UBE2T And CYP3A4: hub genes regulating the transformation of cirrhosis into hepatocellular carcinoma

Cirrhosis is the primary driver of hepatocellular carcinoma (HCC). Blocking the deterioration of cirrhosis into HCC would be of benefit for long–term survival. We applied a series of bioinformatic online databases to select and analyze the hub genes concerning cirrhosis and HCC, and identified UBE2T and CYP3A4 as hub genes for cirrhosis-HCC transformation. An elevated UBE2T and a decreased CYP3A4 were expressed in HCC compared with cirrhosis, which have been confirmed by real-time polymerase chain reaction (RT–PCR), Western Blotting (WB) and immunohistochemistry (IHC). The specificity (89.9%) and sensitivity (74.1%) on the combination of UBE2T and CYP3A4 for predicting HCC development in cirrhosis patients were better than that of UBE2T or CYP3A4 alone, or alpha-fetoprotein. The effectiveness of the combination of UBE2T and CYP3A4 was further verified by 15 paired HCC and paracancerous cirrhosis samples using RT–PCR, with a specificity of 100% and a sensitivity of 80%. HCC patients with elevated UBE2T and decreased CYP3A4 expression demonstrated a poorer overall survival rate (<i>P </i>= 0.0016, 0.019) and disease-free survival rate (<i>P </i>= 0.0013, 0.041). In conclusion, UBE2T and CYP3A4 could be a new combination of biomarkers for the carcinogenesis and progression of cirrhosis into HCC.

肝硬化是肝细胞癌（hepatocellular carcinoma，HCC）的主要致病因素。阻断肝硬化向肝细胞癌的进展，对患者的长期生存具有重要意义。本研究通过一系列生物信息学在线数据库，筛选并分析了与肝硬化及肝细胞癌相关的核心基因，最终确定UBE2T与CYP3A4为肝硬化向肝细胞癌转化的核心基因。相较于肝硬化组织，肝细胞癌组织中UBE2T呈高表达、CYP3A4呈低表达，该结果已通过实时荧光定量聚合酶链反应（real-time polymerase chain reaction，RT-PCR）、蛋白质印迹法（Western Blotting，WB）及免疫组织化学（immunohistochemistry，IHC）得以验证。联合检测UBE2T与CYP3A4用于预测肝硬化患者发生肝细胞癌的特异性为89.9%、灵敏度为74.1%，其诊断效能优于单独检测UBE2T、单独检测CYP3A4，亦优于甲胎蛋白（alpha-fetoprotein）。本研究进一步通过15对肝细胞癌及癌旁肝硬化组织样本，采用RT-PCR验证了联合检测UBE2T与CYP3A4的诊断效能，其特异性达100%、灵敏度达80%。UBE2T高表达且CYP3A4低表达的肝细胞癌患者，其总生存期（<i>P</i> = 0.0016, 0.019）与无病生存期（<i>P</i> = 0.0013, 0.041）均显著更差。综上，UBE2T与CYP3A4可作为肝硬化向肝细胞癌转化过程中的新型联合生物标志物，用于该疾病的癌变与进展监测。