Background:Hepatocellular carcinoma(HCC)is a highly lethal malignancy driven by both intrinsic oncogenic pathways and immune microenvironmental regulation.Emerging evidence suggests that DNASE1L3 may influence tumor b...Background:Hepatocellular carcinoma(HCC)is a highly lethal malignancy driven by both intrinsic oncogenic pathways and immune microenvironmental regulation.Emerging evidence suggests that DNASE1L3 may influence tumor biology and immune responses;however,its specific roles in HCC progression and macrophage-mediated regulation remain unclear.This study aimed to elucidate the biological functions of DNASE1L3 in HCC and to determine how it modulates tumor behavior and immune interactions.Methods:Bioinformatics analyses of the GSE41804 and Cancer Genome Atlas-Liver Hepatocellular Carcinoma(TCGA-LIHC)datasets were used to identify hub genes.Functional assays assessed the impact of DNASE1L3 on HCC cell proliferation,migration,invasion,and cell cycle progression.The effects of DNASE1L3 on macrophage polarization and the Wnt/β-catenin signaling pathway were examined using a co-culture system.An HCC organoid model was established to further validate its regulatory function.Results:Eight prognostic signature genes were identified,with deoxyribonuclease I-like 3(DNase I-like 3)selected as the hub gene.DNASE1L3 overexpression suppressed HCC cell growth,inhibited migration and invasion,induced G1 arrest,and modulated epithelial-mesenchymal transition(EMT)markers.DNASE1L3 knockdown promoted M2-like macrophage polarization.Mechanistically,DNASE1L3 interacted withβ-catenin to enhance its ubiquitination and degradation,thereby inhibiting Wnt/β-catenin signaling and reducing PD-L1 expression.DNASE1L3 overexpression similarly restricted organoid growth and suppressed pathway activity.Conclusion:DNASE1L3 acts as a negative regulator of HCC progression by targeting the Wnt/β-catenin pathway and reducing PD-L1 expression,thereby influencing both tumor cell behavior and macrophage-mediated immune responses.展开更多
目的:探讨系统性红斑狼疮(SLE)患者血清白细胞介素-2受体α(IL-2Rα)、5’-寡腺苷酸合成酶1(OAS1)、脱氧核糖核酸酶1Like3(DNase1L3)与疾病活动度和早期肾损伤的关系。方法:纳入我院2018年1月-2021年12月期间收治的113例SLE患者,根据SL...目的:探讨系统性红斑狼疮(SLE)患者血清白细胞介素-2受体α(IL-2Rα)、5’-寡腺苷酸合成酶1(OAS1)、脱氧核糖核酸酶1Like3(DNase1L3)与疾病活动度和早期肾损伤的关系。方法:纳入我院2018年1月-2021年12月期间收治的113例SLE患者,根据SLE疾病活动度评分(SLEDAI)将患者分为轻度组(n=48,SLEDAI评分0~9分)、中度组(n=28,SLEDAI评分10~14分)、重度组(n=37,SLEDAI评分≥15分)。根据患者肾小球滤过率(eGFR)将患者分为肾功能正常组[n=48,eGFR>90 m L/(min·1.73 m_(2))]和早期肾功能损伤组[n=65,eGFR为60~90 m L/(min·1.73 m_(2))]。对比轻度组、中度组和重度组的血清IL-2Rα、OAS1、DNase1L3水平。采用单因素及多因素Logistic回归分析SLE患者早期肾损伤的影响因素。结果:重度组、中度组的IL-2Rα、OAS1高于轻度组,且重度组高于中度组(P<0.05)。重度组、中度组的DNase1L3低于轻度组,且重度组低于中度组(P<0.05)。单因素分析结果显示,SLE患者早期肾损伤与年龄、SLEDAI评分、病程、三酰甘油(TG)、血小板(PLT)、血红蛋白(Hb)、血白蛋白(ALB)、超敏C反应蛋白(hs-CRP)、血尿素氮(BUN)、血肌酐(Scr)、C3、eGFR、血尿酸(UA)、β2微球蛋白(β2MG)、IL-2Rα、OAS1、DNase1L3有关(P<0.05)。多因素Logistic回归分析结果显示年龄、Scr、UA、β2MG、IL-2Rα、OAS1均是SLE患者早期肾损伤的影响因素(P<0.05)。结论:IL-2Rα、OAS1、DNase1L3参与着SLE的疾病进展,其中IL-2Rα、OAS1可与年龄、Scr、UA、β2MG等因素共同辅助评估早期肾功能损伤。展开更多
基金funded by Shanghai Science and Technology Innovation Action Plan Project(22140901100)Shanghai Key Laboratory of Molecular Imaging(18DZ2260400)Shanghai University of Medicine and Health Science Seed Fund(SSF-24-21-01).
