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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

¹ Department of Surgery Medical Institute of Bioregulation, Kyushu University, Tsurumihara, Beppu, Japan; ² Department of Digestive Surgery, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Toranomon, Minato-ku, Tokyo, Japan; and ³ Laboratory for Bioinformatics, Graduate School of Systems Life Sciences, Kyushu University, Hakozaki, Higashi-ku, Fukuoka, Japan

Requests for reprints: Masaki Mori, Department of Molecular and Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, Tsurumihara 4546, Beppu, 874-0838, Japan. Phone: 81-977-27-1650; Fax: 81-977-27-1651; E-mail: mmori{at}tsurumi.beppu.kyushu-u.ac.jp.

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.

Key Words: Esophagus • Gastrointestinal cancers: other • Chemical carcinogenesis

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