FadA promotes DNA damage and progression of Fusobacterium nucleatum-induced colorectal cancer through up-regulation of chk2.
FadA promotes DNA damage and progression of Fusobacterium nucleatum-induced colorectal cancer through up-regulation of chk2.
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DOI：
10.1186/s13046-020-01677-w
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发表时间：
2020-09-29
期刊：
影响因子：
--
通讯作者：
Yu Y
中科院分区：
文献类型：
--
作者：
Guo P;Tian Z;Kong X;Yang L;Shan X;Dong B;Ding X;Jing X;Jiang C;Jiang N;Yu Y
在全球范围内，结直肠癌 (CRC) 每年影响超过 100 万人。除了不可改变的因素和其他环境风险因素外，具核梭杆菌感染最近也与结直肠癌有关。在这项研究中，我们在小鼠模型中探讨了具核梭杆菌感染在结直肠癌进展中的作用机制。 C57BL/6 J-腺瘤性息肉病大肠杆菌 (APC) Min/J 小鼠 [APC (Min/+)] 用具核梭杆菌（109 cfu/mL，0.2 mL/次/天，即 12 周）、盐水或 FadA 敲除 (FadA−/−) 具核梭杆菌治疗。在分离的肿瘤块中测定CRC肿瘤的数量、大小和重量。用过表达 chk2 或沉默 β-catenin 的慢病毒载体处理人 CRC 细胞系 HCT29 和 HT116。通过彗星试验、γH2AX免疫荧光试验和流式细胞术测定DNA损伤。通过RT-qPCR测定chk2的mRNA表达。通过蛋白质印迹分析测定 FadA、E-钙粘蛋白、β-连环蛋白和 chk2 的蛋白表达。具核梭杆菌治疗促进 APC (Min/+) 小鼠结直肠癌 DNA 损伤。具核梭杆菌还增加了处于细胞周期 S 期的 CRC 细胞的数量。 FadA−/− 减少了体内肿瘤的数量、大小和负荷。 FadA−/− 还减少 DNA 损伤、细胞增殖、E-钙粘蛋白和 chk2 的表达以及 S 期细胞。 Chk2 过表达会增加 APC (Min/+) 小鼠的 DNA 损伤和肿瘤生长。总之，这项研究提供了证据，证明具核梭杆菌通过 FadA 依赖性激活 E-钙粘蛋白/β-连环蛋白途径诱导 CRC 中的 DNA 损伤和细胞生长，从而导致 chk2 上调。
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. 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. 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. 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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DOI：
10.1186/bcr435
发表时间：
2002
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Ingvarsson S;Sigbjornsdottir BI;Huiping C;Hafsteinsdottir SH;Ragnarsson G;Barkardottir RB;Arason A;Egilsson V;Bergthorsson JT
通讯作者：
Bergthorsson JT
影响因子：
14.9
作者：
Magni M;Ruscica V;Buscemi G;Kim JE;Nachimuthu BT;Fontanella E;Delia D;Zannini L
通讯作者：
Zannini L
影响因子：
12.6
作者：
Boardman, Lisa A.;Morlan, Bruce W.;Gallinger, Steven
通讯作者：
Gallinger, Steven
影响因子：
3.7
作者：
Liu P;Liu Y;Wang J;Guo Y;Zhang Y;Xiao S
通讯作者：
Xiao S
影响因子：
4.3
作者：
Li, Yu-Yuan;Ge, Quan-Xing;Nie, Yu-Qiang
通讯作者：
Nie, Yu-Qiang