Bai Changsen, Wang Hailong, Dong Dong, Li Tong, Yu Zhi, Guo Junfei, Zhou Wei, Li Ding, Yan Ruochen, Wang Liyan, Wang Zhaosong, Li Yueguo, Ren Li
Department of Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
Department of Cancer Cell Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
Front Cell Dev Biol. 2021 Apr 1;9:650748. doi: 10.3389/fcell.2021.650748. eCollection 2021.
Hepatocellular carcinoma (HCC) is highly malignant; nearly half of the new cases and deaths are in China. The poor prognosis of HCC is mainly due to late diagnosis; many new biomarkers have been developed for HCC diagnosis. However, few markers are quickly translated into clinical practice; early and differential diagnosis of HCC from cirrhosis and/or hepatitis is still a clinical challenge. Metabolomics and biochemical methods were used to reveal specific serum biomarkers of HCC. Most of the elevated metabolites in HCC and HBV patients were overlapped compared with controls. Urea was the specifically elevated serum biomarker of HCC patients. Moreover, urea combined with AFP and CEA can improve the sensitivity of HCC diagnosis. The plasma ammonia of HCC patients was significantly higher than healthy controls. Co-culture cell model revealed normal liver cells cooperated with cancer cells to metabolize ammonia into urea. The urea metabolism in cancer cells marginally depended on the expression of CPS1. However, the expression of CPS1 did not change with ammonium chloride, which might regulate the urea cycle through enzyme activity. The urea cycle could detoxify high concentrations of ammonia to promote cancer cell proliferation. Therefore, urea was a by-product of ammonia metabolism and could be a potential serum biomarker for HCC. The combined application of metabolomics and biochemical methods can discover new biomarkers for the early diagnosis of HCC and be quickly applied to clinical diagnosis.
肝细胞癌（HCC）具有高度恶性；近一半的新发病例和死亡病例在中国。HCC预后较差主要归因于诊断较晚；目前已开发出许多用于HCC诊断的新生物标志物。然而，很少有标志物能迅速转化为临床应用；从肝硬化和/或肝炎中早期鉴别诊断HCC仍然是一项临床挑战。采用代谢组学和生化方法来揭示HCC的特异性血清生物标志物。与对照组相比，HCC患者和乙肝患者中大多数升高的代谢物存在重叠。尿素是HCC患者血清中特异性升高的生物标志物。此外，尿素联合甲胎蛋白（AFP）和癌胚抗原（CEA）可提高HCC诊断的敏感性。HCC患者的血浆氨水平显著高于健康对照组。共培养细胞模型显示正常肝细胞与癌细胞协同将氨代谢为尿素。癌细胞中的尿素代谢在一定程度上依赖于氨甲酰磷酸合成酶1（CPS1）的表达。然而，CPS1的表达不会随氯化铵而改变，这可能是通过酶活性来调节尿素循环。尿素循环可以将高浓度的氨解毒以促进癌细胞增殖。因此，尿素是氨代谢的副产物，可能是HCC潜在的血清生物标志物。代谢组学和生化方法的联合应用可以发现用于HCC早期诊断的新生物标志物，并迅速应用于临床诊断。
