Bleul Tim, Rühl Ralph, Bulashevska Svetlana, Karakhanova Svetlana, Werner Jens, Bazhin Alexandr V
Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany.
Department of Biochemistry and Molecular Biology, Medical and Health Science Center, Debrecen, Hungary.
Mol Carcinog. 2015 Sep;54(9):870-9. doi: 10.1002/mc.22158. Epub 2014 Apr 11.
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.
胰腺导管腺癌（PDAC）是世界上最致命的癌症之一。全反式维甲酸（ATRA）是维生素A的主要生理活性形式，可调节许多基因的表达。维生素A代谢紊乱在一些癌细胞中很普遍。这项工作的主要目的是深入研究与正常胰腺相比，PDAC中类视黄醇信号通路的组成部分，并证明类视黄醇受体表达的临床重要性。在这项研究中，从PDAC患者获得的人类肿瘤组织和原位Panc02模型的小鼠肿瘤用于类视黄醇分析，采用高效液相色谱质谱法和实时RT-PCR基因表达分析。单因素分析中的生存概率采用Kaplan-Meier方法估计，多因素分析采用Cox比例风险模型。在这项工作中，我们首次表明，与正常组织相比，PDAC组织中ATRA和全反式视黄醇的浓度降低。PDAC组织中RARα和β以及RXRα和β的表达下调。类视黄醇受体的这种表达降低与一些分化标志物、上皮-间质转化标志物以及癌症干细胞标志物的表达相关。重要的是，RARα和RXRβ的表达与PDAC患者更好的总生存期相关。因此，类视黄醇及其受体的减少是PDAC的一个重要特征，并且与患者较差的生存结果相关。
