胆管癌对现有化疗药物不敏感，且极易产生抗药性。我们前期项目研究发现RARγ通过调控Wnt/β-catenin信号通路介导胆管癌产生抗药性，然而其具体机制尚不清楚。本项目预实验表明，RARγ可在胞浆与Axin直接相互作用；Wnt/β-catenin信号通路可上调靶基因单羧酸转运蛋白1（MCT1）及RARγ表达，且MCT1与胆管癌抗药性有关。因此，本项目拟先研究RARγ调控Wnt/β-catenin信号通路的具体机制，以及是否与Wnt/β-catenin信号通路形成正反馈环路进而调控MCT1表达升高；然后确定MCT1介导胆管癌抗药性的作用；最后在整体水平以动物模型和临床样本验证RARγ/β-catenin/MCT1信号链介导胆管癌抗药性的作用。本项目将最终阐明RARγ/Axin/β-catenin正反馈环路介导胆管癌抗药性的机制，以期为RARγ作为临床胆管癌潜在的基因治疗靶点提供科学实验基础。

Cholangiocarcinoma (CCA) is not only lack of susceptibility to present chemotherapy drugs, and is also prone to develop drug resistance in chemotherapy. In our previous project, we found that RARγ mediated the drug resistance of CCA through regulation of Wnt/β-catenin signaling pathway. However, the mechanisms are still unclear. Our preliminary experiments showed that RARγ could directly interact with Axin in cytoplasm, and the expression of RARγ and monocarboxylate transporter 1(MCT1) could be upregulated by Wnt/β-catenin signaling pathway. Furthermore, MCT1 was associated with the drug resistance of CCA. Therefore, our project was designed to study the followings: firstly, to investigate the mechanisms of RARγ on regulating Wnt/β-catenin and the positive feedback loop between RARγ and Wnt/β-catenin, which upregulate the MCT1; secondly, to determine the role of MCT1 in mediating drug resistance of CCA, and thirdly to evaluate the in vivo role of RARγ/β-catenin/MCT1 signaling chain in drug resistance of CCA in animal models and clinical samples, hence to clarify the mechanisms of RARγ/Axin/β-catenin positive feedback loop on the mediating drug resistance of CCA, and finally to provide the scientific basis for RARγ as a potential gene therapy target of CCA.