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 (P = 0.0016, 0.019) and disease-free survival rate (P = 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）的主要致病驱动因素。阻断肝硬化进展为肝细胞癌，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枢纽基因，最终确定UBE2T与CYP3A4为肝硬化向肝细胞癌转化过程中的枢纽基因。与肝硬化组织相比，肝细胞癌组织中UBE2T表达上调、CYP3A4表达下调，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（Western Blotting，WB）及免疫组化（immunohistochemistry，IHC）得到验证。联合检测UBE2T与CYP3A4，用于预测肝硬化患者向肝细胞癌进展的特异性为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或甲胎蛋白（alpha-fetoprotein）。本研究进一步通过15例配对的肝细胞癌组织及癌旁肝硬化组织样本，经RT-PCR验证了该联合检测的效能，其特异性达100%、灵敏度为80%。表达上调UBE2T且下调CYP3A4的肝细胞癌患者，其总体生存率（P=0.0016、0.019）与无病生存率（P=0.0013、0.041）均显著降低。综上，UBE2T与CYP3A4可作为肝硬化向肝细胞癌转化过程中癌变发生与进展的新型联合生物标志物。