Enterococcus faecalis Enhances Cell Proliferation through Hydrogen Peroxide-Mediated Epidermal Growth Factor Receptor Activation

Abstract

f Enterococcus faecalis is a member of the intestinal and oral microbiota that may affect the etiology of colorectal and oral cancers. The mechanisms by which E. faecalis may contribute to the initiation and progression of these cancers remain uncertain. Epidermal growth factor receptor (EGFR) signaling is postulated to play a crucial role in oral carcinogenesis. A link between E. faecalis and EGFR signaling in oral cancer has not been elucidated. The present study aimed to evaluate the association between E. faecalis and oral cancer and to determine the underlying mechanisms that link E. faecalis to EGFR signaling. We report the high frequency of E. faecalis infection in oral tumors and the clinical association with EGFR activation. Using human oral cancer cells, we support the clinical findings and demonstrate that E. faecalis can induce EGFR activation and cell proliferation. E. faecalis activates EGFR through production of H 2 O 2 , a signaling molecule that activates several signaling pathways. Inhibitors of H 2 O 2 (catalase) and EGFR (gefitinib) significantly blocked E. faecalis-induced EGFR activation and cell proliferation. Therefore, E. faecalis infection of oral tumor tissues suggests a possible association between E. faecalis infection and oral carcinogenesis. Interaction of E. faecalis with host cells and production of H 2 O 2 increase EGFR activation, thereby contributing to cell proliferation.

Colorectal cancer mutational profiles correlate with defined microbial communities in the tumor microenvironment

“…Many of the interactions identified here between bacterial taxa and mutations in PID pathways have already been demonstrated experimentally in the literature. For example, in human oral cancer cells, it was shown that bacteria of interest were able to activate EGFR through the generation of hydrogen peroxide [67] . In addition, the correlation between ErbB1 downstream signaling and increase in the abundance of Corynebacterium has been demonstrated mechanistically in a model of atopic dermatitis, whereby EGFR inhibition results in dysbiosis (the appearance of Corynebacterium species) and inflammation [68] .…”

Enterococcus faecalis Inhibits Superantigen Toxic Shock Syndrome Toxin-1-Induced Interleukin-8 from Human Vaginal Epithelial Cells through Tetramic Acids

“…This is primarily due to production of lactic acid by vaginal lactobacilli [7]; however other lactic acid-producing bacteria, such as E. faecalis , can also potentially contribute to the acidic environment. Both lactobacilli [8] and E. faecalis [9], [10] also produce hydrogen peroxide, which is known to be directly cytotoxic to various microorganisms. Additionally, hydrogen peroxide made by commensal organisms can act as a substrate for host-derived peroxidases to make more potent toxic compounds, or even induce host cells to make more hydrogen peroxide themselves [8], [11].…”

Microbiota Alterations in Gastrointestinal Cancers

“…The role of Enterococcus faecalis in cancer development remains unclear. It has been mostly reported as a gut commensal; however, owing to its wide range of virulence factors, especially its metalloprotease production and ability to generate ROS (reactive oxygen species) and extracellular superoxide, it has drawn attention as a carcinogenic [72]. ROS and extracellular superoxide lead to DNA damage, which might result in carcinogenic mutations.…”

“…The study of Boonanantanasarn et al suggested that E. faecalis might enhance cell proliferation through hydrogen peroxide-mediated epidermal growth gactor receptor activation (EGFR). THE EGFR signalling pathway plays a crucial role in the regulation of cell proliferation in many cell types [72]. In contrast, Sivan et al have reported that oral administration of Bifidobacterium to mice significantly increased anti-tumor immunity and improved tumor control on a comparable level to treatment with programmed cell death protein 1 ligand 1-specific antibodies [74].…”