FadA promotes DNA damage and progression of Fusobacterium nucleatum-induced colorectal cancer through up-regulation of chk2

Abstract

Background Globally, colorectal cancer (CRC) affects more than 1 million people each year. In addition to non-modifiable and other environmental risk factors, Fusobacterium nucleatum infection has been linked to CRC recently. In this study, we explored mechanisms underlying the role of Fusobacterium nucleatum infection in the progression of CRC in a mouse model. Methods C57BL/6 J-Adenomatous polyposis coli (APC) Min/J mice [APC (Min/+)] were treated with Fusobacterium nucleatum (109 cfu/mL, 0.2 mL/time/day, i.g., 12 weeks), saline, or FadA knockout (FadA−/−) Fusobacterium nucleatum. The number, size, and weight of CRC tumors were determined in isolated tumor masses. The human CRC cell lines HCT29 and HT116 were treated with lentiviral vectors overexpressing chk2 or silencing β-catenin. DNA damage was determined by Comet assay and γH2AX immunofluorescence assay and flow cytometry. The mRNA expression of chk2 was determined by RT-qPCR. Protein expression of FadA, E-cadherin, β-catenin, and chk2 were determined by Western blot analysis. Results Fusobacterium nucleatum treatment promoted DNA damage in CRC in APC (Min/+) mice. Fusobacterium nucleatum also increased the number of CRC cells that were in the S phase of the cell cycle. FadA−/− reduced tumor number, size, and burden in vivo. FadA−/− also reduced DNA damage, cell proliferation, expression of E-cadherin and chk2, and cells in the S phase. Chk2 overexpression elevated DNA damage and tumor growth in APC (Min/+) mice. Conclusions In conclusion, this study provided evidence that Fusobacterium nucleatum induced DNA damage and cell growth in CRC through FadA-dependent activation of the E-cadherin/β-catenin pathway, leading to up-regulation of chk2.

The dysbiosis signature of Fusobacterium nucleatum in colorectal cancer-cause or consequences? A systematic review

“…This is proposed to be due to the expression of proteins that have antiapoptotic, growth factor or cytokine that enhance cancer cell growth, metastasis or resistance to therapy [ 17 ]. However, F. nucleatum has been shown to also express high levels of virulence factors such as FadA , Fap2 and MORN2 proteins [ 19 ]. Studies have demonstrated that the dominant microbiome is very similar in primary and metastatic tumors [ 20 ].…”

Targeting Dietary and Microbial Tryptophan-Indole Metabolism as Therapeutic Approaches to Colon Cancer

“…Further F. nucleatum elicits substantially greater amounts of pro-inflammatory TNF-α gene expression, which can lead to increased IDO1 activation [ 99 , 106 , 114 , 115 ]. Both F. Nucleatum and Peptostreptococcus anaerobius can attach to the cancer cells through cell surface attachment proteins, activating the PI3k-Akt pathway leading to cell proliferation [ 116 , 117 ]. Intriugingly, both of the species can also produce high levels of indoles from Trp metabolism.…”

Role of Gut Microbiota and Probiotics in Colorectal Cancer: Onset and Progression

“…However, E. coli is far from the only species with this capability. Molecular studies of F. nucleatum have discovered the virulence protein FadA and its involvement in the transformation of epithelial cells and the promotion of colon tumorigenesis [ 63 ]. A meta-analysis of CRC fecal metagenomes confirmed the significant enrichment in both the colibactin-producing gene cluster pks and the F. nucleatum adhesin fadA [ 53 ].…”