目的获取Ras亚家族新分支的创始成员RIT1蛋白(GTP-binding protein Rit1,RIT1)在肝细胞癌(hepatocellular carcinoma,HCC)中的表达水平数据,分析RIT1及其共表达基因在HCC发生发展过程中的作用。方法通过Oncomine数据库和癌症基因图谱(th...目的获取Ras亚家族新分支的创始成员RIT1蛋白(GTP-binding protein Rit1,RIT1)在肝细胞癌(hepatocellular carcinoma,HCC)中的表达水平数据,分析RIT1及其共表达基因在HCC发生发展过程中的作用。方法通过Oncomine数据库和癌症基因图谱(the cancer genome atlas,TCGA)数据库分析RIT1基因在HCC中的表达,及临床特征和预后的关系。利用cBioportal在线分析工具分析RIT1在HCC中的突变情况,并通过GeneMina数据库分析与RIT1相互作用的蛋白。基于LinkedOmics数据库筛选与RIT1在HCC中共表达的蛋白并分析其参与的信号通路。结果HCC组织中RIT1 mRNA表达和DNA拷贝数变异(copy number variation,CNV)显著高于正常组织(P<0.01),HCC患者中肿瘤组织的RIT1转录水平显著高于正常组织;随着肿瘤等级和疾病阶段的升高,RIT1的表达量具有升高的趋势。在360例HCC样本中共有62例发生RIT1基因变异,变异率约为17.2%。生存曲线分析显示,RIT1高表达组和RIT1变异组的总体生存期短于RIT1低表达组和无变异组(P<0.01)。RAF原癌基因丝氨酸/苏氨酸蛋白激酶(RAF proto-oncogene serine/threonine-protein kinase,RAF)、神经营养的酪氨酸激酶1型受体(neurotrophic receptor tyrosine kinase 1,NTRK1)、Ral鸟嘌呤核苷酸解离刺激剂样蛋白1(Ral GDP dissociation stimulator like 1,RGL1)、神经生长因子(nerve growth factor,NGF)、RLF锌指蛋白、鸟嘌呤核苷酸解离刺激因子(Ral guanine nucleotide-dissociation stimulator,RalGDS)、干扰素相关发育调节因子1(interferon-related developmental regulator 1,IFRD1)、Ras相关蛋白1b(RAS-related protein Rap-1b,RAP1B)、Kelch样家族成员12(Kelch like family member 12,KLHL12)、MLLT4、母系DPP同源物3(mothers against decapentaplegic homolog 3,Smad3)等蛋白与RIT1具有明显的相互作用,STX6、MPZL1、PKM2、RNF24和SOAT1等蛋白在HCC中与RIT1共表达,这些蛋白主要涉及小G蛋白信号转导、Ras信号通路和神经营养因子TRK受体信号通路,能够促进DNA构象改变、有丝分裂和细胞周期等。结论RIT1在HCC组织中呈高表达,具有较高的基因变异频率,并且与患者预后不良相关,为之后深入研究RIT1在HCC发生发展中的作用提供了理论依据。展开更多
The zinc finger transcription factor B-cell CLL/lymphoma 11B gene(BCL11B,CTIP2)plays a crucial role in T-cell development,but its role in T-cell malignancies has not yet been definitively clarified.In the literature,2...The zinc finger transcription factor B-cell CLL/lymphoma 11B gene(BCL11B,CTIP2)plays a crucial role in T-cell development,but its role in T-cell malignancies has not yet been definitively clarified.In the literature,2 contradictory hypotheses on the function of BCL11B exist.One suggests that BCL11B functions as tumor suppressor gene,and the other suggests that BCL11B functions as oncogene.The aim of this review is to revise the current knowledge about the function of BCL11B in T-cell malignancies,confront these 2 hypotheses and present a new model of dual role of BCL11B in T-cell malignancies and potential new therapeutic approach,based on recent findings of the function of BCL11B in DNA damage repair.Decreased BCL11B expression,resulting in deficient