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

Zibin Tian,Lin Yang,Na Jiang,Xueli Ding,Yanan Yu,Xue Jing,Xinzhi Shan,Pin Guo,Bingzi Dong,Chen Jiang,Xinjuan Kong

doi:10.1186/s13046-020-01677-w

Abstract

BackgroundGlobally, 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.MethodsC57BL/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.ResultsFusobacterium 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.ConclusionsIn 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.

Highlights

Colorectal cancer (CRC) affects more than 1 million people each year
Checkpoint kinase 2 (Chk2) is a multifunctional enzyme that has been shown to be central to cell cycle arrest and apoptosis by DNA damage [29]. Based on these previous findings, we further investigated the involvement of the E-cadherin/β-catenin pathway and FadA adhesion in Fusobacterium nucleatum-induced colorectal cancer (CRC) that involved DNA damage induced by a common mediator chk2 in a mouse model
WT Fusobacterium nucleatum significantly increased tumor volume induced by HT29 and HCT116 cells when compared to phosphate buffered saline (PBS) or Escherichia coli treatment (Fig. 1a)

Summary

Introduction

Colorectal cancer (CRC) affects more than 1 million people each year. In addition to nonmodifiable and other environmental risk factors, Fusobacterium nucleatum infection has been linked to CRC recently. In addition to non-modifiable risk factors such as age [6, 7], personal history of inflammatory bowel disease or adenomatous polyps [8], family history of CRC [9], ingestion of food that contains carcinogenic compounds [10], lack of physical activity [11], cigarette smoking, and heavy alcohol consumption [12, 13] have been demonstrated to contribute to CRC development. These risk factors suggest that both prevention and treatment of CRC are important

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Results

Conclusion