title: Cyclooxygenase-2 is a target of microRNA-16 in human hepatoma cells.
abstract: Cyclooxygenase-2 (COX-2) expression has been detected in human hepatoma cell lines and in human hepatocellular carcinoma (HCC); however, the contribution of COX-2 to the development of HCC remains controversial. COX-2 expression is higher in the non-tumoral tissue and inversely correlates with the differentiation grade of the tumor. COX-2 expression depends on the interplay between different cellular pathways involving both transcriptional and post-transcriptional regulation. The aim of this work was to assess whether COX-2 could be regulated by microRNAs in human hepatoma cell lines and in human HCC specimens since these molecules contribute to the regulation of genes implicated in cell growth and differentiation. Our results show that miR-16 silences COX-2 expression in hepatoma cells by two mechanisms: a) by binding directly to the microRNA response element (MRE) in the COX-2 3'-UTR promoting translational suppression of COX-2 mRNA; b) by decreasing the levels of the RNA-binding protein Human Antigen R (HuR). Furthermore, ectopic expression of miR-16 inhibits cell proliferation, promotes cell apoptosis and suppresses the ability of hepatoma cells to develop tumors in nude mice, partially through targeting COX-2. Moreover a reduced miR-16 expression tends to correlate to high levels of COX-2 protein in liver from patients affected by HCC. Our data show an important role for miR-16 as a post-transcriptional regulator of COX-2 in HCC and suggest the potential therapeutic application of miR-16 in those HCC with a high COX-2 expression.
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, (Centro Mixto Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, CSIC-UAM), Madrid, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Agra Andrieu
authors.forename: Omar
authors.initials: O
authors.lastname: Motiño
authors.forename: Rafael
authors.initials: R
authors.lastname: Mayoral
authors.forename: Cristina
authors.initials: C
authors.lastname: Llorente Izquierdo
authors.forename: Ana
authors.initials: A
authors.lastname: Fernández-Alvarez
authors.forename: Lisardo
authors.initials: L
authors.lastname: Boscá
authors.forename: Marta
authors.initials: M
authors.lastname: Casado
authors.forename: Paloma
authors.initials: P
authors.lastname: Martín-Sanz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D001706:Biopsy; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D051959:ELAV Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis / Q000235:genetics; D055550:Protein Stability; D020871:RNA Stability / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D051959:ELAV Proteins; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human