Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA.
Department of Veterans Affairs, Miami VA Healthcare System, Miami, Florida, USA.
J Clin Invest. 2020 May 1;130(5):2422-2434. doi: 10.1172/JCI130015.
Approximately half of the world's population is infected with the stomach pathogen Helicobacter pylori. Infection with H. pylori is the main risk factor for distal gastric cancer. Bacterial virulence factors, such as the oncoprotein CagA, augment cancer risk. Yet despite high infection rates, only a fraction of H. pylori-infected individuals develop gastric cancer. This raises the question of defining the specific host and bacterial factors responsible for gastric tumorigenesis. To investigate the tumorigenic determinants, we analyzed gastric tissues from human subjects and animals infected with H. pylori bacteria harboring different CagA status. For laboratory studies, well-defined H. pylori strain B128 and its cancerogenic derivative strain 7.13, as well as various bacterial isogenic mutants were employed. We found that H. pylori compromises key tumor suppressor mechanisms: the host stress and apoptotic responses. Our studies showed that CagA induces phosphorylation of XIAP E3 ubiquitin ligase, which enhances ubiquitination and proteasomal degradation of the host proapoptotic factor Siva1. This process is mediated by the PI3K/Akt pathway. Inhibition of Siva1 by H. pylori increases survival of human cells with damaged DNA. It occurs in a strain-specific manner and is associated with the ability to induce gastric tumor.
世界上大约有一半的人口感染了胃部病原体幽门螺杆菌。感染幽门螺杆菌是导致远端胃癌的主要危险因素。细菌的毒力因子，如癌蛋白 CagA，会增加癌症风险。然而，尽管感染率很高，只有一小部分感染了幽门螺杆菌的人会发展为胃癌。这就提出了一个问题，即确定导致胃肿瘤发生的特定宿主和细菌因素。为了研究致癌决定因素，我们分析了感染了具有不同 CagA 状态的幽门螺杆菌的人类和动物的胃组织。在实验室研究中，我们使用了明确定义的幽门螺杆菌菌株 B128 及其致癌衍生菌株 7.13 以及各种细菌同基因突变体。我们发现，幽门螺杆菌破坏了关键的肿瘤抑制机制：宿主应激和细胞凋亡反应。我们的研究表明，CagA 诱导 XIAP E3 泛素连接酶的磷酸化，从而增强宿主促凋亡因子 Siva1 的泛素化和蛋白酶体降解。这个过程是由 PI3K/Akt 通路介导的。幽门螺杆菌通过抑制 Siva1 增加了具有受损 DNA 的人类细胞的存活率。这种情况以菌株特异性的方式发生，并且与诱导胃癌的能力有关。
