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

• Published in: Journal of experimental & clinical cancer research Vol. 39; no. 1; pp. 1 - 202
• Main Authors: Guo, Pin, Tian, Zibin, Kong, Xinjuan, Yang, Lin, Shan, Xinzhi, Dong, Bingzi, Ding, Xueli, Jing, Xue, Jiang, Chen, Jiang, Na, Yu, Yanan
• Format: Journal Article
• Language: English
• Published: London BioMed Central Ltd 29.09.2020; BioMed Central; BMC
• Subjects: Analysis; Antibodies; Antigens; Cancer genetics; Cell cycle; Colorectal cancer; Deoxyribonucleic acid; Development and progression; Disease; DNA; DNA damage; E coli; E-cadherin/β-catenin pathway; Experiments; FadA, chk2; Fusobacterium nucleatum; Genetic research; Gram-negative bacteria; Health aspects; Infection; Infections; Mortality; Pathogens; RNA; Rodents; Tumors; United Kingdom > UK; United States > US; China
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-020-01677-w

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 (10.sup.9 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 [beta]-catenin. DNA damage was determined by Comet assay and [gamma]H2AX immunofluorescence assay and flow cytometry. The mRNA expression of chk2 was determined by RT-qPCR. Protein expression of FadA, E-cadherin, [beta]-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/[beta]-catenin pathway, leading to up-regulation of chk2. Keywords: Colorectal cancer, Fusobacterium nucleatum, FadA, chk2, DNA damage, E-cadherin/[beta]-catenin pathway