Department of Pathology, Yonsei University College of Medicine, 120-752, Seoul, Republic of Korea.
Exp Mol Pathol. 2011 Apr;90(2):201-9. doi: 10.1016/j.yexmp.2010.12.004. Epub 2010 Dec 24.
A subset of gastric carcinomas shows histologic evidence of a multistep process, progressing from gastric adenoma to gastric carcinoma. We examined gene expression changes during the gastric adenoma-carcinoma sequence in 26 snap-frozen samples (normal mucosa, adenoma, and carcinoma samples from eight patients and two additional carcinomas) by oligonucleotide microarray. Unsupervised hierarchical clustering analysis demonstrated differential gene expression between gastric normal mucosa, adenomas and carcinomas. We identified 319 and 422 genes differentially regulated in adenoma and carcinoma, respectively, relative to normal mucosa, using a combination of Welch's t-test and fold-change analysis. Applying a combination of robust multi-category support vector machines to the data, reveal that 39 and 21 genes were gradually up- and down-regulated, respectively, in succession in normal mucosa, adenoma, and carcinoma samples. We validated gene expression levels of four genes: hydroxyprostaglandin dehydrogenase 15 (HPGD), follistatin-like 1, trefoil factor 1 (TTF1) and trefoil factor 2 (TFF2) by RT-PCR and found direct correlation with microarray results. The expressions of the TFF2 and HPGD genes were further evaluated by immunohistochemistry in 103 adenomas and 70 carcinomas; expression of both proteins was decreased in these tissues. The progressive alteration in gene expression in the transition from normal mucosa to carcinoma suggests that these changes may play critical roles in gastric carcinogenesis.
一部分胃癌表现出组织学上的多步骤过程的证据，从胃腺瘤进展为胃癌。我们通过寡核苷酸微阵列检查了 26 个冷冻样本（正常黏膜、腺瘤和来自 8 名患者和另外 2 个癌的癌样本）中胃腺瘤-癌序列中的基因表达变化。无监督层次聚类分析表明，正常胃黏膜、腺瘤和癌之间存在基因表达差异。我们使用 Welch's t 检验和倍数变化分析相结合，分别鉴定出腺瘤和癌中分别有 319 个和 422 个差异调节基因，相对于正常黏膜。应用稳健多类别支持向量机组合对数据进行分析，表明在正常黏膜、腺瘤和癌样本中，分别有 39 个和 21 个基因逐渐上调和下调。我们通过 RT-PCR 验证了四个基因的基因表达水平：羟前列腺素脱氢酶 15（HPGD）、卵泡抑素样 1、三叶因子 1（TTF1）和三叶因子 2（TFF2），并发现与微阵列结果直接相关。在 103 个腺瘤和 70 个癌中进一步通过免疫组织化学评估了 TFF2 和 HPGD 基因的表达；在这些组织中，这两种蛋白的表达均降低。从正常黏膜到癌的基因表达的逐渐改变表明这些变化可能在胃癌发生中起关键作用。
