ZIC1(zinc finger of the cerebellum 1)基因是一种重要的肿瘤相关基因。近年来研究发现ZIC1基因在多种恶性肿瘤中都有表达并与肿瘤的发生、发展密切相关,但其具体的作用机制仍未完全阐明。随着对ZIC1基因研究的进一步深入,其有可能为...ZIC1(zinc finger of the cerebellum 1)基因是一种重要的肿瘤相关基因。近年来研究发现ZIC1基因在多种恶性肿瘤中都有表达并与肿瘤的发生、发展密切相关,但其具体的作用机制仍未完全阐明。随着对ZIC1基因研究的进一步深入,其有可能为肿瘤的早期诊断、基因治疗和预后评估提供新的思路。展开更多
目的探讨ZIC家族成员1(Zic family member 1,ZIC1)过表达对三阴性乳腺癌细胞增殖及药物敏感性的影响。方法将转染ZIC1基因和空载体的三阴性乳腺癌细胞MDA-MB-231分别作为A组和B组,将转染ZIC1基因和空载体的三阴性乳腺癌细胞MDA-MB-468...目的探讨ZIC家族成员1(Zic family member 1,ZIC1)过表达对三阴性乳腺癌细胞增殖及药物敏感性的影响。方法将转染ZIC1基因和空载体的三阴性乳腺癌细胞MDA-MB-231分别作为A组和B组,将转染ZIC1基因和空载体的三阴性乳腺癌细胞MDA-MB-468分别作为C组和D组。分别采用蛋白质印迹(Western blot)法和实时荧光定量聚合酶链反应(qRT-PCR)检测ZIC1蛋白和ZIC1 mRNA的相对表达量,噻唑蓝(MTT)法检测细胞的增殖能力及对化疗药物顺铂、环磷酰胺、多西他赛、姜黄素、斑蝥素和芹菜素的敏感性。结果A组细胞中ZIC1 mRNA和ZIC1蛋白的相对表达量均明显高于B组(P﹤0.01),C组细胞中ZIC1 mRNA和ZIC1蛋白的相对表达量均明显高于D组(P﹤0.01)。培养24、36、48、60、72 h时,A组细胞的光密度(OD)值均低于同时间点B组细胞(P﹤0.05),C组细胞的OD值均低于同时间点D组细胞(P﹤0.05)。环磷酰胺、多西他赛、芹菜素对A组细胞的半数抑制浓度(IC50)均低于B组细胞(P﹤0.05),多西他赛和芹菜素对C组细胞的IC50均低于D组细胞(P﹤0.05)。结论ZIC1基因过表达能有效抑制三阴性乳腺癌细胞MDA-MB-231和MDA-MB-468的增殖,并能增强乳腺癌细胞对环磷酰胺、多西他赛及芹菜素的药物敏感性。展开更多
Zinc finger in the cerebellum 1 （Zicl） is known to regulate neurogenesis and myogenesis in the develop- mental stage and widely used as one of the brown adipocyte-specific markers. In this study, we examined the eff...Zinc finger in the cerebellum 1 （Zicl） is known to regulate neurogenesis and myogenesis in the develop- mental stage and widely used as one of the brown adipocyte-specific markers. In this study, we examined the effect of Zicl on brown adipogenesis. Overexpression of Zicl attenuated the lipid accumulation and the expressions of PPAR72 and C/EBPα in C3H10T1/2 mesenchymal stem cells. The mRNA levels of BAT-specific thermogenic genes （PRDM16, PGC-1α and UCP1） and fatty acid oxidation regulatory genes （PPARα, CPT1α, CPT1β and COX7α1） were suppressed in Zicl-overexpressed cells. Moreover, overexpression of Zicl reduced the mitochondrial oxidative phosphorylation （OXPHOS） regulatory proteins including ATP5α, UQCRC2, SDHB and NDUFB5. These results indicate a potential role of Zicl in the regulation of brown adipogenesis via inhibiting adipogenesis, fatty acid oxidation and mitochondrial OXPHOS.展开更多
目的:探讨小脑锌指结构1(zinc finger protein of the cerebellum 1,ZIC1)基因在人子宫内膜癌组织中的表达情况及其与临床参数之间的关系和预后预测价值。方法:收集江苏大学附属昆山医院及上海市第六人民医院自2008年1月至2011年12月收...目的:探讨小脑锌指结构1(zinc finger protein of the cerebellum 1,ZIC1)基因在人子宫内膜癌组织中的表达情况及其与临床参数之间的关系和预后预测价值。方法:收集江苏大学附属昆山医院及上海市第六人民医院自2008年1月至2011年12月收治的子宫内膜癌患者43例,取肿瘤组织及相应的距原发灶边缘2 cm以上的癌旁黏膜组织标本。应用免疫组织化学法、Western blotting及RT-PCR法检测43例子宫内膜癌原发灶组织及癌旁黏膜组织中ZIC1的表达,分析其与临床病理参数之间的关系,并通过5年生存情况分析评价其预后价值。结果:子宫内膜癌组织中ZIC1的m RNA水平和蛋白水平均明显高于癌旁组织。ZIC1蛋白在子宫内膜癌组织中呈现高表达,其阳性表达率为72.1%(31/43),在癌旁组织中阳性表达率为39.5%(17/43)。ZIC1 m RNA的表达与淋巴结转移及FIGO分期有关(P<0.01或P<0.05)。ZIC1低表达患者的5年生存率明显高于高表达患者(66.7%vs 38.7%,P<0.05)。单因素分析发现ZIC1(高表达vs低表达)风险比(HR)为2.66,95%CI:1.07-5.89,P=0.047;经多因素分析调整后,HR=2.25,95%CI:1.36-3.71,P=0.002,说明高水平的ZIC1与子宫内膜癌术后预后不良密切相关。结论:ZIC1表达水平的升高在子宫内膜癌的发生发展中起着重要作用,可能成为子宫内膜癌治疗和预后测评的一个新的指标。展开更多
