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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2020

Open Access 01-12-2020 | Escherichia Coli | Research

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

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

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2020

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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.
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Literature
1.
2.
Newton PT. New insights into niclosamide action: autophagy activation in colorectal cancer. Biochem J. 2019;476:779–81.PubMedCrossRef
3.
Antoni S, Soerjomataram I, Moller B, Bray F, Ferlay J. An assessment of GLOBOCAN methods for deriving national estimates of cancer incidence. Bull World Health Organ. 2016;94:174–84.PubMedPubMedCentralCrossRef
4.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.PubMedCrossRef
5.
6.
Fairley TL, Cardinez CJ, Martin J, Alley L, Friedman C, Edwards B, et al. Colorectal cancer in U.S. adults younger than 50 years of age, 1998–2001. Cancer. 2006;107:1153–61.PubMedCrossRef
7.
O'Connell JB, Maggard MA, Liu JH, Etzioni DA, Livingston EH, Ko CY. Rates of colon and rectal cancers are increasing in young adults. Am Surg. 2003;69:866–72.PubMed
8.
de Jong AE, Morreau H, Nagengast FM, Mathus-Vliegen EM, Kleibeuker JH, Griffioen G, et al. Prevalence of adenomas among young individuals at average risk for colorectal cancer. Am J Gastroenterol. 2005;100:139–43.PubMedCrossRef
9.
Boardman LA, Morlan BW, Rabe KG, Petersen GM, Lindor NM, Nigon SK, et al. Colorectal cancer risks in relatives of young-onset cases: is risk the same across all first-degree relatives? Clin Gastroenterol Hepatol. 2007;5:1195–8.PubMedPubMedCentralCrossRef
10.
Santarelli RL, Pierre F, Corpet DE. Processed meat and colorectal cancer: a review of epidemiologic and experimental evidence. Nutr Cancer. 2008;60:131–44.PubMedPubMedCentralCrossRef
11.
Lee KJ, Inoue M, Otani T, Iwasaki M, Sasazuki S, Tsugane S, et al. Physical activity and risk of colorectal cancer in Japanese men and women: the Japan public health center-based prospective study. Cancer Causes Control. 2007;18:199–209.PubMedCrossRef
12.
Zisman AL, Nickolov A, Brand RE, Gorchow A, Roy HK. Associations between the age at diagnosis and location of colorectal cancer and the use of alcohol and tobacco: implications for screening. Arch Intern Med. 2006;166:629–34.PubMedCrossRef
13.
Tsong WH, Koh WP, Yuan JM, Wang R, Sun CL, Yu MC. Cigarettes and alcohol in relation to colorectal cancer: the Singapore Chinese health study. Br J Cancer. 2007;96:821–7.PubMedPubMedCentralCrossRef
14.
Idrissi Janati A, Karp I, Sabri H, Emami E. Is a fusobacterium nucleatum infection in the colon a risk factor for colorectal cancer?: a systematic review and meta-analysis protocol. Syst Rev. 2019;8:114.PubMedPubMedCentralCrossRef
15.
Ray K. Colorectal cancer: Fusobacterium nucleatum found in colon cancer tissue--could an infection cause colorectal cancer? Nat Rev Gastroenterol Hepatol. 2011;8:662.PubMedCrossRef
16.
Li YY, Ge QX, Cao J, Zhou YJ, Du YL, Shen B, et al. Association of Fusobacterium nucleatum infection with colorectal cancer in Chinese patients. World J Gastroenterol. 2016;22:3227–33.PubMedPubMedCentralCrossRef
17.
Liu H, Liu Y, Liu W, Zhang W, Xu J. EZH2-mediated loss of miR-622 determines CXCR4 activation in hepatocellular carcinoma. Nat Commun. 2015;6:8494.PubMedCrossRef
18.
Leung A, Tsoi H, Yu J. Fusobacterium and Escherichia: models of colorectal cancer driven by microbiota and the utility of microbiota in colorectal cancer screening. Expert Rev Gastroenterol Hepatol. 2015;9:651–7.PubMedCrossRef
19.
