Transgenic Mice Expressing Cyclooxygenase-2 in Hepatocytes Reveal a Minor Contribution of This Enzyme to Chemical Hepatocarcinogenesis

Llorente, Cristina; Mayoral, Rafael; Flores, Juana M.; García-Palencia, Pilar; Cucarella, Carme; Casado, Marta; Martı́n-Sanz, Paloma

doi:10.1016/j.ajpath.2010.11.074

Cited by 13 publications

(7 citation statements)

References 44 publications

(54 reference statements)

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“…Moreover, recent data and our present results indicate that COX-2 mRNA levels are significantly higher in the adjacent liver than in the HCC and lower in HCC than in nonalcoholic steatohepatitis [12]. Our previous work demonstrated that COX-2 expression is not sufficient to enhance malignant transformation induced by dyethylnitrosamine in a model of transgenic mice expressing COX-2 in hepatocytes [33]. These results suggest that COX-2 could be related to the inflammatory response occurring in the early phases of chronic liver disease and eventually contribute to the induction of hepatocarcinogenesis.…”

Section: Discussionsupporting

confidence: 46%

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Cyclooxygenase-2 Is a Target of MicroRNA-16 in Human Hepatoma Cells

et al. 2012

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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.

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Section: Discussionsupporting

confidence: 46%

“…pPyCAGIP-hCOX-2 was prepared as described previously [33]. Briefly, human COX-2 ORF was amplified by PCR from human full-length COX-2 cDNA cloned into pcDNA1/Amp, and then, was subcloned into Xho I- Not I restriction site of pPyCAGIP vector.…”

Section: Methodsmentioning

confidence: 99%

Cyclooxygenase-2 Is a Target of MicroRNA-16 in Human Hepatoma Cells

et al. 2012

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“…However, although COX-2 expression is detected in early phases of HCC, contradictory observations have been published regarding the nature of the cells expressing the enzyme (both in normal hepatocytes and in hepatoma cells), the role of this expression pattern and the molecular mechanisms by which COX-2-dependent PGs contribute and/or induce tumorigenesis. Interestingly, work from our group[ 51 ] has shown that COX-2 expression is not sufficient to exacerbate malignant transformation after administration of chemical hepatocarcinogens. Even more, progression of liver oncogenesis in a well-established model of HCC (the c-myc and TGF-α double transgenic mice), is not affected by COX-2 expression[ 52 ].…”

Section: Cox-2 and Hccmentioning

confidence: 99%

Cyclooxygenase 2 in liver dysfunction and carcinogenesis: Facts and perspectives

Martı́n-Sanz

Casado

2017

WJG

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The biosynthesis of prostaglandins and thromboxanes has been a focus of interest in the management of many liver diseases. Cyclooxygenases are the enzymes involved in the first step of the biosynthesis of these lipid mediators and selective inhibitors for these isoenzymes as well as pharmacological analogues of prostaglandins have been developed and are currently applied therapeutically. Here we discuss the implications of these enzymes in the onset of metabolic and lipid disorders in the liver and their potential role in the progression of the diseases towards fibrosis and hepatocellular carcinogenesis.

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“…The PTPRJ ( DEP1 ) cDNA construct was a kind gift from Dr. Nicholas K Tonks (Cold Spring Harbor Laboratory, NY, USA) [27] . The plasmids encoding COX-2 was a kind gift from Dr. Marta Casado (Institute of Biomedicine of Valencia, Valencia, Spain) [28] .…”

Section: Methodsmentioning

confidence: 99%

Regulated Expression of PTPRJ by COX-2/PGE2 Axis in Endothelial Cells

et al. 2014

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BackgroundThis study was designed to examine a novel role of COX-2/PGE2 signaling as a regulator of PTPRJ expression in endothelial cells.MethodsA bioinformatics analysis of a whole genome array was carried out to search for regulators of PTPRJ expression in endothelial cells. PTPRJ expression was also measured in endothelial cells derived from a balloon injury-induced neointimal hyperplasia model in male New Zealand Rabbits. Changes in PTPRJ expression in HUVEC cells was examined by RT-PCR and western blotting after transfection of COX-2 plasmids or treatment with varying concentrations of a COX-2 inhibitor.ResultsA significant correlation was identified between COX-2 and PTPRJ in GSE39264 (Pearson correlation coefficient = −0.87; n = 22; P<0.01, two-tailed). PTPRJ expression was reduced during the progression of neointimal hyperplasia after balloon injury, which correlated with an increase in COX-2 expression. In HUVECs, after transfection with 1 µg/ml, 0.5 µg/ml, or 0.25 µg/ml COX-2 plasmids, PTPRJ protein expression was reduced to 0.60- (±0.08), 0.75- (±0.09), and 0.88- (±0.04) fold, respectively, while mRNA expression was reduced to 0.15- (±0.03), 0.26- (±0.05), and 0.47- (±0.09) fold, respectively. After treatment of HUVECs with 10 µmol/L or 20 µmol/L celecoxib, the reduction in PTPRJ expression induced by COX-2 over-expression was not only rescued but in fact increased by 2.05-fold (±0.28) and 3.34-fold (±0.37), respectively, compared with control.ConclusionsOur results suggest that COX-2/PGE2 signaling may function as a negative regulator of PTPRJ expression in endothelial cells both in vivo and vitro.

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Transgenic Mice Expressing Cyclooxygenase-2 in Hepatocytes Reveal a Minor Contribution of This Enzyme to Chemical Hepatocarcinogenesis

Abstract: Cyclooxygenase-2 (COX-2

Cited by 13 publications

References 44 publications

Cyclooxygenase-2 Is a Target of MicroRNA-16 in Human Hepatoma Cells

Cyclooxygenase-2 Is a Target of MicroRNA-16 in Human Hepatoma Cells

Cyclooxygenase 2 in liver dysfunction and carcinogenesis: Facts and perspectives

Regulated Expression of PTPRJ by COX-2/PGE2 Axis in Endothelial Cells

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