The Function And Mechanism Of Xanthine Oxidoreductase (XOR) In Hepatocellular Carcinoma Stem Cells

Hepatocellular carcinoma(HCC)is one of the most common hepatic malignancy,ranking third in all types of malignant tumors worldwide and ranking second in China,and its incidence and mortality are also on the rise.More than 700,000 new patients are diagnosed with HCC each year.Surgical resection or liver transplantation is an effective clinical treatment for early HCC.However,due to the incidence of HCC is relatively hidden,lack of early diagnostic markers and is prone to recurrence and metastasis,many HCC patients are often in the advanced stage when they are diagnosed,losing the best time of surgery,and resulting in a lower 5-year survival rate.The treatment of patients with advanced HCC mainly includes surgical resection,interventional therapy and molecular targeted therapy,but these treatments can only provide limited survival benefits.Despite significant advances in the prevention,diagnosis,and treatment of HCC,overall prognosis and recurrence were not satisfactory.Therefore,further exploration and clarification of the underlying molecular mechanisms of HCC occurrence and development will provide a solid theoretical basis for finding effective new targets or treatments.Most malignant tumors are composed of a variety of heterogeneous cells.Cancer stem cells(CSCs)are an important subpopulation of tumor cells.It has been proved that CSCs are involved in tumor initiation,reproduction,chemical resistance,metastasis and recurrence.Previous studies have confirmed the presence of liver cancer stem cells(LCSCs)in HCC,and the survival,proliferation and self-renewal of LCSCs are regulated by a variety of signaling pathways or transcription factors.In addition,studies have shown that low levels of Reactive Oxygen Species(ROS)are necessary for CSCs to maintain stem cell characteristics.There is a strong antioxidant regulation system in CSCs cells,which ensure that it is protected from internal and external oxidative stress.The Nrf2-KEAP1 signaling pathway is particularly prominent in the reported molecular mechanisms involved in the regulation of ROS levels in CSCs.Nrf2 is a nuclear import protein that promotes the transcription of downstream antioxidant genes and enhances the clearance of ROS by binding to the antioxidant element(ARE)promoter.KEAP1 is a protein that binds to Nrf2,and its binding to Nrf2 promotes degradation via ubiquitination of Nrf2 protein,resulting in inhibition of transcription of downstream antioxidant genes and promotion of intracellular ROS accumulation.Xanthine oxidoreductase(XOR)is a key enzyme involved in the catabolism of guanidine,which catalyzes the conversion of hypoxanthine to xanthine and further catalyzes the conversion of jaundice to uric acid.Numerous studies have also shown that XOR is involved in the regulation of a variety of human physiological and pathological processes.The association of XOR with tumor has also been confirmed by many studies.XOR enzyme activity and expression are dysregulated in a variety of tumors and are clearly associated with the prognosis of tumor patients.However,the specific role of XOR in HCC has not been reported in depth.In this study,we found that XOR was significantly down-regulated in HCC tissue expression,and clinical correlation analysis showed that XOR was significantly associated with patient outcome.XOR inhibits multiple malignant phenotypes of HCC cells have been found in vitro and in vivo cell functional experiments.Further studies showed that XOR was lowly expressed in LCSCs,and the expression was inversely correlated with the expression of CD13 and CD133 protein.The mouse xenograft model experiment treated with chemotherapeutic drugs also proved that XOR can enhance the sensitivity of HCC to chemotherapy drugs.Mechanistic studies have shown that XOR regulates the Nrf2-KEAP1 pathway by binding to USP15 protein,promotes ubiquitination of Nrf2,leads to transcriptional inhibition of antioxidant genes,and induces intracellular ROS accumulation.In summary,this paper explored the role and mechanism of XOR in HCC occurrence and development,and elucidated the new mechanism of XOR binding to USP15-mediated Nrf2-KEAP1 signaling pathway to regulate cellular ROS based on XOR down-regulation in LCSCs.It provides new potential biological targets for the diagnosis and treatment of liver cancer.