title: Regulation of COX-2 expression by miR-146a in lung cancer cells.
abstract: Prostaglandins are a class of molecules that mediate cellular inflammatory responses and control cell growth. The oxidative conversion of arachidonic acid to prostaglandin H2 is carried out by two isozymes of cyclooxygenase, COX-1 and COX-2. COX-1 is constitutively expressed, while COX-2 can be transiently induced by external stimuli, such as pro-inflammatory cytokines. Interestingly, COX-2 is overexpressed in numerous cancers, including lung cancer. MicroRNAs (miRNAs) are small RNA molecules that function to regulate gene expression. Previous studies have implicated an important role for miRNAs in human cancer. We demonstrate here that miR-146a expression levels are significantly lower in lung cancer cells as compared with normal lung cells. Conversely, lung cancer cells have higher levels of COX-2 protein and mRNA expression. Introduction of miR-146a can specifically ablate COX-2 protein and the biological activity of COX-2 as measured by prostaglandin production. The regulation of COX-2 by miR-146a is mediated through a single miRNA-binding site present in the 3' UTR. Therefore, we propose that decreased miR-146a expression contributes to the up-regulation and overexpression of COX-2 in lung cancer cells. Since potential miRNA-mediated regulation is a functional consequence of alternative polyadenylation site choice, understanding the molecular mechanisms that regulate COX-2 mRNA alternative polyadenylation and miRNA targeting will give us key insights into how COX-2 expression is involved in the development of a metastatic condition.
authors.affiliation: Department of Biochemistry and Molecular Biology, Rutgers, The State University of New Jersey, New Jersey Medical School and the Graduate School of Biomedical Sciences, Newark, New Jersey 07103, USA.
authors.forename: Ashley L
authors.initials: AL
authors.lastname: Cornett
authors.affiliation: Department of Biochemistry and Molecular Biology, Rutgers, The State University of New Jersey, New Jersey Medical School and the Graduate School of Biomedical Sciences, Newark, New Jersey 07103, USA lutzcs@njms.rutgers.edu.
authors.forename: Carol S
authors.initials: CS
authors.lastname: Lutz
mesh_terms: D020413:3' Untranslated Regions; D000230:Adenocarcinoma / Q000235:genetics*; D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D035683:MicroRNAs / Q000502:physiology*; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D012689:Sequence Homology, Nucleic Acid
chemical_list: D020413:3' Untranslated Regions; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human
keywords: COX-2; gene expression; miRNA; regulation