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.

Chemoprevention and Treatment of Pancreatic Cancer: Update and Review of the Literature

“…Bleul et al [107] claim that endogenous retinoids inhibit carcinogenesis and the beneficial effect of retinoid treatment should depend on the expression level of retinoid receptors in tumour tissue. A reduction of retinoids and their receptors is an important feature of pancreatic cancer and is associated with worse patient survival outcomes [107].…”

LncRNAs2Pathways: Identifying the pathways influenced by a set of lncRNAs of interest based on a global network propagation method

“…We downloaded this set from the Lnc2Cancer database, and a total of nine pancreatic-cancer associated lncRNAs were identified in the CNC network (Supplementary Table S6). With FDR < 0.01, LncRNAs2Pathways obtained seven statistically significant pathways (Table 3), examples of which include the following: arachidonic acid metabolism, in which lipoxygenases, which are the key constituents, play a critical role in pancreatic cancer cell proliferation63; oxidative phosphorylation, whose KCa3.1 channel was identified as a regulator in a subset of pancreatic carcinoma cell lines64; the reduction of retinoids and their receptors, which is associated with pancreatic cancer patient survival65; and the overexpression of ribosomal proteins, which can promote tumorigenesis by interacting with the p53 tumor suppressor66. For the significant pathways, such as arachidonic acid metabolism, 14 core genes were identified (Supplementary Figure S4A).…”

MiRNAs are Unlikely to be Involved in Retinoid Receptor Gene Regulation in Pancreatic Cancer Cells

“…Expression of the retinoid receptor was determined by QuantiFast SYBR Green PCR kit (Qiagen, Hilden, Germany) following the manufacturer's instruction and described elsewhere [24]. Briefly, 1 µl of cDNA synthesized before was added to reaction mix in 96-well plate.…”

“…In our previous study, we showed that the down-regulation of retinoid receptors in PDAC is negatively correlated with patient survival, which indicates that retinoid receptors could function as tumor suppressors [24]. To investigate whether retinoid receptor mRNAs are targeted by specific miRNAs, the first step is to predict the specific binding sites in the 3'UTRs.…”