Mechanistic aspects of COX-2 expression in colorectal neoplasia.
The cyclooxygenase-2 (COX-2) enzyme catalyzes the rate-limiting step of prostaglandin formation in pathogenic states and a large amount of evidence has demonstrated constitutive COX-2 expression to be a contributing factor promoting colorectal cancer (CRC). Various genetic, epigenetic, and inflammatory pathways have been identified to be involved in the etiology and development of CRC. Alteration in these pathways can influence COX-2 expression at multiple stages of colon carcinogenesis allowing for elevated prostanoid biosynthesis to occur in the tumor microenvironment. In normal cells, COX-2 expression levels are potently regulated at the post-transcriptional level through various RNA sequence elements present within the mRNA 3' untranslated region (3'UTR). A conserved AU-rich element (ARE) functions to target COX-2 mRNA for rapid decay and translational inhibition through association with various RNA-binding proteins to influence the fate of COX-2 mRNA. Specific microRNAs (miRNAs) bind regions within the COX-2 3'UTR and control COX-2 expression. In this chapter, we discuss novel insights in the mechanisms of altered post-transcriptional regulation of COX-2 in CRC and how this knowledge may be used to develop novel strategies for cancer prevention and treatment.
Department of Cancer Biology, University of Kansas Medical Center, Kansas, KS 66106, USA. ddixon3@kumc.edu
Dan A
DA
Dixon
Fernando F
FF
Blanco
Annalisa
A
Bruno
Paola
P
Patrignani
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000502:physiology*; D044127:Epigenesis, Genetic; D066246:ErbB Receptors / Q000502:physiology; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000502:physiology; D035683:MicroRNAs / Q000502:physiology; D053842:Microsatellite Instability; D047495:PPAR gamma / Q000502:physiology; D000071876:Prostaglandin-E Synthases; D011453:Prostaglandins / Q000378:metabolism
D020413:3' Untranslated Regions; D035683:MicroRNAs; D047495:PPAR gamma; D011453:Prostaglandins; D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases