Kacar Furuzan, Meteoğlu Ibrahim, Yasa Hadi, Levi E
Department of Pathology, Adnan Menderes University, Aydin, Turkey.
Appl Immunohistochem Mol Morphol. 2007 Jun;15(2):224-8. doi: 10.1097/01.pai.0000209863.35828.dd.
Gastric cancers are usually associated with and preceded by Helicobacter pylori (HP) infection, gastric atrophy, intestinal metaplasia, and dysplasia. HP infection alters cell kinetics of the gastric mucosa. Both proliferation and apoptosis are increased. Proinflammatory cytokines are responsible for some of these alterations. The mitogen-activated protein kinase (MAPK) signaling pathway has been implicated as a causative factor in these alterations based on in vitro studies. In this study, we investigated the effects of HP infection on gastric mucosal proliferation, apoptotic mechanisms, and the activation status of the MAPK signaling pathway at various stages of gastric carcinogenesis, especially intestinal metaplasia and dysplasia caused by HP infection.
Stomach biopsies representing normal (n=20), HP+ (n=25), HP+ with intestinal metaplasia (n=25), HP+ with dysplasia (n=15) and gastric adenocarcinoma (n=30; 20 HP+ and 10 HP-) cases were selected. Cell proliferation was assessed by proliferating cell nuclear antigen immunostaining. Apoptosis and survival-related markers; cleaved caspase-3, and phospho-MAPK extracellular signal-regulated kinase (ERK) were detected by immunohistochemical methods.
Proliferation index (proliferating cell nuclear antigen) and cleaved caspase-3 expression were higher in the HP+, HP+ with intestinal metaplasia, and HP+ with dysplasia groups than in normal controls (P<0.05). Cleaved caspase-3 activity was also high in the adenocarcinomas. Phospho-MAPK(ERK) expression was increased in the HP+, HP+ with intestinal metaplasia, HP+ with dysplasia and adenocarcinomas compared with the normal control group. Whereas HP- gastric carcinomas had a lower expression of phospho-MAPK.
HP infection increases the proliferative rate of gastric foveolar cells in conjunction with an increased apoptotic rate and activation of MAPK(ERK). MAPK activation seems to be a significant and persistent event in the HP-induced neoplastic transformation.
胃癌通常与幽门螺杆菌（HP）感染、胃萎缩、肠化生和发育异常相关且先于这些情况出现。HP感染会改变胃黏膜的细胞动力学。增殖和凋亡均增加。促炎细胞因子是其中一些改变的原因。基于体外研究，丝裂原活化蛋白激酶（MAPK）信号通路被认为是这些改变的一个致病因素。在本研究中，我们调查了HP感染在胃癌发生的各个阶段，尤其是HP感染导致的肠化生和发育异常阶段，对胃黏膜增殖、凋亡机制以及MAPK信号通路激活状态的影响。
选取了代表正常（n = 20）、HP阳性（n = 25）、伴有肠化生的HP阳性（n = 25）、伴有发育异常的HP阳性（n = 15）以及胃腺癌（n = 30；20例HP阳性和10例HP阴性）病例的胃活检组织。通过增殖细胞核抗原免疫染色评估细胞增殖。通过免疫组化方法检测凋亡和生存相关标志物；裂解的半胱天冬酶 - 3以及磷酸化的MAPK细胞外信号调节激酶（ERK）。
HP阳性组、伴有肠化生的HP阳性组和伴有发育异常的HP阳性组的增殖指数（增殖细胞核抗原）和裂解的半胱天冬酶 - 3表达高于正常对照组（P < 0.05）。腺癌中的裂解半胱天冬酶 - 3活性也较高。与正常对照组相比，HP阳性组、伴有肠化生的HP阳性组、伴有发育异常的HP阳性组和腺癌中磷酸化的MAPK（ERK）表达增加。而HP阴性的胃癌中磷酸化的MAPK表达较低。
HP感染会增加胃小凹细胞的增殖率，同时凋亡率增加以及MAPK（ERK）激活。MAPK激活似乎是HP诱导肿瘤转化过程中的一个重要且持续的事件。