Chen T, Li Q, Zhang X, Long R, Wu Y, Wu J, et al. TOX expression decreases with progression of colorectal cancers and is associated with CD4 T-cell density and Fusobacterium nucleatum infection. Hum Pathol. 2018;79:93–101.PubMedCrossRef
20.
Tian X, Liu Z, Niu B, Zhang J, Tan TK, Lee SR, et al. E-cadherin/beta-catenin complex and the epithelial barrier. J Biomed Biotechnol. 2011;2011:567305.PubMedPubMedCentral
21.
Bure IV, Nemtsova MV, Zaletaev DV. Roles of E-cadherin and noncoding RNAs in the epithelial-mesenchymal transition and progression in gastric Cancer. Int J Mol Sci. 2019;20:2870.
22.
Colella B, Faienza F, Di Bartolomeo S. EMT Regulation by Autophagy: A new perspective in glioblastoma biology. Cancers (Basel). 2019;11:312.
23.
24.
Temoin S, Wu KL, Wu V, Shoham M, Han YW. Signal peptide of FadA adhesin from Fusobacterium nucleatum plays a novel structural role by modulating the filament's length and width. FEBS Lett. 2012;586:1–6.PubMedCrossRef
25.
Wu J, Li Q, Fu X. Fusobacterium nucleatum contributes to the carcinogenesis of colorectal Cancer by inducing inflammation and suppressing host immunity. Transl Oncol. 2019;12:846–51.PubMedPubMedCentralCrossRef
26.
Rubinstein MR, Wang X, Liu W, Hao Y, Cai G, Han YW. Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/beta-catenin signaling via its FadA adhesin. Cell Host Microbe. 2013;14:195–206.PubMedPubMedCentralCrossRef
27.
Gholizadeh P, Eslami H, Kafil HS. Carcinogenesis mechanisms of Fusobacterium nucleatum. Biomed Pharmacother. 2017;89:918–25.PubMedCrossRef
28.
Ma CT, Luo HS, Gao F, Tang QC, Chen W. Fusobacterium nucleatum promotes the progression of colorectal cancer by interacting with E-cadherin. Oncol Lett. 2018;16:2606–12.PubMedPubMedCentral
29.
Ahn J, Urist M, Prives C. The Chk2 protein kinase. DNA Repair (Amst). 2004;3:1039–47.CrossRef
30.
Yang Y, Weng W, Peng J, Hong L, Yang L, Toiyama Y, et al. Fusobacterium nucleatum increases proliferation of colorectal Cancer cells and tumor development in mice by activating toll-like receptor 4 signaling to nuclear factor-kappaB, and up-regulating expression of MicroRNA-21. Gastroenterology. 2017;152:851–66 e24.PubMedCrossRef
31.
Xu M, Yamada M, Li M, Liu H, Chen SG, Han YW. FadA from Fusobacterium nucleatum utilizes both secreted and nonsecreted forms for functional oligomerization for attachment and invasion of host cells. J Biol Chem. 2007;282:25000–9.PubMedCrossRef
32.
Kostic AD, Chun E, Robertson L, Glickman JN, Gallini CA, Michaud M, et al. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe. 2013;14:207–15.PubMedPubMedCentralCrossRef
33.
Tomkovich S, Yang Y, Winglee K, Gauthier J, Muhlbauer M, Sun X, et al. Locoregional effects of microbiota in a preclinical model of Colon carcinogenesis. Cancer Res. 2017;77:2620–32.PubMedPubMedCentralCrossRef
34.
Bullman S, Pedamallu CS, Sicinska E, Clancy TE, Zhang X, Cai D, et al. Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science. 2017;358:1443–8.PubMedPubMedCentralCrossRef
35.
36.
37.
38.
Liu P, Liu Y, Wang J, Guo Y, Zhang Y, Xiao S. Detection of fusobacterium nucleatum and fadA adhesin gene in patients with orthodontic gingivitis and non-orthodontic periodontal inflammation. PLoS One. 2014;9:e85280.PubMedPubMedCentralCrossRef
39.
Zhang X, Yang M, Shi H, Hu J, Wang Y, Sun Z, et al. Reduced E-cadherin facilitates renal cell carcinoma progression by WNT/beta-catenin signaling activation. Oncotarget. 2017;8:19566–76.PubMedPubMedCentralCrossRef
40.
Gai JQ, Sheng X, Qin JM, Sun K, Zhao W, Ni L. The effect and mechanism of bufalin on regulating hepatocellular carcinoma cell invasion and metastasis via Wnt/beta-catenin signaling pathway. Int J Oncol. 2016;48:338–48.PubMedCrossRef
41.
Rosso M, Lapyckyj L, Amiano N, Besso MJ, Sanchez M, Chuluyan E, et al. Secretory leukocyte protease inhibitor (SLPI) expression downregulates E-cadherin, induces beta-catenin re-localisation and triggers apoptosis-related events in breast cancer cells. Biol Cell. 2014;106:308–22.PubMedCrossRef
