Trx1/FOXO1信号通路调控肝癌耐药的机制研究

Understanding the mechanisms of drug resistance is critically important for the treatment of hepatocellular carcinoma(HCC). The resistance of cancer stem cells (CSCs) to conventional chemotherapeutics was reported to be an obstacle for the total eradication of cancer which might be related to the intracellular redox states. Recently some papers showed that FOXOs were involved in the drug resistance in CSCs, however the working mechanisms remained poorly understood. Our previous work showed that (1) Trx1 and FOXO1 were involved in the drug resistance in HCC；(2) Trx1 interacted with FOXO1 and upregulated FOXO1 activity in HCC. This project will use a mechanical method to select liver CSCs by culturing single HCC cells in soft fibrin gels, and then determine the role of Trx1 redox state and FOXO1 in the drug resistance of liver CSCs. The effects of Trx1 redox state on the interaction with FOXO1 and the regulation of FOXO1 activity will also be determined. The role of FOXO1 regulated by Trx1 redox state in the drug resistance in liver CSCs will be further explored in cell systems, animal models and clinical specimen. The effects of FOXO1 modulated by Trx1 on the expressions of stem cell-related genes will be studied to clarify the mechanism of Trx1/FOXO1-involved drug resistance in liver CSCs. The studies on Trx1/FOXO1 signaling regulated by ROS in liver CSCs will provid an insight into the mechanisms of drug resistance in HCC which may lead to new therapeutic targets and better anticancer strategies.

研究肝癌耐药机制是肝癌治疗的重要课题。肿瘤干细胞被报道是造成肿瘤耐药的主要原因，其机制可能与胞内氧化还原状态有关。研究显示FOXO调控肿瘤干细胞耐药，但其作用机理尚不清楚。我们前期工作发现Trx1和FOXO1调控肝癌细胞耐药，且Trx1 与FOXO1 相互作用并上调FOXO1 活性。本项目以软三维纤维蛋白胶分选肝癌干细胞，研究Trx1 氧化还原状态和FOXO1 在肝癌干细胞耐药中的作用、Trx1 氧化还原状态对其与FOXO1 结合及活性的影响，进一步从细胞、模型动物及临床标本层面探讨Trx1氧化还原状态调控FOXO1活性在肝癌干细胞耐药中的作用；研究Trx1 调控FOXO1 对干细胞功能相关基因表达的影响，阐明Trx1调控FOXO1在肝癌干细胞耐药的机理。本项目研究ROS 调控Trx1/FOXO1 信号通路在肝癌干细胞耐药的作用，为探讨肝癌耐药机理、寻找新靶点及开发抗肝癌药物提供理论基础。

研究肿瘤耐药机制是肿瘤治疗的重要课题。本项目研究发现，Trx1与FOXO1相互作用并上调FOXO1的转录活性，且这种作用与Trx1核易位有关。抗癌药物可诱导肿瘤细胞产生活性氧，促使Trx1与FOXO1入核，增强Trx1与FOXO1相互作用，并上调FOXO1转录活性及其下游靶基因过氧化氢酶、MnSOD的表达水平，调控肿瘤的耐药。本项目阐明Trx1-FOXO1信号通路在肿瘤耐药中的作用，为探讨肿瘤耐药机理、寻找新靶点及开发抗肿瘤药物提供理论基础。在此课题基础上，进一步构建了同时输送Trx1 shRNA和抗癌药物阿霉素的阳离子脂质体来增强肝癌的药物敏感性，并构建了系列肿瘤微环境响应性纳米凝胶载药系统增强肝癌化疗的治疗效果，为肝癌的治疗提供重要策略。