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©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 28, 2019; 25(4): 433-446
Published online Jan 28, 2019. doi: 10.3748/wjg.v25.i4.433
Interplay between post-translational cyclooxygenase-2 modifications and the metabolic and proteomic profile in a colorectal cancer cohort
Patricia Prieto, Rafael I Jaén, Daniel Calle, María Gómez-Serrano, Estefanía Núñez, María Fernández-Velasco, Paloma Martín-Sanz, Sergio Alonso, Jesús Vázquez, Sebastián Cerdán, Miguel Ángel Peinado, Lisardo Boscá
Patricia Prieto, Rafael I Jaén, Paloma Martín-Sanz, Sebastián Cerdán, Lisardo Boscá, Department of Metabolism and Physiopathology of Inflammatory Diseases, Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid 28029, Spain
Patricia Prieto, Rafael I Jaén, María Gómez-Serrano, Estefanía Núñez, María Fernández-Velasco, Paloma Martín-Sanz, Jesús Vázquez, Lisardo Boscá, Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (Ciber-CV), Instituto de Salud Carlos III (ISCIII), Madrid 28029, Spain
Daniel Calle, Laboratorio de Imagen Médica, Hospital Universitario Gregorio Marañón, Madrid 28007, Spain
María Gómez-Serrano, Estefanía Núñez, Jesús Vázquez, Laboratorio de Proteómica Cardiovascular, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain
María Fernández-Velasco, Instituto de Investigación Sanitaria del Hospital Universitario la Paz (IdiPaz), Madrid 28046, Spain
Sergio Alonso, Miguel Ángel Peinado, Programa de Medicina Predictiva y Personalizada del Cáncer (PMPPC), Fundación Instituto de investigación en ciencias de la salud Germans Trias i Pujol, Ctra Can Ruti, Badalona 08916, Spain
Author contributions: Prieto P and Jaén RI are the co-first authors. Prieto P performed the experiments, analyzed data and wrote the manuscript; Jaén RI performed the experiments and analyzed data, Calle D and Cerdán S designed, performed and analyzed the high resolution magic angle spinning experiments; Gómez-Serrano M, Núñez E, and Vázquez J designed and performed the proteomics analysis; Fernández-Velasco M and Martín-Sanz P revised critically the manuscript; Alonso S and Peinado MÁ collected colon biopsies from CRC patients and Boscá L conceived the experiments and revised critically the manuscript.
Supported by MINECO, No. SAF2017-82436R, SAF2016-75004R, RTC-2017-6283-1, PRB3 (IPT17/0019-ISCIII-SGEFI/ERDF) and BIO2015-67580P; Comunidad de Madrid, No. S2017/BMD-3686; Fundación Ramón Areces, No. 2016/CIVP18A3864; Instituto de Salud Carlos III, Spain, CIBERCV, No. CB/11/00222 and CB16/11/00277; FEDER, CIBEREHD; the Ministerio de Ciencia, Innovación y Universidades (MCNU); the Pro CNIC Foundation; and Severo Ochoa Center of Excellence, No. SEV-2015-0505.
Institutional review board statement: Colorectal cancer biopsies were obtained from 45 patients under informed consent, and were used in accordance with the procedures approved by Clinical Investigation ethics committees of the Germans Trias i Pujol Hospital (Badalona, Spain) and Bellvitge Hospital (Barcelona, Spain).
Conflict-of-interest statement: MAP is cofounder and equity holder of Aniling, a biotech company with no interests in this work. MAP lab has received research funding from Celgene. The rest of the authors declare no conflict of interest.
Data sharing statement: No additional data is available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Lisardo Boscá, PhD, Professor, Department of Metabolism and Physiopathology of Inflammatory Diseases, Instituto de investigaciones Biomédicas “Alberto Sols”, Arturo Duperier 4, Madrid 28029, Spain.
lbosca@iib.uam.es
Telephone: +34-91-4972747 Fax: +34-91-4972747
Received: October 17, 2018
Peer-review started: October 17, 2018
First decision: December 5, 2018
Revised: December 21, 2018
Accepted: January 9, 2019
Article in press: January 10, 2019
Published online: January 28, 2019
Processing time: 101 Days and 23.4 Hours
ARTICLE HIGHLIGHTS
Research 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 very low is known about the nature and effects of the post-translational modifications of this enzyme within the tumor environment. Using metabolic and proteomic profile analyses which are essential for cancer prognosis and diagnosis, our hypothesis is that integrating these parameters with the study of COX-2 post-translational modifications in a high number of CRC patients may provide new insights on the implications of post-translational modifications for CRC prognosis and therapeutics.
Research motivation
Many medical and research efforts have been made trying to better evaluate CRC progression. Nevertheless, it is still necessary to study in depth the molecular, metabolic and proteomic features to unravel the mechanisms leading to CRC progression and to provide a rationale for a personalized therapeutic approach.
Research objectives
The aim of this study was to analyze the regulation of COX-2 in samples from patients with colorectal cancer and to perform a detailed analysis of both the metabolic profile and the proteomic content of the tumor tissue compared to the non-tumor adjacent area.
Research methods
Both normal and tumor tissue obtained from CRC patients were processed and the protein levels of COX-2 were determined. Deglycosylation assays were performed in both cells and tumor samples before measuring prostaglandin E2 (PGE2) levels. Moreover, metabolic and proteomic profile in both samples types were carried out to complete the study.
Research results
Tumor tissue of colorectal cancer patients of our cohort presents an altered COX-2 protein expression profile, which correspond to a glycosylated state of the protein. This was associated to a lesser PGE2 production in tumors. Moreover, high resolution magic angle spinning (HRMAS) analysis indicated that tumor tissue exhibits increased levels of certain metabolites as taurine and phosphocholine and lower levels of lactate. Moreover, we detected an enlarged number of proteins in tumors that are mainly implicated in basic biological functions. Due to the high variability between patients, it will be necessary to analyze a large number of samples in order to achieve sufficient statistical power to find a biomarker that will be applicable in the future as a tool to improve both the diagnosis and prognosis of CRC patients.
Research conclusions
In our colorectal cancer cohort, tumor tissue presents a differential COX-2 expression pattern compared to non-tumor and a lower activity of this enzyme. Moreover, this tissue showed an altered metabolic and proteomics profile that can be correlated to post-translational COX-2 modifications. The analysis of correlations between metabolic and molecular parameters in tumors of a high number of CRC patients could be useful for the understanding of the basis of this cancer in humans.
Research perspectives
Our results relate by the first time post-translational COX-2 modifications with a metabolic and proteomic profile and can be useful in building new multivariate classifiers looking for a robust cross-talk among molecular, metabolic and proteomics data to improve the knowledge on CRC contributing to establish new protocols for the diagnosis, prognosis and therapeutics for this cancer. However, more samples should be analyzed in the future in order to discriminate a robust biomarker that can be useful in CRC diagnosis and prognosis.
