Global analysis of altered gene expressions during the process of esophageal squamous cell carcinogenesis in the rat: a study combined with a laser microdissection and a cDNA microarray.
Global analysis of altered gene expressions during the process of esophageal squamous cell carcinogenesis in the rat: a study combined with a laser microdissection and a cDNA microarray.
复制标题
DOI：
10.1158/0008-5472.401.65.2
复制
发表时间：
2005-01
期刊：
影响因子：
11.2
通讯作者：
K. Nishida;S. Mine;T. Utsunomiya;H. Inoue;M. Okamoto;H. Udagawa;T. Hanai;M. Mori
中科院分区：
文献类型：
--
作者：
K. Nishida;S. Mine;T. Utsunomiya;H. Inoue;M. Okamoto;H. Udagawa;T. Hanai;M. Mori
在食道肿瘤发生过程中发生的遗传改变尚未确定。我们建立了Wister大鼠食管鳞状细胞癌的癌变模型。为了进一步了解癌变过程中的分子机制，我们给大鼠注射n -amyl- n - methyl亚硝胺和12- o - tetradecanoylphorol -13-acetate，产生食管癌病变。我们使用激光显微解剖从正常上皮、乳头状瘤、非典型增生和浸润性癌中特异性分离细胞。利用14815个克隆的cDNA微阵列，我们分析了每个食管病变的基因表达谱。与正常对照相比，差异表达基因的数量从正常上皮（1,151 +/- 119个基因）到乳头状瘤（1,899 +/- 543个基因）、发育不良（1,991 +/- 193个基因）和浸润性癌（2,756 +/- 87个基因）逐步显著增加。分层聚类分析显示正常上皮、非典型增生（乳头状瘤）和浸润性癌三个阶段可以明确划分，而乳头状瘤和非典型增生的基因表达模式无法区分。使用Fisher标准，我们还发现了50个基因，这些基因的表达水平在正常上皮到非典型增生，最后到浸润性癌的过程中逐步增加或减少。其中许多基因以前并不知道与食管癌的发生有关。因此，在我们的大鼠模型中，目前的发现似乎为我们提供了对食管癌发生过程中发生的分子改变的更好理解，并有望有助于开发新的诊断和治疗靶点。
The genetic alterations that occur during esophageal tumorigenesis have yet to be determined. We previously established a Wister rat carcinogenesis model of esophageal squamous cell carcinoma. To understand more about the molecular mechanisms during carcinogenesis, we produced esophageal neoplastic lesions by administering N-amyl-N-methylnitrosamine and 12-O-tetradecanoylphorbol-13-acetate to rats. We used laser microdissection to specifically isolate the cells from the normal epithelium, papilloma, dysplasia, and invasive carcinoma. Using a cDNA microarray representing 14,815 clones, we then analyzed the gene expression profiles for each esophageal lesion. The number of differentially expressed genes compared with the normal control dramatically increased in a step-by-step fashion from normal epithelium (1,151 +/- 119 genes) to papilloma (1,899 +/- 543 genes), dysplasia (1,991 +/- 193 genes), and invasive carcinoma (2,756 +/- 87 genes). A hierarchical clustering analysis showed that the three stages of normal epithelium, dysplasia (papilloma), and invasive carcinoma could be clearly classified, whereas the gene expression patterns of papilloma and dysplasia were indistinguishable. Using the Fisher criterion, we also identified 50 genes whose expression level had either significantly increased or decreased in a step-by-step manner from the normal epithelium to dysplasia and then finally to invasive carcinoma. Many of these genes were not previously known to be associated with esophageal carcinogenesis. The present findings in our rat model thus seem to provide us with a better understanding of the molecular alterations that occur during esophageal carcinogenesis and hopefully will also help lead to the development of novel diagnostic and therapeutic targets.