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.
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-3beta, forms a complex necessary for the degradation of beta-catenin, thereby preventing beta-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.
Reichling
Tim
T
Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45267, USA.
Goss
Kathleen Heppner
KH
Carson
Daniel J
DJ
Holdcraft
Robert W
RW
Ley-Ebert
Cathy
C
Witte
Dave
D
Aronow
Bruce J
BJ
Groden
Joanna
J
D000236:Adenoma / Q000235:genetics; D000818:Animals; D003110:Colonic Neoplasms / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D004379:Duodenal Neoplasms / Q000235:genetics; D005770:Gastrointestinal Neoplasms / Q000235:genetics; D017353:Gene Deletion; D017491:Genes, APC; D005819:Genetic Markers; D006801:Humans; D007422:Intestines / Q000196:embryology*; D007580:Jejunal Neoplasms / Q000235:genetics; D051379:Mice; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
D018076:DNA, Complementary; D005819:Genetic Markers