Clinical Pharmacology and Gastroenterology Unit, Sao Francisco University Medical School, Bragança Paulista, São Paulo, Brazil; Women's Health Hospital Prof Dr José Aristodemo Pinotti, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
Clinical Pharmacology and Gastroenterology Unit, Sao Francisco University Medical School, Bragança Paulista, São Paulo, Brazil.
Am J Pathol. 2018 Feb;188(2):329-335. doi: 10.1016/j.ajpath.2017.10.005. Epub 2017 Nov 9.
Gastric cancer (GC) is the second leading cause of cancer-related mortality worldwide. The disease develops from the accumulation of several genetic and epigenetic changes. Among other risk factors, Helicobacter pylori infection is considered the main driving factor of GC development. H. pylori infection increases DNA damage levels and leads to epigenetic dysregulation, which may favor gastric carcinogenesis. An early step in double-strand break repair is the recruitment of ataxia-telangiectasia mutated serine/threonine kinase (ATM) to the damaged site, where it plays a key role in advancing the DNA damage checkpoint process. H. pylori infection has been associated with the introduction of double-strand breaks in epithelial cells, triggering damage signaling and repair response involving ATM. Thus, the current study analyzed the effect of H. pylori infection on the DNA damage response sensor, ATM, in gastric epithelial cells and in biopsy specimens from patients with GC. In this study, we identified that H. pylori infection stimulated DNA damage, and therefore induced ATM in a virulence factor-dependent manner. In addition, we found that H. pylori might activate ATM through histone H3 and H4 hyperacetylation and DNA promoter hypomethylation. Our findings show a mechanism associating ATM signaling induction with H. pylori infection.
胃癌（GC）是全球癌症相关死亡的第二大主要原因。这种疾病的发展源于多种遗传和表观遗传变化的积累。在其他风险因素中，幽门螺杆菌感染被认为是 GC 发展的主要驱动因素。幽门螺杆菌感染会增加 DNA 损伤水平，并导致表观遗传失调，这可能有利于胃致癌作用。双链断裂修复的早期步骤是将共济失调毛细血管扩张突变蛋白丝氨酸/苏氨酸激酶（ATM）募集到受损部位，在那里它在推进 DNA 损伤检查点过程中发挥关键作用。幽门螺杆菌感染与上皮细胞中的双链断裂的引入有关，从而引发涉及 ATM 的损伤信号和修复反应。因此，本研究分析了幽门螺杆菌感染对胃上皮细胞和 GC 患者活检标本中 DNA 损伤反应传感器 ATM 的影响。在这项研究中，我们发现幽门螺杆菌感染刺激了 DNA 损伤，因此以毒力因子依赖的方式诱导了 ATM。此外，我们发现幽门螺杆菌可能通过组蛋白 H3 和 H4 的过度乙酰化和 DNA 启动子低甲基化来激活 ATM。我们的研究结果表明了一种与幽门螺杆菌感染相关的 ATM 信号诱导机制。
