Claudin-4, mitogen-activated protein kinase kinase 4, and stratifin are markers of gastric adenocarcinoma precursor lesions
Claudin-4, mitogen-activated protein kinase kinase 4, and stratifin are markers of gastric adenocarcinoma precursor lesions
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DOI：
10.1158/1055-9965.epi-05-0539
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发表时间：
2006-02-01
影响因子：
3.8
通讯作者：
Montgomery, E
中科院分区：
文献类型：
--
作者：
Cunningham, SC;Kamangar, F;Montgomery, E
在美国，每年大约有23,000例新的胃癌病例和12,000例相关死亡。肠化生和胃上皮异常增生是胃腺癌的先兆病变，但在临床、影像学或内镜下不易检测到。一种非侵入性的前体检测方法需要将前体病变与邻近的正常粘膜区分开来。为了寻找这样的标记，我们为133例切除的胃腺癌患者制备了组织微阵列。组织微阵列包含原发癌、正常胃、肠化生和胃上皮异常增生，并对9种潜在标记物进行抗体检测，这些标记物要么在胃腺癌中过表达的基因数据库中被鉴定出来，要么是我们实验室已经感兴趣的。cladin -4、丝裂原活化蛋白激酶激酶4 （MKK4）、14-3-3 sigma （stratifin）、S100A4、间皮素、束状蛋白、拓扑异构酶II α HER-2/neu和上皮生长因子受体。三个标志物区分胃腺癌前体病变与正常胃粘膜。在36个肠化生病变（100%）和14个胃上皮发育不良病变（100%）中存在Claudin-4表达引入，而在16个正常胃样本中仅存在Claudin-4表达（15%）。MKK4在24个肠化生病变（89%）和12个胃上皮发育不良病变（100%）中表达，而在6个正常胃标本（8%）中表达。在29个肠化生病变（97%）和8个胃上皮异常增生病变（100%）中存在Stratifin表达，而在2个正常胃样本中仅表达（3%）。claudin-4检测肠化生前体病变的敏感性为100%，特异性为85%；MKK4分别为89%和92%；而对于stratifin，则分别为97%和97%。在原发性癌症中，125例患者中有123例（98.4%）cludin -4阳性，126例患者中有116例（94%）MKK4阳性，120例患者中有120例（92%）stratifin阳性。总之，claudin-4、MKK4和层析免疫标记可以检测到胃腺癌的前驱病变，而这些病变在临床上、影像学上和内镜下都是不明显的。这些发现可能有助于胃腺癌前体病变的诊断和治疗靶向。
Approximately 23,000 new gastric cancer cases and 12,000 associated deaths occur annually in the United States. Intestinal metaplasia and gastric epithelial dysplasia are precursor lesions to gastric adenocarcinoma, but are not readily detectable clinically, radiographically, or endoscopically. A noninvasive method of precursor detection would require the ability to distinguish precursor lesions from adjacent normal mucosa. In search of such markers, tissue microarrays were prepared for 133 patients of resected gastric adenocarcinoma. Tissue microarrays contained primary cancer, normal stomach, intestinal metaplasia, and gastric epithelial dysplasia and were probed with antibodies against nine potential markers that were either identified in a database of genes overexpressed in gastric adenocarcinoma or were already of interest to our laboratory: claudin-4, mitogen-activated protein kinase kinase 4 (MKK4), 14-3-3 sigma (stratifin), S100A4, mesothelin, fascin, topoisomerase II alpha HER-2/neu, and epithelial growth factor receptor. Three markers discriminated gastric adenocarcinoma precursor lesions from normal gastric mucosa. Claudin-4 expression Introduction was present in 36 intestinal metaplasia lesions (100%) and 14 gastric epithelial dysplasia lesions (100%), but in only 16 normal stomach samples (15%). MKK4 expression was present in 24 intestinal metaplasia lesions (89%) and 12 gastric epithelial dysplasia lesions (100%), but in only 6 normal stomach samples (8%). Stratifin expression was present in 29 intestinal metaplasia lesions (97%) and 8 gastric epithelial dysplasia lesions (100%), but in only 2 normal stomach samples (3%). Sensitivity and specificity for detection of the precursor lesion intestinal metaplasia were 100% and 85%, respectively, for claudin-4; 89% and 92%, respectively, for MKK4; and 97% and 97%, respectively, for stratifin. In primary cancers, 123 of 125 (98.4%) were positive for claudin-4, 116 of 126 (94%) for MKK4, and Ill of 120 (92%) for stratifin. In conclusion, claudin-4, MKK4, and stratifin immunolabeling detects precursor lesions of gastric adenocarcinoma that are otherwise clinically, radiographically, and endoscopically inapparent. These findings may prove useful in the diagnosis and therapeutic targeting of gastric adenocarcinoma precursor lesions.