肝癌严重威胁病人生命，OAT2（SLC22A7）是肝中表达量第二的摄取转运体。我们前期实验表明，OAT2在肝癌组织中mRNA、总蛋白和细胞膜蛋白均呈现低表达，其机制与DNA甲基化无关，而涉及组蛋白修饰，并且可被表观遗传药物逆转恢复摄取药物的功能。本项目针对肝癌中OAT2低表达引起耐药这个临床问题，围绕组蛋白乙酰化和非编码RNA调节机制，在分子、细胞和动物模型三个层次开展探索，以期发现特定的表观遗传学动态修饰信号，并据此制定表观遗传药物（伏立诺他等）与OAT2化疗药物底物（5-氟尿嘧啶）联合用药方案，采用肝癌细胞异种移植瘤裸鼠和PDX模型，检测并比较mRNA、总蛋白和膜蛋白表达、组蛋白乙酰化水平及相关的酶、化疗药物动力学和肝癌组织蓄积量以及初步肝肾毒性等，验证疗效与动态修饰调节机制的关系。本研究可为临床用药提供潜在的作用靶标，对提高相关抗肿瘤药物的敏感性和指导临床肿瘤个体化用药具有参考意义。

Hepatocellular carcinoma（HCC）is a serious threat to the life of patients. OAT2 is the uptake transporter of second abundance in the liver. Our previous experiments showed that OAT2 has low expression of mRNA, protein and membrane protein in HCC tissues, and it is not related to DNA methylation and involved histone modifications can be reversed by epigenetic drugs to restore the function of uptake drug. This project is aimed at the clinical problem of OAT2 low expression in HCC, and explores histone acetylation and non-coding RNA regulation mechanisms at three levels of molecular, cellular and animal models in order to discover specific epigenetic dynamic modification signal, and accordingly, the combination of epigenetic drugs (vorinostat) and OAT2 chemotherapeutic drug substrate (5-fluorouracil) will be studied in liver cancer cell xenograft nude mice and PDX model to verify efficacy and dynamic modification regulatory mechanisms such as mRNA and protein expression, histone acetylation levels and related enzymes, chemotherapeutic pharmacokinetics, and liver cancer tissue accumulation and initial toxicity and to provide potential drug targets for clinical use. This study has reference significance for improving the sensitivity of related anti-tumor drugs and guiding individualized drug use in clinical tumors.