醛酮还原酶AKR1C1介导性激素失衡与肝癌预后关联的机制研究

Hepatocellular carcinoma (HCC) is sex hormone-dependent tumor, and closely related to hormone level. Gender difference between male and female runs throughout the entire process of HCC. Aldo-Keto Reductase family 1, member C1 (AKR1C1) converts androgen to estrogen. Our previous research shows that AKR1C1 promotes the development of HCC. The expression level of AKR1C1 shows different HCC prognostic indication effect between men and women. Through this study, we will further reveal how AKR1C1 exerts as a prognosis indicator of HCC that mediated by hormone imbalance. We will establish an AKR1C1-sex hormones prognostic indicator model of HCC, and use iTRAQ-based quantitative proteomics technology to screen differential target proteins. We will construct male and female mouse spontaneous HCC model. The phenotypes combined with levels of sex hormones in peripheral blood, and differential expressed proteins affected by knocking down Akr1c21 from mouse HCC model, we will optimize the prognostic indicator model of human. Eventually, we will accumulate both theoretical and experimental evidences of AKR1C1 as a novel HCC prognostic indicator, as well as individualized clinical treatment based on gender differences of HCC.

肝细胞肝癌（HCC）是性激素依赖性肿瘤，其发生发展与体内性激素水平密切相关，性别差异贯穿于疾病全过程。醛酮还原酶1C1（AKR1C1）可将雄激素转化为雌激素，我们前期研究发现AKR1C1促进肝癌的发生发展，其表达水平在男女患者中具有不同的预后指示效果。本研究将深入揭示AKR1C1如何介导性激素失衡在肝癌中发挥作用，并尝试将其开发为新的HCC预后诊断分子。本研究拟在男女性肝癌病人中建立AKR1C1-性激素预后指示模型，通过iTRAQ差异定量蛋白质组学技术筛选AKR1C1表达水平不同的男女性肝癌组织中的关键变化蛋白；并分别在雌性和雄性小鼠自发肝癌模型中，验证小鼠Akr1c21表达下调后的体内表型和下游效应分子，对肝癌病人中建立的模型进一步优化。本项目有望积累AKR1C1作为肝癌预后指示分子的理论及实验依据，为进一步揭示肝癌的男女性别差异成因和个体化临床治疗提供重要线索。

肝细胞肝癌（HCC）是性激素依赖性肿瘤，其发生发展与体内性激素水平密切相关，性别差异贯穿于疾病全过程。醛酮还原酶1C1（AKR1C1）可将雄激素转化为雌激素，我们前期研究发现AKR1C1促进肝癌的发生发展，其表达水平在男女患者中具有不同的预后指示效果。本研究深入揭示AKR1C1如何介导性激素失衡在肝癌中发挥作用，探讨AKR1C1作为新的HCC预后诊断分子的临床应用前景。首先在TCGA(The Cancer Genome Atlas)数据库中进行AKR1C1表达水平与肝癌预后状态的关联分析，我们针对该数据库中的大量肝癌病例信息，运用信息学方法分析AKR1C1在肝癌中的表达水平差异。其次在体内外研究中建立AKR1C1促进肝癌发展转移的功能实验研究。激素调节机制方面，运用GC-MS方法分别在AKR1C1表达水平不同的肝癌细胞中检测相关激素的水平变化。结果显示AKR1C1可以调节肝癌细胞中的激素代谢，为进一步揭示肝癌的男女性别差异成因和个体化临床治疗提供重要线索。