title: Reduced retinoids and retinoid receptors' expression in pancreatic cancer: A link to patient survival.
abstract: Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers in the world. All-trans retinoic acid (ATRA) is the major physiologically active form of vitamin A, regulating expression of many genes. Disturbances of vitamin A metabolism are prevalent in some cancer cells. The main aim of this work was to investigate deeply the components of retinoid signaling in PDAC compared to in the normal pancreas and to prove the clinical importance of retinoid receptor expression. For the study, human tumor tissues obtained from PDAC patients and murine tumors from the orthotopic Panc02 model were used for the analysis of retinoids, using high performance liquid chromatography mass spectrometry and real-time RT-PCR gene expression analysis. Survival probabilities in univariate analysis were estimated using the Kaplan-Meier method and the Cox proportional hazards model was used for the multivariate analysis. In this work, we showed for the first time that the ATRA and all-trans retinol concentration is reduced in PDAC tissue compared to their normal counterparts. The expression of RARα and β as well as RXRα and β are down-regulated in PDAC tissue. This reduced expression of retinoid receptors correlates with the expression of some markers of differentiation and epithelial-to-mesenchymal transition as well as of cancer stem cell markers. Importantly, the expression of RARα and RXRβ is associated with better overall survival of PDAC patients. Thus, reduction of retinoids and their receptors is an important feature of PDAC and is associated with worse patient survival outcomes.
authors.affiliation: Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Bleul
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical and Health Science Center, Debrecen, Hungary.|Paprika Bioanalytics BT, Debrecen, Hungary.
authors.forename: Ralph
authors.initials: R
authors.lastname: Rühl
authors.affiliation: Department of Life Science Informatics, B-IT, University of Bonn, Bonn, Germany.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Bulashevska
authors.affiliation: Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Karakhanova
authors.affiliation: Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Werner
authors.affiliation: Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany.|Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Alexandr V
authors.initials: AV
authors.lastname: Bazhin
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010179:Pancreas / Q000378:metabolism / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D016016:Proportional Hazards Models; D018168:Receptors, Retinoic Acid / Q000032:analysis / Q000235:genetics*; D012176:Retinoids / Q000032:analysis / Q000235:genetics*; D016019:Survival Analysis
chemical_list: D018168:Receptors, Retinoic Acid; D012176:Retinoids
keywords: epithelial-to-mesenchymal transition; pancreatic ductal adenocarcinoma; retinoid receptors; retinoids