核酸外切酶1对肝癌化疗药物顺铂和5-氟尿嘧啶耐药性的调控OA

OBJECTIVE:To investigate regulatory roles of exonuclease 1(EXO1)on chemotherapy sensitivity in liver cancer and to evaluate its potential as a predictive molecular biomarker for clinical efficacy.METHODS:Differential gene expression and KEGG pathway enrichment analyses between high-and low-EXO1 expression groups were performed using the TCGA database.The Cancer Cell Line Encyclopedia(CCLE)was utilized to correlate baseline EXO1 mRNA levels in liver cancer cell lines with their sensitivity(expressed as area under the curve,AUC)to cisplatin and 5-fluorouracil(5-FU).In vitro,cell growth inhibition and half-maximal inhibitory concentrations(IC50)were determined using CCK-8 assays,while long-term proliferative capacity was assessed through colony formation assays.Subcutaneous xenograft models were established in nude mice to evaluate impact of EXO1 expression on tumor volume and terminal weight under cisplatin or 5-FU treatment.RESULTS:Bioinformatics analysis indicated that EXO1 overexpression potentially drove tumor progression by activating cell cycle and DNA replication pathways,while modulating chemotherapy sensitivity via downregulation of drug metabolism-related pathways.CCLE data confirmed a significant correlation between EXO1 expression and drug response to both cisplatin and 5-FU(|r|>0.5,P<0.05).In in vitro studies,compared with the Huh7 empty vector control group,the CCK-8 assay showed that EXO1 overexpression significantly enhanced cisplatin resistance and increased sensitivity to 5-FU in Huh7 cells(P<0.05).Plate colony formation assay revealed that EXO1 overexpression antagonized cytotoxic effect of cisplatin and markedly strengthened inhibitory effect of 5-FU on cell colony formation(P<0.05).These findings suggest that EXO1 overexpression exerted a differential regulatory effect on colony-inhibitory capacity of cisplatin and 5-FU,which was fully consistent with the drug resistance trend reflected by the IC50 values.In vivo xenograft tumor assays in nude mice further demonstrated that EXO1 overexpression attenuated antitumor efficacy of cisplatin,while remarkably improved inhibitory efficiency of 5-FU against xenograft tumors(P<0.05).CONCLUSION:Our data shows that EXO1 served as a critical regulator of chemotherapy sensitivity in liver cancer,exerting divergent effects on cisplatin and 5-FU resistance.High EXO1 expression induced cisplatin resistance while sensitizing liver cancer cells to 5-FU,a mechanism potentially mediated by activation of DNA replication and inhibition of drug metabolism.Considering recent clinical advances in Hepatic Arterial Infusion Chemotherapy(HAIC),EXO1 expression levels may provide a valuable reference for personalized selection of HAIC regimens or combined systemic therapies.Collectively,EXO1 represents a promising predictive biomarker and therapeutic target,offering a theoretical and practical basis for precision oncology in HCC.