Epigenetic therapies that cause genome-wide epigenetic alterations,could trigger local interplay between different histone marks,leading to a switch of transcriptional outcome and therapeutic responses of epigenetic t...Epigenetic therapies that cause genome-wide epigenetic alterations,could trigger local interplay between different histone marks,leading to a switch of transcriptional outcome and therapeutic responses of epigenetic treatment.However,in human cancers with diverse oncogenic activation,how oncogenic pathways cooperate with epigenetic modifiers to regulate the histone mark interplay is poorly understood.We herein discover that the hedgehog(Hh)pathway reprograms the histone methylation landscape in breast cancer,especially in triple-negative breast cancer(TNBC).This facilitates the histone acetylation caused by histone deacetylase(HDAC)inhibitors and gives rise to new therapeutic vulnerability of combination therapies.Specifically,overexpression of zinc finger protein of the cerebellum 1(ZIC1)in breast cancer promotes Hh activation,facilitating the switch of H3K27 methylation(H3K27me)to acetylation(H3K27ac).The mutually exclusive relationship of H3K27me and H3K27ac allows their functional interplay at oncogenic gene locus and switches therapeutic outcomes.Using multiple in vivo breast cancer models including patient-derived TNBC xenograft,we show that Hh signaling-orchestrated H3K27me and H3K27ac interplay tailors combination epigenetic drugs in treating breast cancer.Together,this study reveals the new role of Hh signaling-regulated histone modifications interplay in responding to HDAC inhibitors and suggests new epigenetically-targeted therapeutic solutions for treating TNBC.展开更多
文摘ZIC1(zinc finger of the cerebellum 1)基因是一种重要的肿瘤相关基因。近年来研究发现ZIC1基因在多种恶性肿瘤中都有表达并与肿瘤的发生、发展密切相关,但其具体的作用机制仍未完全阐明。随着对ZIC1基因研究的进一步深入,其有可能为肿瘤的早期诊断、基因治疗和预后评估提供新的思路。
文摘目的探讨ZIC家族成员1(Zic family member 1,ZIC1)过表达对三阴性乳腺癌细胞增殖及药物敏感性的影响。方法将转染ZIC1基因和空载体的三阴性乳腺癌细胞MDA-MB-231分别作为A组和B组,将转染ZIC1基因和空载体的三阴性乳腺癌细胞MDA-MB-468分别作为C组和D组。分别采用蛋白质印迹(Western blot)法和实时荧光定量聚合酶链反应(qRT-PCR)检测ZIC1蛋白和ZIC1 mRNA的相对表达量,噻唑蓝(MTT)法检测细胞的增殖能力及对化疗药物顺铂、环磷酰胺、多西他赛、姜黄素、斑蝥素和芹菜素的敏感性。结果A组细胞中ZIC1 mRNA和ZIC1蛋白的相对表达量均明显高于B组(P﹤0.01),C组细胞中ZIC1 mRNA和ZIC1蛋白的相对表达量均明显高于D组(P﹤0.01)。培养24、36、48、60、72 h时,A组细胞的光密度(OD)值均低于同时间点B组细胞(P﹤0.05),C组细胞的OD值均低于同时间点D组细胞(P﹤0.05)。环磷酰胺、多西他赛、芹菜素对A组细胞的半数抑制浓度(IC50)均低于B组细胞(P﹤0.05),多西他赛和芹菜素对C组细胞的IC50均低于D组细胞(P﹤0.05)。结论ZIC1基因过表达能有效抑制三阴性乳腺癌细胞MDA-MB-231和MDA-MB-468的增殖,并能增强乳腺癌细胞对环磷酰胺、多西他赛及芹菜素的药物敏感性。
基金supported by the Strategic Priority Research Program(XDB13030000)Key Research Program(KJZD-EW-L01-3)+1 种基金the One Hundred Talents Program of the Chinese Academy of Sciences and the Ministry of Science and Technology of China(2012CBA01301 and 2012CB944701,respectively)the National Natural Science Foundation of China(31171131,81370951)
