Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
Department of Gastroenterology and Hepatology, Monash Health, Melbourne, Victoria, Australia.
Am J Pathol. 2020 Jun;190(6):1256-1270. doi: 10.1016/j.ajpath.2020.01.021. Epub 2020 Mar 19.
Gastric cancer is associated with chronic inflammation (gastritis) triggered by persistent Helicobacter pylori (H. pylori) infection. Elevated tyrosine phosphorylation of the latent transcription factor STAT3 is a feature of gastric cancer, including H. pylori-infected tissues, and aligns with nuclear transcriptional activity. However, the transcriptional role of STAT3 serine phosphorylation, which promotes STAT3-driven mitochondrial activities, is unclear. Here, by coupling serine-phosphorylated (pS)-STAT3-deficient Stat3 mice with chronic H. felis infection, which mimics human H. pylori infection in mice, we reveal a key role for pS-STAT3 in promoting Helicobacter-induced gastric pathology. Immunohistochemical staining for infiltrating immune cells and expression analyses of inflammatory genes revealed that gastritis was markedly suppressed in infected Stat3 mice compared with wild-type mice. Stomach weight and gastric mucosal thickness were also reduced in infected Stat3 mice, which was associated with reduced proliferative potential of infected Stat3 gastric mucosa. The suppressed H. felis-induced gastric phenotype of Stat3 mice was phenocopied upon genetic ablation of signaling by the cytokine IL-11, which promotes gastric tumorigenesis via STAT3. pS-STAT3 dependency by Helicobacter coincided with transcriptional activity on STAT3-regulated genes, rather than mitochondrial and metabolic genes. In the gastric mucosa of mice and patients with gastritis, pS-STAT3 was constitutively expressed irrespective of Helicobacter infection. Collectively, these findings suggest an obligate requirement for IL-11 signaling via constitutive pS-STAT3 in Helicobacter-induced gastric carcinogenesis.
胃癌与持续的幽门螺杆菌（H. pylori）感染引起的慢性炎症（胃炎）有关。潜伏转录因子 STAT3 的酪氨酸磷酸化升高是胃癌的一个特征，包括 H. pylori 感染的组织，并且与核转录活性一致。然而，促进 STAT3 驱动的线粒体活性的 STAT3 丝氨酸磷酸化的转录作用尚不清楚。在这里，我们通过将丝氨酸磷酸化（pS）-STAT3 缺陷型 Stat3 小鼠与慢性 H. felis 感染（模拟人类 H. pylori 在小鼠中的感染）相结合，揭示了 pS-STAT3 在促进幽门螺杆菌诱导的胃病理中的关键作用。浸润免疫细胞的免疫组织化学染色和炎症基因的表达分析表明，与野生型小鼠相比，感染 Stat3 小鼠的胃炎明显受到抑制。感染 Stat3 小鼠的胃重量和胃黏膜厚度也减少，这与感染 Stat3 胃黏膜的增殖潜力降低有关。在通过细胞因子 IL-11 信号转导的遗传消融中，感染 Stat3 小鼠的受抑制的 H. felis 诱导的胃表型被模拟，IL-11 通过 STAT3 促进胃肿瘤发生。幽门螺杆菌的 pS-STAT3 依赖性与 STAT3 调节基因的转录活性一致，而与线粒体和代谢基因无关。在小鼠和胃炎患者的胃黏膜中，pS-STAT3 持续表达，而与幽门螺杆菌感染无关。总之，这些发现表明，IL-11 信号转导通过 STAT3 的组成性 pS-STAT3 在幽门螺杆菌诱导的胃癌发生中是必需的。
