Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Cancer Epidemiol Biomarkers Prev. 2011 Oct;20(10):2237-49. doi: 10.1158/1055-9965.EPI-11-0548. Epub 2011 Aug 22.
Helicobacter pylori infection is a risk factor for the development of gastric cancer, and the bacterial oncoprotein CagA contributes to gastric carcinogenesis.
We analyzed H. pylori isolates from persons in Colombia and observed that there was marked variation among strains in levels of CagA expression. To elucidate the basis for this variation, we analyzed sequences upstream from the CagA translational initiation site in each strain.
A DNA motif (AATAAGATA) upstream of the translational initiation site of CagA was associated with high levels of CagA expression. Experimental studies showed that this motif was necessary but not sufficient for high-level CagA expression. H. pylori strains from a region of Colombia with high gastric cancer rates expressed higher levels of CagA than did strains from a region with lower gastric cancer rates, and Colombian strains of European phylogeographic origin expressed higher levels of CagA than did strains of African origin. Histopathologic analysis of gastric biopsy specimens revealed that strains expressing high levels of CagA or containing the AATAAGATA motif were associated with more advanced precancerous lesions than those found in persons infected with strains expressing low levels of CagA or lacking the AATAAGATA motif.
CagA expression varies greatly among H. pylori strains. The DNA motif identified in this study is associated with high levels of CagA expression, and may be a useful biomarker to predict gastric cancer risk.
These findings help to explain why some persons infected with cagA-positive H. pylori develop gastric cancer and others do not.
幽门螺杆菌感染是胃癌发展的一个危险因素，细菌癌蛋白 CagA 促进胃癌的发生。
我们分析了来自哥伦比亚人的幽门螺杆菌分离株，观察到菌株中 CagA 表达水平存在明显差异。为了解释这种差异的基础，我们分析了每个菌株中 CagA 翻译起始位点上游的序列。
CagA 翻译起始位点上游的一个 DNA 基序（AATAAGATA）与 CagA 的高表达水平相关。实验研究表明，该基序是高水平 CagA 表达所必需的，但不是充分的。来自胃癌发病率较高地区的哥伦比亚幽门螺杆菌菌株比来自胃癌发病率较低地区的菌株表达更高水平的 CagA，而具有欧洲系统发育起源的哥伦比亚菌株比具有非洲起源的菌株表达更高水平的 CagA。胃活检标本的组织病理学分析表明，与表达低水平 CagA 或缺乏 AATAAGATA 基序的菌株相比，表达高水平 CagA 或含有 AATAAGATA 基序的菌株与更晚期的癌前病变相关。
CagA 在幽门螺杆菌菌株中表达差异很大。本研究中鉴定的 DNA 基序与 CagA 的高表达水平相关，可能是预测胃癌风险的有用生物标志物。
这些发现有助于解释为什么一些感染 cagA 阳性幽门螺杆菌的人会发展为胃癌，而另一些人则不会。
