胃菌损害人类DNA——胃癌的风险因素
Sciencedaily · 2011/09/07
苏黎世大学的分子学家识别出幽门螺旋菌的致癌机制,后者在胃粘膜中能损害细胞DNA并诱发这些细胞恶性转化。

幽门螺旋杆菌是胃癌形成的最大风险因素之一,全球范围内,胃癌列于最常见癌症致死病例的第3位。如今,苏黎世大学的分子学家识别出幽门螺旋菌的致癌机制,后者在胃粘膜中能损害细胞DNA并诱发这些细胞恶性转化。

绿色的幽门螺旋杆菌分布在胃上

胃癌是最常见、往往致命的癌症之一。每3个癌症致死病例中就有1个死于胃癌,而胃癌形成的主要风险因素是胃粘膜慢性感染幽门螺旋杆菌。自从这种细菌在1983年被发现以来,科学家一直对它的诱癌机制感到困惑。如今,苏黎世大学分子癌症研究学院的Anne Müller 教授和 Massimo Lopes 教授领导这项研究,该小组揭示出在体外条件下幽门螺旋杆菌如何损害人体和动物的细胞。寄主细胞感染后,DNA双螺旋的2条链都会断裂。研究发表在《Proceedings of the National Academy of Sciences》期刊上。

损害程度取决于感染的持续时间

研究人员表明了双链断裂的频率取决于感染的强度和持续时间。DNA断裂产生于幽门螺旋杆菌的作用,并引发细胞中DNA损伤信号和修复机制。如果感染后几个小时内这种细菌能够被抗生素清除掉,大多数的断裂可成功地修复。然而,延长的感染期将拖垮细胞修复反应,以及危害的双链断裂将不能或不准确地修复,最终引起遗传突变或细胞的死亡。胃癌细胞的基因组具有不稳定性,在这一点上新研究与之前的研究保持一致。此外,新研究能更好地理解关于促进胃癌发生的病理机制。

这项研究由瑞士国家科学基金会,瑞士癌症协会和苏黎世大学的资助。(生物探索译 Pobee)

 

生物探索推荐摘要

The bacterial pathogen Helicobacter pylori chronically infects the human gastric mucosa and is the leading risk factor for the development of gastric cancer. The molecular mechanisms of H. pylori-associated gastric carcinogenesis remain ill defined. In this study, we examined the possibility that H. pylori directly compromises the genomic integrity of its host cells. We provide evidence that the infection introduces DNA double-strand breaks (DSBs) in primary and transformed murine and human epithelial and mesenchymal cells. The induction of DSBs depends on the direct contact of live bacteria with mammalian cells. The infection-associated DNA damage is evident upon separation of nuclear DNA by pulse field gel electrophoresis and by high-magnification microscopy of metaphase chromosomes. Bacterial adhesion (e.g., via blood group antigen-binding adhesin) is required to induce DSBs; in contrast, the H. pylori virulence factors vacuolating cytotoxin A, γ-glutamyl transpeptidase, and the cytotoxin-associated gene (Cag) pathogenicity island are dispensable for DSB induction. The DNA discontinuities trigger a damage-signaling and repair response involving the sequential ataxia telangiectasia mutated (ATM)-dependent recruitment of repair factors—p53-binding protein (53BP1) and mediator of DNA damage checkpoint protein 1 (MDC1)—and histone H2A variant X (H2AX) phosphorylation. Although most breaks are repaired efficiently upon termination of the infection, we observe that prolonged active infection leads to saturation of cellular repair capabilities. In summary, we conclude that DNA damage followed by potentially imprecise repair is consistent with the carcinogenic properties of H. pylori and with its mutagenic properties in vitro and in vivo and may contribute to the genetic instability and frequent chromosomal aberrations that are a hallmark of gastric cancer.

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