In addition, the expression of cancer-related pathway genes was up-regulated but tight junction-related gene expression was down-regulated. The Sonic hedgehog pathway was abnormally activated, and its inhibition reduced the pathogenic effect of P. gingivalis cultured media.ConclusionsWe revealed that the cultured media of the key periodontal pathogen, P. gingivalis, can induce the malignant transformation of normal esophageal epithelium through the Sonic hedgehog pathway.

Promising dawn in tumor microenvironment therapy: engineering oral bacteria

“… 202 Moreover, studies have indicated that the sonic hedgehog pathway and other cancer-related pathway genes are abnormally activated in the presence of P. gingivalis culture media. 203 Gao et al 204 demonstrated that the fimbriae (FimA) of P. gingivalis exerted a potent influence on the expression of glycoprotein A repetition predominant (GARP), consequently triggering the activation of the TGFβ/Smad signaling cascade, thus fostering cancer cell proliferation and facilitating lung metastasis. Nod-like receptor (NLR) is a kind of innate immune receptor involved in the assembly of inflammasomes, and it participates in the innate immune response against pathogens such as P. gingivalis .…”

The relationship between Porphyromonas gingivalis and oesophageal squamous cell carcinoma: a literature review

“…Importantly, P. gingivalis infection increased the incidence of developing invasive carcinoma in a mouse oesophageal tumour model induced by 4-nitroquinoline 1-oxide. A recent article by Jia et al [ 48 ] revealed that in the presence of P. gingivalis , normal human oesophageal epithelial cell proliferation and migration increased, and aneuploid cells appeared. This study indicated that P. gingivalis can induce the malignant transformation of normal oesophageal epithelium by activating HHIP and GLI1, which are key genes in Sonic hedgehog pathways.…”