Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University; Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China.
Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University; Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China.
Mutat Res Rev Mutat Res. 2014 Jan-Mar;759:14-26. doi: 10.1016/j.mrrev.2013.09.002. Epub 2013 Sep 25.
The interindividual differences in risk of Helicobacter pylori (H. pylori)-associated gastric cancer involve significant heterogeneities of both host genetics and H. pylori strains. Several recent studies proposed a distinct sequence for H. pylori exerting its virulence in the host stomach: (i) adhering to and colonizing the surface of gastric epithelial cells, (ii) evading and attenuating the host defense, and (iii) invading and damaging the gastric mucosa. This review focuses on several key issues that still need to be clarified, such as which virulence factors of H. pylori are involved in the three pathogenic steps, which host genes respond to the step-specific virulence factors, and whether and/or how the corresponding host genetic variations influence the risk of gastric carcinogenesis. Urease, BabA and SabA in the adhesion-step, PGN and LPS in the immune evasion-step, and CagA, VacA and Tipα in the mucosal damage-step were documented to play an important role in step-specific pathogenicity of H. pylori infection. There is evidence further supporting a role of potentially functional polymorphisms of host genes directly responding to these pathogenic step-specific virulence factors in the susceptibility of gastric carcinogenesis, especially for urease-interacting HLA class II genes, BabA-interacting MUC1, PGN-interacting NOD1, LPS-interacting TLR4, and CagA-interacting PTPN11 and CDH1. With the continuous improvement of understanding the genetic profile of H. pylori-associated gastric carcinogenesis, a person at increased risk for gastric cancer may benefit from several aspects of efforts: (i) prevent H. pylori infection with a vaccine targeting certain step-specific virulence factor; (ii) eradicate H. pylori infection by blocking step-specific psychopathological characteristics of virulence factors; and (iii) adjust host physiological function to resist the carcinogenic role of step-specific virulence factors or interrupt the cellular signal transduction of the interplay between H. pylori and host in each pathogenic step, especially for the subjects with precancerous lesions in the stomach.
个体间幽门螺杆菌（H. pylori）相关胃癌风险的差异涉及宿主遗传学和 H. pylori 菌株的显著异质性。最近的几项研究提出了 H. pylori 在宿主胃中发挥其毒力的一个不同序列：（i）黏附并定植于胃上皮细胞表面，（ii）逃避和减弱宿主防御，以及（iii）侵袭和损伤胃黏膜。本综述重点关注仍需阐明的几个关键问题，例如 H. pylori 的哪些毒力因子参与了这三个致病步骤，哪些宿主基因对特定于步骤的毒力因子作出反应，以及相应的宿主遗传变异是否以及/或如何影响胃癌发生的风险。在黏附步骤中，尿素酶、BabA 和 SabA，在免疫逃避步骤中，PGN 和 LPS，以及在黏膜损伤步骤中，CagA、VacA 和 Tipα，被证明在 H. pylori 感染的特定于步骤的致病性中发挥重要作用。有证据进一步支持宿主基因的潜在功能性多态性在胃癌发生易感性中的作用，这些基因直接针对这些特定于步骤的毒力因子，特别是对于与尿素酶相互作用的 HLA Ⅱ类基因、与 BabA 相互作用的 MUC1、与 PGN 相互作用的 NOD1、与 LPS 相互作用的 TLR4，以及与 CagA 相互作用的 PTPN11 和 CDH1。随着对 H. pylori 相关胃癌发病机制遗传特征的不断深入了解，增加患胃癌风险的人可能会从以下几个方面受益：（i）通过针对特定于步骤的毒力因子的疫苗预防 H. pylori 感染；（ii）通过阻断毒力因子的特定于步骤的心理病理学特征来根除 H. pylori 感染；以及（iii）调整宿主生理功能以抵抗特定于步骤的毒力因子的致癌作用或中断 H. pylori 和宿主在每个致病步骤中的相互作用的细胞信号转导，特别是对于胃有癌前病变的患者。
