Simple Summary

Colitis-associated cancer (CAC) are associated with the development and progression of colorectal cancer (CRC). And Fusobacterium nucleatum (F. nucleatum), a major pathogen involved in chronic periodontitis, may play an important role in CRC progression. Though the importance of F. nucleatum in CRC has attracted attention, its exact role and related mechanism in CAC progression remain unclear. We investigated the effects of F. nucleatum in both in vitro and in vivo colitis models induced with dextran sodium sulfate (DSS), a well-known colitis-inducing chemical, on the aggressiveness of CAC and its related mechanism. This study showed that F. nucleatum accelerates the progression of CAC cancer by promoting epithelial–mesenchymal transition (EMT). This study provides a novel mechanism involved F. nucleatum in the development of colitis-associated CRC.

Abstract

Recently, it has been reported that Fusobacterium nucleatum, a major pathogen involved in chronic periodontitis, may play an important role in colorectal cancer (CRC) progression. In addition, inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease represent major predisposing conditions for the development of CRC, and this subtype of cancer is called colitis-associated cancer (CAC). Although the importance of F. nucleatum in CRC has attracted attention, its exact role and related mechanism in CAC progression remain unclear. In this study, we investigated the effects of F. nucleatum in experimental colitis induced with dextran sodium sulfate (DSS), which is a well-known colitis-inducing chemical, on the aggressiveness of CAC and its related mechanism in both in vitro and in vivo models. F. nucleatum synergistically increased the aggressiveness and epithelial–mesenchymal transition (EMT) characteristics of CRC cells that were treated with DSS compared to those in non-treated CRC cells. The role of F. nucleatum in CAC progression was further confirmed in mouse models, as F. nucleatum was found to significantly increase the malignancy of azoxymethane (AOM)/DSS-induced colon cancer. This promoting effect of F. nucleatum was based on activation of the EGFR signaling pathways, including protein kinase B (AKT) and extracellular signal-regulated kinase (ERK), and epidermal growth factor receptor (EGFR) inhibition significantly reduced the F. nucleatum-induced EMT alteration. In conclusion, F. nucleatum accelerates the progression of CAC by promoting EMT through the EGFR signaling pathway.