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活化的中性粒细胞在结肠上皮细胞中诱导依赖于人错配修复蛋白2（hMSH2）的G2/M期检查点停滞以及在（CA）13重复序列处出现复制错误。

Activated neutrophils induce an hMSH2-dependent G2/M checkpoint arrest and replication errors at a (CA)13-repeat in colon epithelial cells.

作者信息

Campregher C, Luciani M G, Gasche C

机构信息

AKH Wien, Division of Gastroenterology and Hepatology, Währinger Gürtel 18, A-1090 Vienna, Austria.

出版信息

Gut. 2008 Jun;57(6):780-7. doi: 10.1136/gut.2007.141556. Epub 2008 Feb 13.

DOI:10.1136/gut.2007.141556
PMID:18272544
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2564829/
Abstract

OBJECTIVE

Chronic inflammation in ulcerative colitis is associated with increased risk for colorectal cancer. Its molecular pathway of cancer development is poorly understood. We investigated the role of neutrophil-derived cellular stress in an in vitro model of neutrophils as effectors and colon epithelial cells as targets, and tested for changes in cell cycle distribution and the appearance of replication errors.

DESIGN

Colon epithelial cells with different mismatch repair phenotypes were co-cultured with activated neutrophils. Target cells were analysed for cell cycle distribution and replication errors by flow cytometry. Changes in nuclear and DNA-bound levels of mismatch repair- and checkpoint-related proteins were analysed by western blotting.

RESULTS

Activated neutrophils cause an accumulation of target cells in G2/M, consistent with the installation of a DNA-damage checkpoint. Cells that do not express hMSH2, p53 or p21(waf1/cip1) failed to undergo the G2/M arrest. Phosphorylation of p53 at site Ser15 and Chk1 at Ser317, as well as accumulation of p21(waf1/cip1), was observed within 8-24 h. Superoxide dismutase and catalase were unable to overcome this G2/M arrest, possibly indicating that neutrophil products other than superoxide or H(2)O(2) are involved in this cellular response. Finally, exposure to activated neutrophils increased the number of replication errors.

CONCLUSIONS

By using an in vitro co-culture model that mimics intestinal inflammation in ulcerative colitis, we provide molecular evidence for an hMSH2-dependent G2/M checkpoint arrest and for the presence of replication errors.

摘要

目的

溃疡性结肠炎中的慢性炎症与结直肠癌风险增加相关。其癌症发展的分子途径尚不清楚。我们在一个以中性粒细胞为效应细胞、结肠上皮细胞为靶细胞的体外模型中研究了中性粒细胞衍生的细胞应激的作用，并检测了细胞周期分布的变化和复制错误的出现情况。

设计

将具有不同错配修复表型的结肠上皮细胞与活化的中性粒细胞共培养。通过流式细胞术分析靶细胞的细胞周期分布和复制错误。通过蛋白质印迹法分析错配修复和检查点相关蛋白的核水平和与DNA结合水平的变化。

结果

活化的中性粒细胞导致靶细胞在G2/M期积累，这与DNA损伤检查点的建立一致。不表达hMSH2、p53或p21（waf1/cip1）的细胞未能经历G2/M期阻滞。在8 - 24小时内观察到p53的Ser15位点和Chk1的Ser317位点磷酸化，以及p21（waf1/cip1）的积累。超氧化物歧化酶和过氧化氢酶无法克服这种G2/M期阻滞，这可能表明除超氧化物或H₂O₂之外的中性粒细胞产物参与了这种细胞反应。最后，暴露于活化的中性粒细胞会增加复制错误的数量。

结论

通过使用一种模拟溃疡性结肠炎肠道炎症的体外共培养模型，我们为hMSH2依赖的G2/M检查点阻滞和复制错误的存在提供了分子证据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b6a/2564829/267d515dc012/GUT-57-06-0780-f07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b6a/2564829/60654349d9d6/GUT-57-06-0780-f01.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b6a/2564829/267d515dc012/GUT-57-06-0780-f07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b6a/2564829/60654349d9d6/GUT-57-06-0780-f01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b6a/2564829/e385a1e51f90/GUT-57-06-0780-f02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b6a/2564829/ead0990e1aec/GUT-57-06-0780-f03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b6a/2564829/7ea3e7345165/GUT-57-06-0780-f04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b6a/2564829/279b6193a123/GUT-57-06-0780-f05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b6a/2564829/8c4ff6c26aec/GUT-57-06-0780-f06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b6a/2564829/267d515dc012/GUT-57-06-0780-f07.jpg

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