Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai, 200438, China.
Cancer Lett. 2019 Jul 10;454:14-25. doi: 10.1016/j.canlet.2019.03.030. Epub 2019 Mar 22.
Patients receiving sorafenib treatment for hepatocellular carcinoma (HCC) experience different treatment efficacy. Personalized sorafenib treatment should be achieved through the identification of predictors of therapeutic response. In the current study, we found that high UGT1A9 expression indicated better prognosis for HCC patients treated with sorafenib after surgery. In silico analysis predicted microRNA-200a/-183 as potential regulators of the UGT1A gene family via binding to the shared UGT1A9 3'-UTR. A significant inverse correlation between microRNA-200a/-183 and UGT1A9 mRNA level was observed in a panel of HCC specimens. Direct binding was further demonstrated by luciferase reporter gene vector carrying wild-type or binding site truncated UGT1A9 3'-UTR. MicroRNA-200a/-183 downregulated UGT1A9 expression in a dose-dependent manner and significantly reduced sorafenib β-D-glucuronide formation in HCC cells. These data indicated that UGT1A9, under epigenetic regulation of microRNA-200a/-183, could predict patients who might benefit from adjuvant sorafenib treatment after surgery.
接受索拉非尼治疗肝细胞癌（HCC）的患者的治疗效果不同。通过识别治疗反应的预测因子，可以实现个性化的索拉非尼治疗。在本研究中，我们发现高 UGT1A9 表达表明接受索拉非尼治疗的 HCC 患者手术后的预后更好。通过与共享的 UGT1A9 3'UTR 结合，计算分析预测 microRNA-200a/-183 作为潜在的 UGT1A 基因家族调节剂。在一组 HCC 标本中观察到 microRNA-200a/-183 和 UGT1A9 mRNA 水平之间存在显著的负相关。通过携带野生型或结合位点截断的 UGT1A9 3'UTR 的荧光素酶报告基因载体进一步证明了直接结合。microRNA-200a/-183 以剂量依赖性方式下调 UGT1A9 的表达，并显著减少 HCC 细胞中索拉非尼β-D-葡糖苷酸的形成。这些数据表明，在 microRNA-200a/-183 的表观遗传调控下，UGT1A9 可以预测手术后可能受益于辅助索拉非尼治疗的患者。
