Crawford Howard C, Krishna Uma S, Israel Dawn A, Matrisian Lynn M, Washington M Kay, Peek Richard M
Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York, USA.
Gastroenterology. 2003 Oct;125(4):1125-36. doi: 10.1016/s0016-5085(03)01206-x.
Helicobacter pylori strains that possess the cag pathogenicity island (cag(+)) augment the risk for distal gastric cancer. Matrix metalloproteinase (MMP)-7, an epithelial cell-derived MMP that is induced by bacterial contact, is overexpressed within human gastric adenocarcinoma specimens and enhances tumor formation in rodents. We determined whether H. pylori alters MMP-7 expression and investigated the molecular pathways required for these events.
MMP-7 was detected in human gastric mucosa by immunohistochemistry and in H. pylori/AGS gastric epithelial cell coculture supernatants by Western analysis. AGS cells were cocultured with wild-type H. pylori, or isogenic cagA(-), cagE(-), or vacA(-) mutants, in the absence or presence of inhibitors of nuclear factor kappaB activation, p38, or extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase.
H. pylori cag(+) strains increased MMP-7 expression in AGS cells 5-7-fold, whereas cag(-) isolates had no effect. Inactivation of cagE, but not cagA or vacA, completely attenuated induction of MMP-7, and inhibition of ERK 1/2 decreased MMP-7 production. In vivo, MMP-7 was expressed in gastric epithelial cells in specimens from 80% of cag(+)-colonized persons but in none of the cag(-) or uninfected subjects.
H. pylori cag(+) strains enhance levels of MMP-7 within inflamed mucosa. In vitro, cag(+) isolates selectively induce MMP-7, and this is dependent on activation of ERK 1/2 by specific components within the cag island. Differential induction of MMP-7 by H. pylori cag(+) isolates may explain in part the augmentation in gastric cancer risk associated with these strains.
携带细胞毒素相关基因（cag）致病岛的幽门螺杆菌菌株（cag(+)）会增加患远端胃癌的风险。基质金属蛋白酶（MMP）-7是一种由上皮细胞产生的MMP，可被细菌接触诱导，在人胃腺癌标本中过度表达，并能促进啮齿动物的肿瘤形成。我们确定了幽门螺杆菌是否会改变MMP-7的表达，并研究了这些事件所需的分子途径。
通过免疫组织化学检测人胃黏膜中的MMP-7，通过蛋白质印迹分析检测幽门螺杆菌/AGS胃上皮细胞共培养上清液中的MMP-7。AGS细胞与野生型幽门螺杆菌或同基因的cagA(-)、cagE(-)或vacA(-)突变体在有无核因子κB激活抑制剂、p38或细胞外信号调节激酶（ERK）丝裂原活化蛋白激酶的情况下进行共培养。
幽门螺杆菌cag(+)菌株使AGS细胞中MMP-7的表达增加5至7倍，而cag(-)菌株则无此作用。cagE失活而非cagA或vacA失活可完全减弱MMP-7的诱导，抑制ERK 1/2可降低MMP-7的产生。在体内，80%的cag(+)定植者标本中的胃上皮细胞表达MMP-7，而cag(-)或未感染受试者的标本中均未表达。
幽门螺杆菌cag(+)菌株可提高炎症黏膜中MMP-7的水平。在体外，cag(+)菌株选择性诱导MMP-7，这依赖于cag岛内特定成分对ERK 1/2的激活。幽门螺杆菌cag(+)菌株对MMP-7的差异诱导可能部分解释了与这些菌株相关的胃癌风险增加。
