目的研究肌动蛋白结合蛋白(ANLN)、细胞色素P450(Cytochromes P 450,CYPs)亚家族成员CYP2C9、透明质酸介导运动因子受体(HMMR)在乙型肝炎病毒相关肝细胞癌(HBV-HCC)组织中的表达及对其预后的影响。方法收集手术切除的25份HCC标本。采用...目的研究肌动蛋白结合蛋白(ANLN)、细胞色素P450(Cytochromes P 450,CYPs)亚家族成员CYP2C9、透明质酸介导运动因子受体(HMMR)在乙型肝炎病毒相关肝细胞癌(HBV-HCC)组织中的表达及对其预后的影响。方法收集手术切除的25份HCC标本。采用免疫组织化学方法分析ANLN、CYP2C9、HMMR蛋白表达水平在癌组织及癌旁组织的差别,采用Log-Rank检验评估三者对HCC患者术后复发及远期存活的影响。结果HCC患者癌组织的ANLN、CYP2C9免疫反应性评分(IRS)低于癌旁组织分别为(2.4±2.5)分比(3.7±2.7)分(t=2.18,P=0.039)和(4.2±2.8)分比(8.6±1.4)分(t=6.21,P<0.01),癌组织中的HMMR IRS高于癌旁组织为8.0(4.0,8.0)分比4.0(2.5,4.0)分(Z=3.94,P<0.01)。但不同ANLN、CYP2C9、HMMR蛋白表达水平对HCC患者术后复发时间及5年存活率影响差异无统计学意义(中位复发时间高水平比低水平:ANLN 38.6月比33.3月,CYP2C936.5月比35.5月,HMMR 33.1月比41.3月;中位生存时间高水平比低水平:ANLN 56.3月比51.1月,CYP2C955.1月比51.5月,HMMR 53.0月比55.2月;均P>0.05)。多因素Cox回归分析提示,BCLC、家族史对术后复发时间的影响差异有统计学意义(HR=2.435,P=0.025;HR=0.165,P=0.009),AFP、家族史与术后5年存活率独立相关(HR=229.488,P=0.041;HR=0.054,P=0.014)。结论ANLN、CYP2C9、HMMR蛋白表达水平在HCC患者癌组织及癌旁组织存在差异,但对预后未产生影响,提示其可作为HCC诊断的潜在标志物。展开更多
Background The mechanism of hepatitis B virus(HBV)-induced carcinogenesis remains an area of interest.The accumulation of hepatitis B surface antigen in the endoplasmic reticulum(ER)of hepatocytes stimulates persisten...Background The mechanism of hepatitis B virus(HBV)-induced carcinogenesis remains an area of interest.The accumulation of hepatitis B surface antigen in the endoplasmic reticulum(ER)of hepatocytes stimulates persistent ER stress.Activity of the unfolded protein response(UPR)pathway of ER stress may play an important role in inflammatory cancer transformation.How the protective UPR pathway is hijacked by cells as a tool for malignant transformation in HBV-related hepatocellular carcinoma(HCC)is still unclear.Here,we aimed to define the key molecule hyaluronan-mediated motility receptor(HMMR)in this process and explore its role under ER stress in HCC development.Methods An HBV-transgenic mouse model was used to characterize the pathological changes during the tumor progression.Proteomics and transcriptomics analyses were performed to identify the potential key molecule,screen the E3 ligase,and define the activation pathway.Quantitative real-time PCR and Western blotting were conducted to detect the expression of genes in tissues and cell lines.Luciferase reporter assay,chromatin immunoprecipitation,coimmunoprecipitation,immunoprecipitation,and immunofluorescence were employed to investigate the molecular mechanisms of HMMR under ER stress.Immunohistochemistry was used to clarify the expression patterns of HMMR and related molecules in human tissues.Results We found sustained activation of ER stress in the HBV-transgenic mouse model of hepatitis-fibrosis-HCC.HMMR was transcribed by c/EBP homologous protein(CHOP)and degraded by tripartite motif containing 29(TRIM29)after ubiquitination under ER stress,which caused the inconsistent expression of mRNA and protein.Dynamic expression of TRIM29 in the HCC progression regulated the dynamic expression of HMMR.HMMR could alleviate ER stress by increasing autophagic lysosome activity.The negative correlation between HMMR and ER stress,positive correlation between HMMR and autophagy,and negative correlation between ER stress and autophagy were verified in human tissues.Conclusions This study identified the complicated role of HMMR in autophagy and ER stress,that HMMR controls the intensity of ER stress by regulating autophagy in HCC progression,which could be a novel explanation for HBV-related carcinogenesis.展开更多
基金National Natural Science Foundation of China,Grant/Award Number:82130084Shaanxi Provincial Key R&D Program,Grant/Award Number:2021SF-110。
文摘Background The mechanism of hepatitis B virus(HBV)-induced carcinogenesis remains an area of interest.The accumulation of hepatitis B surface antigen in the endoplasmic reticulum(ER)of hepatocytes stimulates persistent ER stress.Activity of the unfolded protein response(UPR)pathway of ER stress may play an important role in inflammatory cancer transformation.How the protective UPR pathway is hijacked by cells as a tool for malignant transformation in HBV-related hepatocellular carcinoma(HCC)is still unclear.Here,we aimed to define the key molecule hyaluronan-mediated motility receptor(HMMR)in this process and explore its role under ER stress in HCC development.Methods An HBV-transgenic mouse model was used to characterize the pathological changes during the tumor progression.Proteomics and transcriptomics analyses were performed to identify the potential key molecule,screen the E3 ligase,and define the activation pathway.Quantitative real-time PCR and Western blotting were conducted to detect the expression of genes in tissues and cell lines.Luciferase reporter assay,chromatin immunoprecipitation,coimmunoprecipitation,immunoprecipitation,and immunofluorescence were employed to investigate the molecular mechanisms of HMMR under ER stress.Immunohistochemistry was used to clarify the expression patterns of HMMR and related molecules in human tissues.Results We found sustained activation of ER stress in the HBV-transgenic mouse model of hepatitis-fibrosis-HCC.HMMR was transcribed by c/EBP homologous protein(CHOP)and degraded by tripartite motif containing 29(TRIM29)after ubiquitination under ER stress,which caused the inconsistent expression of mRNA and protein.Dynamic expression of TRIM29 in the HCC progression regulated the dynamic expression of HMMR.HMMR could alleviate ER stress by increasing autophagic lysosome activity.The negative correlation between HMMR and ER stress,positive correlation between HMMR and autophagy,and negative correlation between ER stress and autophagy were verified in human tissues.Conclusions This study identified the complicated role of HMMR in autophagy and ER stress,that HMMR controls the intensity of ER stress by regulating autophagy in HCC progression,which could be a novel explanation for HBV-related carcinogenesis.
