Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse
Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse
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DOI：
10.1073/pnas.0711183105
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发表时间：
2008-01-22
影响因子：
11.1
通讯作者：
Hatakeyama, Masanori
中科院分区：
文献类型：
--
作者：
Ohnishi, Naomi;Yuasa, Hitomi;Hatakeyama, Masanori
cagA阳性幽门螺杆菌感染与胃腺癌和B细胞来源的胃粘膜相关淋巴组织（MALT）淋巴瘤相关。cagA编码的CagA蛋白通过细菌IV型分泌系统递送到胃上皮细胞中，并且在Src家族激酶的酪氨酸磷酸化后，特异性结合并异常激活SHIP-2酪氨酸磷酸酶，SHIP-2酪氨酸磷酸酶是人类恶性肿瘤中的一种真正的癌蛋白。CagA还通过与不依赖于CagA酪氨酸磷酸化的分配缺陷型1（PAR 1）/微管亲和力调节激酶（MARK）相互作用并抑制其而引起上皮细胞中的连接和极性缺陷。尽管这些CagA的活动，有助于肿瘤转化，CagA和体内肿瘤发生之间的因果关系仍然未知。在这里，我们产生了在全身或主要在胃中表达野生型或磷酸化抗性CagA的转基因小鼠。野生型CagA转基因小鼠表现出胃上皮增生，一些小鼠发展为胃息肉和胃和小肠腺癌。野生型CagA的全身表达进一步诱导白细胞增多伴IL-3/GM-CSF超敏反应，一些小鼠发生髓性白血病和B细胞淋巴瘤，这些血液恶性肿瘤也是由功能获得性SHIP-2突变引起的。在表达抗磷酸化CagA的转基因小鼠中未观察到这种病理学异常。这些结果为CagA作为一种在哺乳动物中起作用的细菌源性癌蛋白（细菌癌蛋白）的作用提供了第一个直接证据，并进一步表明CagA酪氨酸磷酸化的重要性，这使得CagA能够解除SHIP-2在H.幽门相关肿瘤
Infection with cagA-positive Helicobacter pylori is associated with gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma of B cell origin. The cagA-encoded CagA protein is delivered into gastric epithelial cells via the bacterial type IV secretion system and, upon tyrosine phosphorylation by Src family kinases, specifically binds to and aberrantly activates SHIP-2 tyrosine phosphatase, a bona fide oncoprotein in human malignancies. CagA also elicits junctional and polarity defects in epithelial cells by interacting with and inhibiting partitioning-defective 1 (PAR1)/microtubule affinity-regulating kinase (MARK) independently of CagA tyrosine phosphorylation. Despite these CagA activities that contribute to neoplastic transformation, a causal link between CagA and in vivo oncogenesis remains unknown. Here, we generated transgenic mice expressing wild-type or phosphorylation-resistant CagA throughout the body or predominantly in the stomach. Wild-type CagA transgenic mice showed gastric epithelial hyperplasia and some of the mice developed gastric polyps and adenocarcinomas of the stomach and small intestine. Systemic expression of wild-type CagA further induced leukocytosis with IL-3/GM-CSF hypersensitivity and some mice developed myeloid leukemias and B cell lymphomas, the hematological malignancies also caused by gain-of-function SHIP-2 mutations. Such pathological abnormalities were not observed in transgenic mice expressing phosphorylation-resistant CagA. These results provide first direct evidence for the role of CagA as a bacterium-derived oncoprotein (bacterial oncoprotein) that acts in mammals and further indicate the importance of CagA tyrosine phosphorylation, which enables CagA to deregulate SHIP-2, in the development of H. pylori-associated neoplasms.