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Transcriptional Profiles of Intestinal Tumors in Apc^Min Mice are Unique from those of Embryonic Intestine and Identify Novel Gene Targets Dysregulated in Human Colorectal Tumors

¹ Department of Molecular Genetics, Biochemistry and Microbiology, and ² Howard Hughes Medical Institute, University of Cincinnati College of Medicine and Divisions of ³ Developmental Biology and Pediatric Informatics and ⁴ Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

Requests for reprints: Joanna Groden, Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0524. Phone: 513-558-0088; Fax: 513-558-2794; E-mail: joanna.groden{at}uc.edu

The adenomatous polyposis coli (APC) tumor suppressor is a major regulator of the Wnt signaling pathway in normal intestinal epithelium. APC, in conjunction with AXIN and GSK-3ß, forms a complex necessary for the degradation of ß-catenin, thereby preventing ß-catenin/T-cell factor interaction and alteration of growth-controlling genes such as c-MYC and cyclin D1. Inappropriate activation of the Wnt pathway, via Apc/APC mutation, leads to gastrointestinal tumor formation in both the mouse and human. In order to discover novel genes that may contribute to tumor progression in the gastrointestinal tract, we used cDNA microarrays to identify 114 genes with altered levels of expression in Apc^Min mouse adenomas from the duodenum, jejunum, and colon. Changes in the expression of 24 of these 114 genes were not observed during mouse development at embryonic day 16.5, postnatal day 1, or postnatal day 14 (relative to normal adult intestine). These 24 genes are not previously known Wnt targets. Seven genes were validated by real-time reverse transcription-PCR analysis, whereas four genes were validated by in situ hybridization to mouse adenomas. Real-time reverse transcription-PCR analysis of human colorectal cancer cell lines and adenocarcinomas revealed that altered expression levels were also observed for six of the genes Igfbp5, Lcn2, Ly6d, N4wbp4 (PMEPA1), S100c, and Sox4.

Key Words: adenoma • APC • gastrointestinal cancer • mouse models of cancer • transcriptional profile

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