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Cyclooxygenase 2 in liver dysfunction and carcinogenesis: Facts and perspectives

World Journal of Gastroenterology 2017年第20期23卷 3572-3580页

作者： Paloma Martín-Sanz Marta Casado lisardo boscá Department of Metabolism and Cell Signaling Institute of Biomedical Research Alberto Sols Biomedical Network Center for the Study of Hepatic and Digestive Disease and Cardiovascular Diseases Metabolic Experimental Pathology Unit Biomedical Institute of ValenciaJaume Roig 11

The biosynthesis of prostaglandins and thromboxanes has been a focus of interest in the management of many liver *** 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 *** 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.

关键词： Cyclooxygenase-2 NAS Prostaglandin Non-alcoholic steatohepatitis Hepatocellular carcinoma

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Post-translational modifications of prostaglandin-endoperoxide synthase 2 in colorectal cancer:An update

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World Journal of Gastroenterology 2018年第48期24卷 5454-5461页

作者： Rafael I Jaén Patricia Prieto Marta Casado Paloma Martín-Sanz lisardo boscá Department of Metabolism and Physiopathology of Inflammatory Diseases Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM) Department of Biomedicine Instituto de Biomedicina de Valencia (CSIC) Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares y Hepáticas y DigestivasISCⅢ Unidad Asociada IIBMULPGC Universidad de las Palmas de Gran Canaria (ULPGC)

The biosynthesis of prostanoids is involved in both physiological and pathological processes. The expression of prostaglandin-endoperoxide synthase 2(PTGS2; also known as COX-2) has been traditionally associated to the onset of several pathologies, from inflammation to cardiovascular, gastrointestinal and oncologic events. For this reason, the search of selective PTGS2 inhibitors has been a focus for therapeutic interventions. In addition to the classic non-steroidal anti-inflammatory drugs, selective and specific PTGS2 inhibitors, termed coxibs, have been generated and widely used. PTGS2 activity is less restrictive in terms of substrate specificity than the homeostatic counterpart PTGS1, and it accounts for the elevated prostanoid synthesis that accompanies several pathologies. The main regulation of PTGS2 occurs at the transcription level. In addition to this, the stability of the mRNA is finely regulated through the interaction with several cytoplasmic elements, ranging from specificmicroR NAs to proteins that control mR NA degradation. Moreover, the protein has been recognized to be the substrate for several post-translational modifications that affect both the enzyme activity and the targeting for degradation via proteasomal and non-proteasomal mechanisms. Among these modifications, phosphorylation, glycosylation and covalent modifications by reactive lipidic intermediates and by free radicals associated to the proinflammatory condition appear to be the main changes. Identification of these post-translational modifications is relevant to better understand the role of PTGS2 in several pathologies and to establish a correct analysis of the potential function of this protein in diseases progress. Finally, these modifications can be used as biomarkers to establish correlations with other parameters, including the immunomodulation dependent on molecular pathological epidemiology determinants, which may provide a better frame for potential therapeutic interventions.

关键词： Prostaglandins Prostaglandin-endoperoxide synthase 2 Post-translational modifications Glycosylation Colorectal cancer Inflammation

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COX-2 in liver,from regeneration to hepatocarcinogenesis:What we have learned from animal models?

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World Journal of Gastroenterology 2010年第12期16卷 1430-1435页

作者： Paloma Martín-Sanz Rafael Mayoral Marta Casado lisardo boscá Biomedical Network Center for the Study of Hepatic and Digestive Diseases(CIBERehd) Department of Metabolism and Cell Signaling Institute of Biomedical Research "Alberto Sols"(CSIC-UAM) Department of Pathology and Molecular and Cellular Therapy Institute of Biomedicine of Valencia(IBV-CSIC)

The use of animals lacking genes or expressing genes under the control of cell-specific promoters has signifi cantly increased our knowledge of the genetic and molecular basis of physiopathology,allowing testing of functional hypotheses and validation of biochemical and pharmacologic approaches in order to understand cell ***,with unexpected frequency,gene knockout animals and,more commonly,animal models of transgenesis give experimental support to even opposite conclusions on gene *** we summarize what we learned on the role of cyclooxygenase 2(COX-2) in liver and revise the results obtained in 3 independent models of mice expressing a COX-2 transgene specifi cally in the *** challenge with pro-inflammatory stimuli,the animals behave very differently,some transgenic models having a protective effect but others enhancing the *** addition,one transgene exerts differential effects on normal liver physiology depending on the transgenic animal model used.

关键词： Cyclooxygenase 2 Prostaglandins Liver diseases Apoptosis Inflammation Animal models

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Interplay between post-translational cyclooxygenase-2 modifications and the metabolic and proteomic profile in a colorectal cancer cohort

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World Journal of Gastroenterology 2019年第4期25卷 433-446页

作者： Patricia Prieto Rafael I Jaén Daniel Calle María Gómez-Serrano Estefanía Nú?ez María Fernández-Velasco Paloma Martín-Sanz Sergio Alonso Jesús Vázquez Sebastián Cerdán Miguel ángel Peinado lisardo boscá Department of Metabolism and Physiopathology of Inflammatory Diseases Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM) Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (Ciber-CV) Instituto de Salud Carlos III (ISCIII) Laboratorio de Imagen Médica Hospital Universitario Gregorio Mara?ón Laboratorio de Proteómica Cardiovascular Centro Nacional de Investigaciones Cardiovasculares (CNIC) Instituto de Investigación Sanitaria del Hospital Universitario la Paz(IdiPaz) Programa de Medicina Predictiva y Personalizada del Cáncer (PMPPC) Fundación Instituto de investigación en ciencias de la salud Germans Trias i PujolCtra Can Ruti

BACKGROUND Colorectal cancer(CRC) is the second most common cause of cancer death worldwide. It is broadly described that cyclooxygenase-2(COX-2) is mainly overexpressed in CRC but less is known regarding post-translational modifications of this enzyme that may regulate its activity, intracellular localization and stability. Since metabolic and proteomic profile analysis is essential for cancer prognosis and diagnosis, our hypothesis is that the analysis of correlations between these specific parameters and COX-2 state in tumors of a high number of CRC patients could be useful for the understanding of the basis of this cancer in *** To analyze COX-2 regulation in colorectal cancer and to perform a detailed analysis of their metabolic and proteomic *** Biopsies from both healthy and pathological colorectal tissues were taken under informed consent from patients during standard colonoscopy procedure in the University Hospital of Bellvitge(Barcelona, Spain) and Germans Trias i Pujol University Hospital(Campus Can Ruti)(Barcelona, Spain). Western blot analysis was used to determine COX-2 levels. Deglycosylation assays were performed in both cells and tumor samples incubating each sample with peptide N-glycosidase F(PNGase F). Prostaglandin E2(PGE2) levels were determined using a specific ELISA. 1 H high resolution magic angle spinning(HRMAS) analysis was performed using a Bruker AVIII 500 MHz spectrometer and proteomic analysis was performed in a nano-liquid chromatography-tandem mass spectrometer(nano LC-MS/MS) using a QExactive HF orbitrap *** Our data show that COX-2 has a differential expression profile in tumor tissue of CRC patients vs the adjacent non-tumor area, which correspond to a glycosylated and less active state of the protein. This fact was associated to a lesser PGE2 production in tumors. These results were corroborated in vitro performing deglycosylation assays in HT29 cell line where COX-2 protein profile was modified after PN

关键词： Colon Carcinoma Cyclooxygenase Prostaglandin Proteomics High resolution magic angle spinning

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