Enterococcus faecalis induces aneuploidy and tetraploidy in colonic epithelial cells through a bystander effect.
Enterococcus faecalis induces aneuploidy and tetraploidy in colonic epithelial cells through a bystander effect.
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DOI：
10.1158/0008-5472.can-08-1551
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发表时间：
2008-12-01
期刊：
影响因子：
11.2
通讯作者：
Huycke MM
中科院分区：
文献类型：
--
作者：
Wang X;Allen TD;May RJ;Lightfoot S;Houchen CW;Huycke MM
肠道细菌是散发性结直肠癌的潜在重要病因，但细菌引发肿瘤的机制仍不确定。在这里，我们描述的机制，链接粪肠球菌，一种已知的细菌产生细胞外超氧化物，急性诱导染色体不稳定。永生化的人和非转化的鼠结肠上皮细胞，沿着小鼠结肠结扎模型，用于评估E. faecalis对基因组DNA稳定性和损伤的影响。我们发现，这种人肠上皮细胞在HCT 116、RKO和YAMC细胞中产生非整倍体、四倍体和γH2AX灶。此外，直接暴露E.粪便对这些细胞诱导G2细胞周期停滞。将细胞暴露于大肠杆菌也观察到类似的观察结果。粪便感染的巨噬细胞在双室共培养系统中检测旁观者效应。锰超氧化物歧化酶，过氧化氢酶，和生育酚衰减，咖啡因和谷胱甘肽合成酶的抑制剂加剧，非整倍体和cyclomodulatory的影响，并联系氧化还原活性表型，这种肠道肠道寄生虫潜在的转化事件。这些发现为E.粪便和肠粘膜可促进细胞转化和肿瘤发生。
Intestinal commensals are potential important contributors to the etiology of sporadic colorectal cancer but mechanisms by which bacteria can initiate tumors remain uncertain. Herein we describe mechanisms that link Enterococcus faecalis, a bacterium known to produce extracellular superoxide, to the acute induction of chromosomal instability. Immortalized human and non-transformed murine colonic epithelial cells, along with a mouse colonic ligation model, were used to assess the effect of E. faecalis on genomic DNA stability and damage. We found that this human intestinal commensal generated aneuploidy, tetraploidy, and γH2AX foci in HCT116, RKO, and YAMC cells. In addition, direct exposure of E. faecalis to these cells induced a G2 cell cycle arrest. Similar observations were noted by exposuring cells to E. faecalis-infected macrophages in a dual-chamber co-culture system for detecting bystander effects. Manganese superoxide dismutase, catalase, and tocopherols attenuated, caffeine and inhibitor of glutathione synthase exacerbated, aneugenic and cyclomodulatory effects and linked the redox-active phenotype of this intestinal commensal to potentially transforming events. These findings provide novel insights into mechanisms by which E. faecalis and intestinal commensals can contribute to cellular transformation and tumorigenesis.