The molecular pathogenesis of STAT3-driven gastric tumourigenesis in mice is independent of IL-17
The molecular pathogenesis of STAT3-driven gastric tumourigenesis in mice is independent of IL-17
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DOI：
10.1002/path.2933
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发表时间：
2011-10-01
影响因子：
7.3
通讯作者：
Jenkins, Brendan J.
中科院分区：
文献类型：
--
作者：
Kennedy, Catherine L.;Najdovska, Men;Jenkins, Brendan J.
胃粘膜获得性免疫反应的慢性激活是胃癌的一个特征。最近出现了一种新的辅助性T细胞(Th)，其定义是产生白细胞介素17A(Th17)的能力，与包括胃炎在内的一系列炎症反应有关。然而，这些Th17细胞在胃癌发病机制中的作用尚不清楚。为了正式解决这个问题，我们使用了gp130(F/F)小鼠，它们自发地发展为类似于人类肠型胃癌的胃炎症相关肿瘤。在分子水平上，这些肿瘤通过IL-6细胞因子家族成员IL-11表现出潜伏的转录因子信号转导和转录激活因子(STAT)3的高度激活。在gp130F/F小鼠中，与野生型gp130(+/+)小鼠相比，Th17细胞的产生以及IL-17a和其他Th17相关因子(Ror-Gamma t，IL-23)的胃表达增加。与IL-6和STAT3在调节IL-17A中的作用一致，在显示正常STAT3活性的gp130(F/F)：STAT3(-/+)小鼠以及gp130(F/F)：IL-6(-/-)小鼠中，gp130(F/F)：IL-6(-/-)小鼠增加的Th17生成和胃内Th17相关因子的表达减少到野生型水平。重要的是，在gp130(F/F)：IL-17a(-/-)小鼠中基因切除IL-17A并没有抑制胃癌的开始和生长。此外，IL-17A和RORC基因在胃炎患者的胃组织中表达显著增加，但在胃癌患者中未见表达。总而言之，我们的数据表明，Th17相关因子的表达增加与胃肿瘤发生的分子发病机制无关。(#)版权所有(C)2011年英国和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
Chronic activation of the gastric mucosal adaptive immune response is a characteristic trait of gastric cancer. It has recently emerged that a new class of T helper (Th) cells, defined by their ability to produce interleukin (IL)-17A (Th17), is associated with a host of inflammatory responses, including gastritis. However, the role of these Th17 cells in the pathogenesis of gastric cancer is less clear. To formally address this, we employed gp130(F/F) mice, which spontaneously develop gastric inflammation-associated tumours akin to human intestinal-type gastric cancer. At the molecular level, these tumours demonstrate hyper-activation of the latent transcription factor signal transducer and activator of transcription (STAT)3 via the IL-6 cytokine family member, IL-11. In gp130F/F mice, the generation of Th17 cells, as well as the gastric expression of IL-17a and other Th17-related factors (Ror gamma t, IL-23), were augmented compared to wild-type gp130(+/+) mice. Consistent with a role for IL-6 and STAT3 in regulating IL-17A, increased Th17 generation and gastric expression of Th17-related factors in gp130F/F mice were reduced to wild-type levels in gp130(F/F):Stat3(-/+) mice displaying normalized STAT3 activity, and also in gp130(F/F):IL-6(-/-) mice. Importantly, genetic ablation of IL-17A in gp130(F/F):IL-17a(-/-) mice did not suppress the initiation and growth of gastric tumours. Furthermore, IL-17A and RORC gene expression was strongly increased in human gastric biopsies from patients with gastritis, but not gastric cancer. Collectively, our data suggest that increased expression of Th17-related factors does not correlate with the molecular pathogenesis of gastric tumourigenesis.(#) Copyright (C) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.