Genomic analysis of alachlor-induced oncogenesis in rat olfactory mucosa

• Published in: Physiological genomics 2002-12, Vol.12 (1), p.35-45
• Main Authors: Genter, Mary Beth, Burman, Dawn M, Vijayakumar, Soundarapandian, Ebert, Cathy L, Aronow, Bruce J
• Format: Article
• Language: English
• Subjects: Acetamides - pharmacology; Adenocarcinoma - chemically induced; Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Animals; beta Catenin; Carcinogens - pharmacology; Cell Transformation, Neoplastic; Cytoskeletal Proteins - analysis; Disease Progression; Extracellular Matrix - metabolism; Gene Expression Profiling; Genomics; Male; Nose Neoplasms - chemically induced; Nose Neoplasms - genetics; Nose Neoplasms - metabolism; Nose Neoplasms - pathology; Olfactory Mucosa - drug effects; Oligonucleotide Array Sequence Analysis; Rats; Rats, Long-Evans; RNA, Neoplasm - biosynthesis; Trans-Activators - analysis; Up-Regulation
• ISSN: 1094-8341; 1531-2267
• DOI: 10.1152/physiolgenomics.00120.2002

1 Departmet of Environmental Health, University of Cincinnati, Cincinnati, Ohio 45267-0056 2 Department of Medicine, Columbia University, New York, New York 10032 3 Children’s Hospital Medical Center, Cincinnati, Ohio 45229 Alachlor induces olfactory mucosal tumors in rats in a highly ordered temporal process. We used GeneChip analysis to test the hypothesis that histological progression and oncogenic transformation are accompanied by gene expression changes that might yield clues as to the molecular pathogenesis of tumor formation. Acute alachlor exposure caused upregulation of matrix metalloproteinases (MMP)-2 and -9, tissue inhibitor of metalloproteinase-1, carboxypeptidase Z, and other genes related to extracellular matrix homeostasis. Heme oxygenase was upregulated acutely and maintained elevated expression. Expression of ebnerin, related to the putative human tumor suppressor gene DMBT1, progressively increased in alachlor-treated olfactory mucosa. Progression from adenomas to adenocarcinoma was correlated with upregulation of genes in the wnt signaling pathway. Activated wnt signaling was confirmed by immunohistochemical localization of ß-catenin to nuclei of adenocarcinomas, but not earlier lesions. These observations suggest that initiation and progression of alachlor-induced olfactory mucosal tumors is associated with alterations in extracellular matrix components, induction of oxidative stress, upregulation of ebnerin, and final transformation to a malignant state by wnt pathway activation. gene expression; carcinogenesis; ß-catenin