文摘Zinc finger in the cerebellum 1 （Zicl） is known to regulate neurogenesis and myogenesis in the develop- mental stage and widely used as one of the brown adipocyte-specific markers. In this study, we examined the effect of Zicl on brown adipogenesis. Overexpression of Zicl attenuated the lipid accumulation and the expressions of PPAR72 and C/EBPα in C3H10T1/2 mesenchymal stem cells. The mRNA levels of BAT-specific thermogenic genes （PRDM16, PGC-1α and UCP1） and fatty acid oxidation regulatory genes （PPARα, CPT1α, CPT1β and COX7α1） were suppressed in Zicl-overexpressed cells. Moreover, overexpression of Zicl reduced the mitochondrial oxidative phosphorylation （OXPHOS） regulatory proteins including ATP5α, UQCRC2, SDHB and NDUFB5. These results indicate a potential role of Zicl in the regulation of brown adipogenesis via inhibiting adipogenesis, fatty acid oxidation and mitochondrial OXPHOS.
文摘目的:探讨小脑锌指结构1(zinc finger protein of the cerebellum 1,ZIC1)基因在人子宫内膜癌组织中的表达情况及其与临床参数之间的关系和预后预测价值。方法:收集江苏大学附属昆山医院及上海市第六人民医院自2008年1月至2011年12月收治的子宫内膜癌患者43例,取肿瘤组织及相应的距原发灶边缘2 cm以上的癌旁黏膜组织标本。应用免疫组织化学法、Western blotting及RT-PCR法检测43例子宫内膜癌原发灶组织及癌旁黏膜组织中ZIC1的表达,分析其与临床病理参数之间的关系,并通过5年生存情况分析评价其预后价值。结果:子宫内膜癌组织中ZIC1的m RNA水平和蛋白水平均明显高于癌旁组织。ZIC1蛋白在子宫内膜癌组织中呈现高表达,其阳性表达率为72.1%(31/43),在癌旁组织中阳性表达率为39.5%(17/43)。ZIC1 m RNA的表达与淋巴结转移及FIGO分期有关(P<0.01或P<0.05)。ZIC1低表达患者的5年生存率明显高于高表达患者(66.7%vs 38.7%,P<0.05)。单因素分析发现ZIC1(高表达vs低表达)风险比(HR)为2.66,95%CI:1.07-5.89,P=0.047;经多因素分析调整后,HR=2.25,95%CI:1.36-3.71,P=0.002,说明高水平的ZIC1与子宫内膜癌术后预后不良密切相关。结论:ZIC1表达水平的升高在子宫内膜癌的发生发展中起着重要作用,可能成为子宫内膜癌治疗和预后测评的一个新的指标。
基金supported by the National Natural Science Foundation of China(Nos.82225046,81821005,and 81903640)the Program of Shanghai Academic Research Leader(20XD1424800,China)。
文摘Epigenetic therapies that cause genome-wide epigenetic alterations,could trigger local interplay between different histone marks,leading to a switch of transcriptional outcome and therapeutic responses of epigenetic treatment.However,in human cancers with diverse oncogenic activation,how oncogenic pathways cooperate with epigenetic modifiers to regulate the histone mark interplay is poorly understood.We herein discover that the hedgehog(Hh)pathway reprograms the histone methylation landscape in breast cancer,especially in triple-negative breast cancer(TNBC).This facilitates the histone acetylation caused by histone deacetylase(HDAC)inhibitors and gives rise to new therapeutic vulnerability of combination therapies.Specifically,overexpression of zinc finger protein of the cerebellum 1(ZIC1)in breast cancer promotes Hh activation,facilitating the switch of H3K27 methylation(H3K27me)to acetylation(H3K27ac).The mutually exclusive relationship of H3K27me and H3K27ac allows their functional interplay at oncogenic gene locus and switches therapeutic outcomes.Using multiple in vivo breast cancer models including patient-derived TNBC xenograft,we show that Hh signaling-orchestrated H3K27me and H3K27ac interplay tailors combination epigenetic drugs in treating breast cancer.Together,this study reveals the new role of Hh signaling-regulated histone modifications interplay in responding to HDAC inhibitors and suggests new epigenetically-targeted therapeutic solutions for treating TNBC.
