Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Cancer Res. 2010 Jul 15;70(14):5740-8. doi: 10.1158/0008-5472.CAN-09-4690. Epub 2010 Jun 29.
Infection by cagA-positive Helicobacter pylori (H. pylori) is strongly associated with gastric carcinomas and gastric mucosa-associated lymphoid tissue (MALT) lymphomas. H. pylori translocates the bacterial protein CagA into gastric epithelial cells, and the translocated CagA deregulates intracellular signaling pathways and thereby initiates pathogenesis. This in turn raised the possibility that H. pylori is associated with the development of MALT lymphomas during persistent infection by direct interaction with B lymphocytes. In this work, we showed that CagA can be directly translocated into human B lymphoid cells by H. pylori, and the translocated CagA undergoes tyrosine phosphorylation and binds to intracellular SH-2. Meanwhile, the translocated CagA induces activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase in human B lymphoid cells, and upregulates the expressions of Bcl-2 and Bcl-X(L), which prevents apoptosis. These results provide the first direct evidence for the role of CagA as a bacterium-derived oncoprotein that acts in human B cells, and further implies that CagA is directly delivered into B cells by H. pylori and is associated with the development of MALT lymphomas.
CagA 阳性幽门螺杆菌（H. pylori）感染与胃癌和胃黏膜相关淋巴组织（MALT）淋巴瘤密切相关。H. pylori 将细菌蛋白 CagA 易位至胃上皮细胞，易位的 CagA 使细胞内信号通路失调，从而引发发病机制。这反过来又提出了一种可能性，即 H. pylori 通过与 B 淋巴细胞的直接相互作用，在持续感染期间与 MALT 淋巴瘤的发展有关。在这项工作中，我们表明 CagA 可被 H. pylori 直接易位至人 B 淋巴样细胞，并且易位的 CagA 发生酪氨酸磷酸化并与细胞内 SH-2 结合。同时，易位的 CagA 诱导人 B 淋巴样细胞中细胞外信号调节激酶和 p38 丝裂原活化蛋白激酶的激活，并上调 Bcl-2 和 Bcl-X(L)的表达，从而阻止细胞凋亡。这些结果为 CagA 作为一种细菌来源的癌蛋白在人 B 细胞中发挥作用提供了首个直接证据，并进一步表明 CagA 由 H. pylori 直接递送至 B 细胞，并与 MALT 淋巴瘤的发展有关。
