title: The adenomatous polyposis coli tumor suppressor gene regulates expression of cyclooxygenase-2 by a mechanism that involves retinoic acid.
abstract: Mutations in the adenomatous polyposis coli (APC) gene result in uncontrolled proliferation of intestinal epithelial cells and are associated with the earliest stages of colorectal carcinogenesis. Cyclooxygenase-2 (COX-2) is elevated in human colorectal cancers and plays an important role in colorectal tumorigenesis; however, the mechanisms by which APC mutations result in increased COX-2 expression remain unclear. We utilized APC mutant zebrafish and human cancer cells to investigate how APC modulates COX-2 expression. We report that COX-2 is up-regulated in APC mutant zebrafish because of a deficiency in retinoic acid biosynthesis. Treatment of both APC mutant zebrafish and human carcinoma cell lines with retinoic acid significantly reduces COX-2 expression. Retinoic acid regulates COX-2 levels by a mechanism that involves participation of the transcription factor C/EBP-beta. APC mutant zebrafish express higher levels of C/EBP-beta than wild-type animals, and retinoic acid supplementation reduces C/EBP-beta expression to basal levels. Both morpholino knockdown of C/EBP-beta in APC mutant zebrafish and silencing of C/EBP-beta using small interfering RNA in HT29 colon cancer cells robustly decrease COX-2 expression. Our findings support a sequence of events in which mutations in APC result in impaired retinoic acid biosynthesis, elevated levels of C/EBP-beta, up-regulation of COX-2, increased prostaglandin E(2) accumulation, and activation of Wnt target genes.
authors.affiliation: Department of Oncological Sciences, University of Utah, Salt Lake City, Utah 84112, USA.
authors.forename: Annie L
authors.initials: AL
authors.lastname: Eisinger
authors.forename: Lincoln D
authors.initials: LD
authors.lastname: Nadauld
authors.forename: Dawne N
authors.initials: DN
authors.lastname: Shelton
authors.forename: Peter W
authors.initials: PW
authors.lastname: Peterson
authors.forename: Reid A
authors.initials: RA
authors.lastname: Phelps
authors.forename: Stephanie
authors.initials: S
authors.lastname: Chidester
authors.forename: Diana M
authors.initials: DM
authors.lastname: Stafforini
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Prescott
authors.forename: David A
authors.initials: DA
authors.lastname: Jones
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics*; D017931:DNA Primers; D015232:Dinoprostone / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D017491:Genes, APC; D006801:Humans; D009025:Morpholines; D012333:RNA, Messenger / Q000235:genetics; D014212:Tretinoin / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics; D015027:Zebrafish; D051176:beta Catenin / Q000502:physiology
chemical_list: D017931:DNA Primers; D009025:Morpholines; D012333:RNA, Messenger; D051153:Wnt Proteins; D051176:beta Catenin; D014212:Tretinoin; D051546:Cyclooxygenase 2; D015232:Dinoprostone