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Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis.
Cellular & Molecular Immunology ( IF 24.1 ) Pub Date : 2019-12-05 , DOI: 10.1038/s41423-019-0339-5
Atsushi Takahashi-Kanemitsu 1 , Christopher T Knight 1 , Masanori Hatakeyama 1
Affiliation  

Chronic infection with Helicobacter pylori cagA-positive strains is the strongest risk factor for gastric cancer. The cagA gene product, CagA, is delivered into gastric epithelial cells via the bacterial type IV secretion system. Delivered CagA then undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs in its C-terminal region and acts as an oncogenic scaffold protein that physically interacts with multiple host signaling proteins in both tyrosine phosphorylation-dependent and -independent manners. Analysis of CagA using in vitro cultured gastric epithelial cells has indicated that the nonphysiological scaffolding actions of CagA cell-autonomously promote the malignant transformation of the cells by endowing the cells with multiple phenotypic cancer hallmarks: sustained proliferation, evasion of growth suppressors, invasiveness, resistance to cell death, and genomic instability. Transgenic expression of CagA in mice leads to in vivo oncogenic action of CagA without any overt inflammation. The in vivo oncogenic activity of CagA is further potentiated in the presence of chronic inflammation. Since Helicobacter pylori infection triggers a proinflammatory response in host cells, a feedforward stimulation loop that augments the oncogenic actions of CagA and inflammation is created in CagA-injected gastric mucosa. Given that Helicobacter pylori is no longer colonized in established gastric cancer lesions, the multistep nature of gastric cancer development should include a "hit-and-run" process of CagA action. Thus, acquisition of genetic and epigenetic alterations that compensate for CagA-directed cancer hallmarks may be required for completion of the "hit-and-run" process of gastric carcinogenesis.

中文翻译:

支持胃癌发生的幽门螺杆菌 CagA 的分子解剖学和致病作用。

幽门螺杆菌cagA阳性菌株的慢性感染是胃癌的最强危险因素。cagA 基因产物 CagA 通过细菌 IV 型分泌系统传递到胃上皮细胞中。递送的 CagA 然后在其 C 末端区域的 Glu-Pro-Ile-Tyr-Ala (EPIYA) 基序处发生酪氨酸磷酸化,并作为致癌支架蛋白,在酪氨酸磷酸化依赖性和 -独立的举止。使用体外培养的胃上皮细胞对 CagA 的分析表明,CagA 细胞的非生理支架作用——通过赋予细胞多种表型癌症标志——自主促进细胞的恶性转化:持续增殖、逃避生长抑制因子、侵袭性、抗细胞死亡和基因组不稳定性。CagA 在小鼠中的转基因表达导致 CagA 的体内致癌作用,而没有任何明显的炎症。在存在慢性炎症的情况下,CagA 的体内致癌活性会进一步增强。由于幽门螺杆菌感染会在宿主细胞中引发促炎反应,因此在注射了 CagA 的胃粘膜中会产生一个增强 CagA 的致癌作用和炎症的前馈刺激回路。鉴于幽门螺杆菌不再定植于已确定的胃癌病变中,胃癌发展的多步骤性质应包括 CagA 作用的“打了就跑”的过程。因此,
更新日期:2019-12-05
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