Keates Sarah, Keates Andrew C, Katchar Kianoosh, Peek Richard M, Kelly Ciaran P
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
J Infect Dis. 2007 Jul 1;196(1):95-103. doi: 10.1086/518440. Epub 2007 May 16.
Helicobacter pylori infection increases the risk of gastric carcinogenesis. The aim of the present study was to determine whether H. pylori could up-regulate the expression of the epidermal growth factor receptor (EGFR), a critical gene in the carcinogenic process.
AGS gastric epithelial cells were infected with cag(+) toxigenic or cag(-) nontoxigenic strains of H. pylori or isogenic mutants. EGFR protein expression was determined by Western blotting and immunofluorescence. EGFR mRNA levels were evaluated using real-time polymerase chain reaction. The signaling pathways leading to EGFR up-regulation were examined using the ERK1/2 inhibitor PD98059, the Src inhibitor pp2, the nuclear factor- kappa B inhibitor caffeic acid phenethyl ester, EGFR neutralizing antibodies, and the EGFR kinase inhibitor AG1478.
Infection of AGS cells by H. pylori significantly increased EGFR mRNA and protein levels. We found that this effect was limited to cag(+) H. pylori strains and that mutants with a defective type IV secretion system were unable to cause EGFR up-regulation. Increased EGFR expression was found to be dependent on EGFR receptor transactivation, ERK1/2 phosphorylation, and Src activation.
Infection of gastric epithelial cells by H. pylori triggers an autocrine loop whereby EGFR transactivation leads to the up-regulation of EGFR expression. This, in turn, may contribute to unrestrained epithelial cell proliferation and carcinogenesis.
幽门螺杆菌感染会增加胃癌发生风险。本研究的目的是确定幽门螺杆菌是否能上调表皮生长因子受体（EGFR）的表达，EGFR是致癌过程中的关键基因。
用幽门螺杆菌的cag(+)产毒株或cag(-)非产毒株或同基因突变体感染AGS胃上皮细胞。通过蛋白质印迹法和免疫荧光法测定EGFR蛋白表达。使用实时聚合酶链反应评估EGFR mRNA水平。使用ERK1/2抑制剂PD98059、Src抑制剂pp2、核因子-κB抑制剂咖啡酸苯乙酯、EGFR中和抗体以及EGFR激酶抑制剂AG1478研究导致EGFR上调的信号通路。
幽门螺杆菌感染AGS细胞显著增加了EGFR mRNA和蛋白水平。我们发现这种作用仅限于cag(+)幽门螺杆菌菌株，且IV型分泌系统有缺陷的突变体无法引起EGFR上调。发现EGFR表达增加依赖于EGFR受体反式激活、ERK1/2磷酸化和Src激活。
幽门螺杆菌感染胃上皮细胞会触发一个自分泌环，由此EGFR反式激活导致EGFR表达上调。这反过来可能导致上皮细胞不受控制地增殖和致癌。
