肝癌细胞中P3H2高表达增强蟾毒灵衍生物 （RX108）敏感性的机制研究

蟾毒灵衍生物（RX108）在I期临床试验中已经取得初步疗效，但是患者对药物反应性存在差异，因此寻找预测RX108疗效敏感的生物标志物极为重要。我们前期研究结果表明81株肝癌细胞系与TCGA数据库中肝癌患者的基因表达和突变谱一致，即可以用该细胞系平台进行药物敏感生物标志物的研究。本课题利用肝癌细胞系平台和siRNA库筛选与RX108反应性相关的基因，发现P3H2高表达与RX108的敏感性相关，通过基因过表达和干扰实验进行候选基因的鉴定，结合RNA测序和KEGG信号通路富集等方法明确P3H2高表达增强RX108敏感性的机制，并用体内异种移植小鼠模型进一步验证。该研究为RX108的临床应用奠定了理论基础，指导临床用药，筛选有效治疗人群。

Bufalin derivative (RX108) has achieved initial efficacy in phase I clinical trials, but patients show different responses to RX108. Therefore, it is extremely important to find sensitive biomarkers to predict the efficacy of RX108. Our previous research results showed that the 81 hepatocellular carcinoma (HCC) cell lines have the same gene expression and mutation profiles as those in the TCGA database, which means the platform can be used to study drug sensitive biomarkers. In this study, high throughput drug screening and siRNA library were used to find out biomarkers to predict the response of RX108.The results showed high expression of P3H2 was correlated with the sensitivity of RX108. The identification of candidate genes was carried out through gene knockdown and over-expression experiments, and the mechanism of enhancing the sensitivity of RX108 by P3H2 high expression was verified via RNA sequencing, KEGG signal pathway enrichment and so on. Thus, the study aims to provide theoretical basis for biomarkers reflecting the sensitivity of RX108 and promote the clinical application.