title: Epigenetics override pro-inflammatory PTGS transcriptomic signature towards selective hyperactivation of PGE2 in colorectal cancer.
abstract: BACKGROUND
  Misregulation of the PTGS (prostaglandin endoperoxide synthase, also known as cyclooxygenase or COX) pathway may lead to the accumulation of pro-inflammatory signals, which constitutes a hallmark of cancer. To get insight into the role of this signaling pathway in colorectal cancer (CRC), we have characterized the transcriptional and epigenetic landscapes of the PTGS pathway genes in normal and cancer cells.
  
  
  RESULTS
  Data from four independent series of CRC patients (502 tumors including adenomas and carcinomas and 222 adjacent normal tissues) and two series of colon mucosae from 69 healthy donors have been included in the study. Gene expression was analyzed by real-time PCR and Affymetrix U219 arrays. DNA methylation was analyzed by bisulfite sequencing, dissociation curves, and HumanMethylation450K arrays. Most CRC patients show selective transcriptional deregulation of the enzymes involved in the synthesis of prostanoids and their receptors in both tumor and its adjacent mucosa. DNA methylation alterations exclusively affect the tumor tissue (both adenomas and carcinomas), redirecting the transcriptional deregulation to activation of prostaglandin E2 (PGE2) function and blockade of other biologically active prostaglandins. In particular, PTGIS, PTGER3, PTGFR, and AKR1B1 were hypermethylated in more than 40 % of all analyzed tumors.
  
  
  CONCLUSIONS
  The transcriptional and epigenetic profiling of the PTGS pathway provides important clues on the biology of the tumor and its microenvironment. This analysis renders candidate markers with potential clinical applicability in risk assessment and early diagnosis and for the design of new therapeutic strategies.
authors.affiliation: Institute of Predictive and Personalized Medicine of Cancer (IMPPC, Ctra Can Ruti, Cami de les Escoles, Badalona, 08916 Spain ; Current address: Department of Medicine, Imperial College London, London, UK.
authors.forename: Inês
authors.initials: I
authors.lastname: Cebola
authors.affiliation: Institute of Predictive and Personalized Medicine of Cancer (IMPPC, Ctra Can Ruti, Cami de les Escoles, Badalona, 08916 Spain ; Current address: Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Custodio
authors.affiliation: Institute of Predictive and Personalized Medicine of Cancer (IMPPC, Ctra Can Ruti, Cami de les Escoles, Badalona, 08916 Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Muñoz
authors.affiliation: Institute of Predictive and Personalized Medicine of Cancer (IMPPC, Ctra Can Ruti, Cami de les Escoles, Badalona, 08916 Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Díez-Villanueva
authors.affiliation: Unit of Biomarkers and Susceptibility, Cancer Prevention and Control Program, Catalan Institute of Oncology (ICO), IDIBELL and CIBERESP, Hospitalet de Llobregat, Barcelona Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Paré
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Prieto
authors.affiliation: Unit of Biomarkers and Susceptibility, Cancer Prevention and Control Program, Catalan Institute of Oncology (ICO), IDIBELL and CIBERESP, Hospitalet de Llobregat, Barcelona Spain.
authors.forename: Susanna
authors.initials: S
authors.lastname: Aussó
authors.affiliation: Institute of Predictive and Personalized Medicine of Cancer (IMPPC, Ctra Can Ruti, Cami de les Escoles, Badalona, 08916 Spain.
authors.forename: Llorenç
authors.initials: L
authors.lastname: Coll-Mulet
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain.
authors.forename: Lisardo
authors.initials: L
authors.lastname: Boscá
authors.affiliation: Unit of Biomarkers and Susceptibility, Cancer Prevention and Control Program, Catalan Institute of Oncology (ICO), IDIBELL and CIBERESP, Hospitalet de Llobregat, Barcelona Spain ; Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Moreno
authors.affiliation: Institute of Predictive and Personalized Medicine of Cancer (IMPPC, Ctra Can Ruti, Cami de les Escoles, Badalona, 08916 Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Peinado
keywords: COX pathway; DNA methylation; Gene expression; Inflammation; Prostaglandins; Prostanoids