42.
Gu J, Cui CF, Yang L, Wang L, Jiang XH. Emodin inhibits Colon Cancer cell invasion and migration by suppressing epithelial-Mesenchymal transition via the Wnt/beta-catenin pathway. Oncol Res. 2019;27:193–202.PubMedCrossRefPubMedCentral
43.
Tafrihi M, Nakhaei Sistani R. E-cadherin/beta-catenin complex: a target for anticancer and Antimetastasis plants/plant-derived compounds. Nutr Cancer. 2017;69:702–22.PubMedCrossRef
44.
Zhang LN, Zhao L, Yan XL, Huang YH. Loss of G3BP1 suppresses proliferation, migration, and invasion of esophageal cancer cells via Wnt/beta-catenin and PI3K/AKT signaling pathways. J Cell Physiol. 2019;234:20469–84.PubMedCrossRef
45.
Zhao Y, Yu T, Zhang N, Chen J, Zhang P, Li S, et al. Nuclear E-cadherin acetylation promotes colorectal tumorigenesis via enhancing beta-catenin activity. Mol Cancer Res. 2019;17:655–65.PubMedCrossRef
46.
Ingvarsson S, Sigbjornsdottir BI, Huiping C, Hafsteinsdottir SH, Ragnarsson G, Barkardottir RB, et al. Mutation analysis of the CHK2 gene in breast carcinoma and other cancers. Breast Cancer Res. 2002;4:R4.PubMedPubMedCentralCrossRef
47.
Lipton L, Fleischmann C, Sieber OM, Thomas HJ, Hodgson SV, Tomlinson IP, et al. Contribution of the CHEK2 1100delC variant to risk of multiple colorectal adenoma and carcinoma. Cancer Lett. 2003;200:149–52.PubMedCrossRef
48.
Stawinska M, Cygankiewicz A, Trzcinski R, Mik M, Dziki A, Krajewska WM. Alterations of Chk1 and Chk2 expression in colon cancer. Int J Color Dis. 2008;23:1243–9.CrossRef
49.
Pires IM, Ward TH, Dive C. Oxaliplatin responses in colorectal cancer cells are modulated by CHK2 kinase inhibitors. Br J Pharmacol. 2010;159:1326–38.PubMedPubMedCentralCrossRef
50.
Yao J, Huang A, Zheng X, Liu T, Lin Z, Zhang S, et al. 53BP1 loss induces chemoresistance of colorectal cancer cells to 5-fluorouracil by inhibiting the ATM-CHK2-P53 pathway. J Cancer Res Clin Oncol. 2017;143:419–31.PubMedCrossRef
51.
Takemura H, Rao VA, Sordet O, Furuta T, Miao ZH, Meng L, et al. Defective Mre11-dependent activation of Chk2 by ataxia telangiectasia mutated in colorectal carcinoma cells in response to replication-dependent DNA double strand breaks. J Biol Chem. 2006;281:30814–23.PubMedCrossRef
52.
Oka K, Tanaka T, Enoki T, Yoshimura K, Ohshima M, Kubo M, et al. DNA damage signaling is activated during cancer progression in human colorectal carcinoma. Cancer Biol Ther. 2010;9:246–52.PubMedCrossRef
53.
Varmark H, Kwak S, Theurkauf WE. A role for Chk2 in DNA damage induced mitotic delays in human colorectal cancer cells. Cell Cycle. 2010;9:312–20.PubMedCrossRef
54.
Bartek J, Lukas J. Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell. 2003;3:421–9.PubMedCrossRef
55.
Freiberg RA, Hammond EM, Dorie MJ, Welford SM, Giaccia AJ. DNA damage during reoxygenation elicits a Chk2-dependent checkpoint response. Mol Cell Biol. 2006;26:1598–609.PubMedPubMedCentralCrossRef
56.
Magni M, Ruscica V, Buscemi G, Kim JE, Nachimuthu BT, Fontanella E, et al. Chk2 and REGgamma-dependent DBC1 regulation in DNA damage induced apoptosis. Nucleic Acids Res. 2014;42:13150–60.PubMedPubMedCentralCrossRef
57.
Stolz A, Ertych N, Bastians H. Loss of the tumour-suppressor genes CHK2 and BRCA1 results in chromosomal instability. Biochem Soc Trans. 2010;38:1704–8.PubMedCrossRef
Metadata
Title
FadA promotes DNA damage and progression of Fusobacterium nucleatum-induced colorectal cancer through up-regulation of chk2
Authors
Pin Guo
Zibin Tian
Xinjuan Kong
Lin Yang
Xinzhi Shan
Bingzi Dong
Xueli Ding
Xue Jing
Chen Jiang
Na Jiang
Yanan Yu
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2020
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-020-01677-w

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