Wu Le, Yang Wenlong, Zhang Yu, Du Xiaoyue, Jin Nan, Chen Wen, Li Huangbao, Zhang Shouhua, Xie Baogang
Department of Pharmaceutics, Medical College of Jiaxing University, Jiaxing, China.
School of Pharmaceutical Science, Nanchang University, Nanchang, China.
Front Pharmacol. 2021 Nov 11;12:778890. doi: 10.3389/fphar.2021.778890. eCollection 2021.
Serum uric acid is associated with tumor progression and hepatocarcinogenesis. Here, we aimed to determine whether serum uric acid is related to the survival time of patients with hepatocellular carcinoma (HCC) and whether the inhibition of uric acid production affects the progression and survival of rats with HCC. The follow-up data of 288 patients with advanced HCC were analyzed. Ten purine metabolites in serum and liver samples of diethylnitrosamine (DEN)-induced HCC rats were quantitatively determined by an established UPLC-MS/MS method. On this basis, febuxostat, a specific inhibitor of xanthine oxidase (XOD), was used to interfere with HCC rats. The serum uric acid level of HCC patients was significantly negatively correlated with survival days ( = -0.155). The median survival time was 133.5 days in the high uric acid group (>360 μmol/L, = 80) and 176.0 days in the normal serum uric acid group (<360 μmol/L, = 208, = 0.0013). The levels of hypoxanthine, guanine, and uric acid; XOD activity; and xanthine dehydrogenase mRNA expression in the serum or liver samples of HCC rats were significantly upregulated compared with those in the control group. After febuxostat intervention in DEN-induced HCC rats, the number of atypical cells and inflammatory cells decreased significantly; the serum alpha fetoprotein level and Fisher's ratio tended to return to normal; the median survival time increased from 36 to 96 days ( = 0.08). In addition, serum malondialdehyde, superoxide dismutase, and glutathione activity nearly returned to the level of the healthy control group. The elevation of serum uric acid implies a risk of poor survival in advanced HCC patients and Febuxostat can reduce the generation of reactive oxygen species, thereby playing a role in delaying the progression of liver cancer.
血清尿酸与肿瘤进展及肝癌发生相关。在此，我们旨在确定血清尿酸是否与肝细胞癌（HCC）患者的生存时间有关，以及抑制尿酸生成是否会影响HCC大鼠的进展和生存。分析了288例晚期HCC患者的随访数据。采用已建立的超高效液相色谱-串联质谱（UPLC-MS/MS）方法定量测定二乙基亚硝胺（DEN）诱导的HCC大鼠血清和肝脏样本中的10种嘌呤代谢物。在此基础上，使用黄嘌呤氧化酶（XOD）的特异性抑制剂非布司他来干预HCC大鼠。HCC患者的血清尿酸水平与生存天数显著负相关（r = -0.155）。高尿酸组（>360 μmol/L，n = 80）的中位生存时间为133.5天，正常血清尿酸组（<360 μmol/L，n = 208，P = 0.0013）的中位生存时间为176.0天。与对照组相比，HCC大鼠血清或肝脏样本中的次黄嘌呤、鸟嘌呤和尿酸水平；XOD活性；以及黄嘌呤脱氢酶mRNA表达均显著上调。对DEN诱导的HCC大鼠进行非布司他干预后，非典型细胞和炎性细胞数量显著减少；血清甲胎蛋白水平和费舍尔比值趋于恢复正常；中位生存时间从36天增加到96天（P = 0.08）。此外，血清丙二醛、超氧化物歧化酶和谷胱甘肽活性几乎恢复到健康对照组水平。血清尿酸升高意味着晚期HCC患者生存不良的风险，非布司他可减少活性氧的产生，从而在延缓肝癌进展中发挥作用。
