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Epidermal growth factor receptor inhibition downregulates Helicobacter pylori -induced epithelial inflammatory responses, DNA damage and gastric carcinogenesis
Gut ( IF 24.5 ) Pub Date : 2017-05-04 , DOI: 10.1136/gutjnl-2016-312888
Johanna C Sierra , Mohammad Asim , Thomas G Verriere , M Blanca Piazuelo , Giovanni Suarez , Judith Romero-Gallo , Alberto G Delgado , Lydia E Wroblewski , Daniel P Barry , Richard M Peek , Alain P Gobert , Keith T Wilson

Objective Gastric cancer is the third leading cause of cancer death worldwide and infection by Helicobacter pylori is the strongest risk factor. We have reported increased epidermal growth factor receptor (EGFR) phosphorylation in the H. pylori-induced human carcinogenesis cascade, and association with DNA damage. Our goal was to determine the role of EGFR activation in gastric carcinogenesis. Design We evaluated gefitinib, a specific EGFR inhibitor, in chemoprevention of H. pylori-induced gastric inflammation and cancer development. Mice with genetically targeted epithelial cell-specific deletion of Egfr (EfgrΔepi mice) were also used. Results In C57BL/6 mice, gefitinib decreased Cxcl1 and Cxcl2 expression by gastric epithelial cells, myeloperoxidase-positive inflammatory cells in the mucosa and epithelial DNA damage induced by H. pylori infection. Similar reductions in chemokines, inflammatory cells and DNA damage occurred in infected EgfrΔepi versus Egfrfl/fl control mice. In H. pylori-infected transgenic insulin-gastrin (INS-GAS) mice and gerbils, gefitinib treatment markedly reduced dysplasia and carcinoma. Gefitinib blocked H. pylori-induced activation of mitogen-activated protein kinase 1/3 (MAPK1/3) and activator protein 1 in gastric epithelial cells, resulting in inhibition of chemokine synthesis. MAPK1/3 phosphorylation and JUN activation was reduced in gastric tissues from infected wild-type and INS-GAS mice treated with gefitinib and in primary epithelial cells from EfgrΔepi versus Egfrfl/fl mice. Epithelial EGFR activation persisted in humans and mice after H. pylori eradication, and gefitinib reduced gastric carcinoma in INS-GAS mice treated with antibiotics. Conclusions These findings suggest that epithelial EGFR inhibition represents a potential strategy to prevent development of gastric carcinoma in H. pylori-infected individuals.

中文翻译:

表皮生长因子受体抑制下调幽门螺杆菌诱导的上皮炎症反应、DNA 损伤和胃癌发生

目的胃癌是全球癌症死亡的第三大原因,幽门螺杆菌感染是最强的危险因素。我们报告了幽门螺杆菌诱导的人类致癌级联反应中表皮生长因子受体 (EGFR) 磷酸化增加,并与 DNA 损伤相关。我们的目标是确定 EGFR 激活在胃癌发生中的作用。设计 我们评估了吉非替尼(一种特异性 EGFR 抑制剂)在化学预防幽门螺杆菌诱导的胃部炎症和癌症发展方面的作用。还使用了具有 Egfr 基因靶向上皮细胞特异性缺失的小鼠(EfgrΔepi 小鼠)。结果 在 C57BL/6 小鼠中,吉非替尼降低了胃上皮细胞、黏膜中髓过氧化物酶阳性炎症细胞和由幽门螺杆菌诱导的上皮 DNA 损伤的 Cxcl1 和 Cxcl2 表达。幽门螺杆菌感染。与 Egfrfl/fl 对照小鼠相比,受感染的 EgfrΔepi 中趋化因子、炎症细胞和 DNA 损伤发生了类似的减少。在 H. pylori 感染的转基因胰岛素胃泌素 (INS-GAS) 小鼠和沙鼠中,吉非替尼治疗显着减少了发育不良和癌症。吉非替尼阻断了幽门螺杆菌诱导的胃上皮细胞中丝裂原活化蛋白激酶 1/3 (MAPK1/3) 和激活蛋白 1 的激活,从而抑制了趋化因子的合成。在用吉非替尼治疗的受感染野生型和 INS-GAS 小鼠的胃组织中以及来自 EfgrΔepi 与 Egfrfl/fl 小鼠的原代上皮细胞中,MAPK1/3 磷酸化和 JUN 活化降低。根除幽门螺杆菌后,人类和小鼠的上皮 EGFR 激活持续存在,吉非替尼减少了用抗生素治疗的 INS-GAS 小鼠的胃癌。
更新日期:2017-05-04
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