文摘Background:Hepatocellular carcinoma(HCC)is a highly lethal malignancy driven by both intrinsic oncogenic pathways and immune microenvironmental regulation.Emerging evidence suggests that DNASE1L3 may influence tumor biology and immune responses;however,its specific roles in HCC progression and macrophage-mediated regulation remain unclear.This study aimed to elucidate the biological functions of DNASE1L3 in HCC and to determine how it modulates tumor behavior and immune interactions.Methods:Bioinformatics analyses of the GSE41804 and Cancer Genome Atlas-Liver Hepatocellular Carcinoma(TCGA-LIHC)datasets were used to identify hub genes.Functional assays assessed the impact of DNASE1L3 on HCC cell proliferation,migration,invasion,and cell cycle progression.The effects of DNASE1L3 on macrophage polarization and the Wnt/β-catenin signaling pathway were examined using a co-culture system.An HCC organoid model was established to further validate its regulatory function.Results:Eight prognostic signature genes were identified,with deoxyribonuclease I-like 3(DNase I-like 3)selected as the hub gene.DNASE1L3 overexpression suppressed HCC cell growth,inhibited migration and invasion,induced G1 arrest,and modulated epithelial-mesenchymal transition(EMT)markers.DNASE1L3 knockdown promoted M2-like macrophage polarization.Mechanistically,DNASE1L3 interacted withβ-catenin to enhance its ubiquitination and degradation,thereby inhibiting Wnt/β-catenin signaling and reducing PD-L1 expression.DNASE1L3 overexpression similarly restricted organoid growth and suppressed pathway activity.Conclusion:DNASE1L3 acts as a negative regulator of HCC progression by targeting the Wnt/β-catenin pathway and reducing PD-L1 expression,thereby influencing both tumor cell behavior and macrophage-mediated immune responses.
文摘目的:探讨系统性红斑狼疮(SLE)患者血清白细胞介素-2受体α(IL-2Rα)、5’-寡腺苷酸合成酶1(OAS1)、脱氧核糖核酸酶1Like3(DNase1L3)与疾病活动度和早期肾损伤的关系。方法:纳入我院2018年1月-2021年12月期间收治的113例SLE患者,根据SLE疾病活动度评分(SLEDAI)将患者分为轻度组(n=48,SLEDAI评分0~9分)、中度组(n=28,SLEDAI评分10~14分)、重度组(n=37,SLEDAI评分≥15分)。根据患者肾小球滤过率(eGFR)将患者分为肾功能正常组[n=48,eGFR>90 m L/(min·1.73 m_(2))]和早期肾功能损伤组[n=65,eGFR为60~90 m L/(min·1.73 m_(2))]。对比轻度组、中度组和重度组的血清IL-2Rα、OAS1、DNase1L3水平。采用单因素及多因素Logistic回归分析SLE患者早期肾损伤的影响因素。结果:重度组、中度组的IL-2Rα、OAS1高于轻度组,且重度组高于中度组(P<0.05)。重度组、中度组的DNase1L3低于轻度组,且重度组低于中度组(P<0.05)。单因素分析结果显示,SLE患者早期肾损伤与年龄、SLEDAI评分、病程、三酰甘油(TG)、血小板(PLT)、血红蛋白(Hb)、血白蛋白(ALB)、超敏C反应蛋白(hs-CRP)、血尿素氮(BUN)、血肌酐(Scr)、C3、eGFR、血尿酸(UA)、β2微球蛋白(β2MG)、IL-2Rα、OAS1、DNase1L3有关(P<0.05)。多因素Logistic回归分析结果显示年龄、Scr、UA、β2MG、IL-2Rα、OAS1均是SLE患者早期肾损伤的影响因素(P<0.05)。结论:IL-2Rα、OAS1、DNase1L3参与着SLE的疾病进展,其中IL-2Rα、OAS1可与年龄、Scr、UA、β2MG等因素共同辅助评估早期肾功能损伤。
