Costa Angela M, Ferreira Rui M, Pinto-Ribeiro Ines, Sougleri Ioanna S, Oliveira Maria J, Carreto Laura, Santos Manuel A, Sgouras Dionyssios N, Carneiro Fatima, Leite Marina, Figueiredo Ceu
i3S - Instituto de Investigação e Inovação em Saúde Ipatimup - Institute of Molecular Pathology and Immunology.
Laboratory of Medical Microbiology, Hellenic Pasteur Institute, Athens, Greece.
J Infect Dis. 2016 Jun 1;213(11):1767-76. doi: 10.1093/infdis/jiw031. Epub 2016 Jan 21.
Helicobacter pylori colonizes the human stomach and increases the risk for peptic ulcer disease and gastric carcinoma. H. pylori upregulates the expression and activity of several matrix metalloproteinases (MMPs) in cell lines and in the gastric mucosa. The aim of this study was to explore the mechanisms leading to upregulation of MMP10 in gastric epithelial cells induced by H. pylori Infection of gastric cells with H. pylori led to an increase in levels of MMP-10 messenger RNA, protein secretion, and activity. cagA knockout mutants or CagA phosphorylation-defective mutants failed to increase MMP10 expression. These results were confirmed in infection experiments with clinical isolates with known cagA status and in human gastric biopsy specimens. Treatment of cells with chemical inhibitors of the receptor tyrosine kinase EGFR and the kinase Src abrogated H. pylori-induced MMP10 expression. Inhibitors of ERK1/2 and JNK kinases abolished and significantly decreased H. pylori-induced MMP10 expression, respectively, whereas inhibition of the kinase p38 had no effect. Finally, inhibition of MMP10 expression by small interfering RNA led to a decrease in the gastric cell-invasive phenotype mediated by the infection. In conclusion, CagA-positive H. pylori strains stimulate MMP10 expression. MMP-10 modulation occurs via EGFR activation in a process that involves Src, ERK, and JNK pathways. MMP-10 may be implicated in H. pylori-mediated extracellular matrix remodeling.
幽门螺杆菌定殖于人的胃部，会增加患消化性溃疡病和胃癌的风险。幽门螺杆菌可上调细胞系和胃黏膜中几种基质金属蛋白酶（MMPs）的表达及活性。本研究的目的是探究幽门螺杆菌诱导胃上皮细胞中MMP10上调的机制。用幽门螺杆菌感染胃细胞会导致MMP - 10信使核糖核酸水平、蛋白质分泌及活性增加。cagA基因敲除突变体或CagA磷酸化缺陷突变体无法增加MMP10的表达。在对已知cagA状态的临床分离株进行的感染实验以及人胃活检标本中证实了这些结果。用受体酪氨酸激酶EGFR和激酶Src的化学抑制剂处理细胞可消除幽门螺杆菌诱导的MMP10表达。ERK1/2和JNK激酶的抑制剂分别消除并显著降低了幽门螺杆菌诱导的MMP10表达，而抑制激酶p38则没有效果。最后，小干扰RNA抑制MMP10表达导致感染介导的胃细胞侵袭表型降低。总之，CagA阳性的幽门螺杆菌菌株刺激MMP10表达。MMP - 10的调节通过EGFR激活，此过程涉及Src、ERK和JNK途径。MMP - 10可能参与幽门螺杆菌介导的细胞外基质重塑。