DNA repair,may facilitate DNA mutations in rapidly proliferating T-cell progenitors that undergo gene rearrangements,thereby leading to malignant transformation.On the other hand,decreased BCL11B expression and inefficient DNA repair may result in accumulation of DNA damages in genes crucial for the cell survival and in apoptosis of malignant T cells.We hypothesize that T-cell malignancies expressing high levels of BCL11B might be dependent on it.In those cases,targeted inhibition of BCL11B expression may have a therapeutic effect.The antitumor effect of BCL11B suppression might be strengthened by generation of induced T to NK cells(ITNK).Therefore,there is an urgent need to develop a specific BCL11B inhibitor.展开更多
文摘目的获取Ras亚家族新分支的创始成员RIT1蛋白(GTP-binding protein Rit1,RIT1)在肝细胞癌(hepatocellular carcinoma,HCC)中的表达水平数据,分析RIT1及其共表达基因在HCC发生发展过程中的作用。方法通过Oncomine数据库和癌症基因图谱(the cancer genome atlas,TCGA)数据库分析RIT1基因在HCC中的表达,及临床特征和预后的关系。利用cBioportal在线分析工具分析RIT1在HCC中的突变情况,并通过GeneMina数据库分析与RIT1相互作用的蛋白。基于LinkedOmics数据库筛选与RIT1在HCC中共表达的蛋白并分析其参与的信号通路。结果HCC组织中RIT1 mRNA表达和DNA拷贝数变异(copy number variation,CNV)显著高于正常组织(P<0.01),HCC患者中肿瘤组织的RIT1转录水平显著高于正常组织;随着肿瘤等级和疾病阶段的升高,RIT1的表达量具有升高的趋势。在360例HCC样本中共有62例发生RIT1基因变异,变异率约为17.2%。生存曲线分析显示,RIT1高表达组和RIT1变异组的总体生存期短于RIT1低表达组和无变异组(P<0.01)。RAF原癌基因丝氨酸/苏氨酸蛋白激酶(RAF proto-oncogene serine/threonine-protein kinase,RAF)、神经营养的酪氨酸激酶1型受体(neurotrophic receptor tyrosine kinase 1,NTRK1)、Ral鸟嘌呤核苷酸解离刺激剂样蛋白1(Ral GDP dissociation stimulator like 1,RGL1)、神经生长因子(nerve growth factor,NGF)、RLF锌指蛋白、鸟嘌呤核苷酸解离刺激因子(Ral guanine nucleotide-dissociation stimulator,RalGDS)、干扰素相关发育调节因子1(interferon-related developmental regulator 1,IFRD1)、Ras相关蛋白1b(RAS-related protein Rap-1b,RAP1B)、Kelch样家族成员12(Kelch like family member 12,KLHL12)、MLLT4、母系DPP同源物3(mothers against decapentaplegic homolog 3,Smad3)等蛋白与RIT1具有明显的相互作用,STX6、MPZL1、PKM2、RNF24和SOAT1等蛋白在HCC中与RIT1共表达,这些蛋白主要涉及小G蛋白信号转导、Ras信号通路和神经营养因子TRK受体信号通路,能够促进DNA构象改变、有丝分裂和细胞周期等。结论RIT1在HCC组织中呈高表达,具有较高的基因变异频率,并且与患者预后不良相关,为之后深入研究RIT1在HCC发生发展中的作用提供了理论依据。
基金supported in part by the National Centre for Research and Development,Poland(No.WPC/BCL/2019)the Intergovernmental International Cooperation on Scientific and Technological Innovation Project of Chinese Ministry of Science and Technology(No.2017YFE0131600).
文摘The zinc finger transcription factor B-cell CLL/lymphoma 11B gene(BCL11B,CTIP2)plays a crucial role in T-cell development,but its role in T-cell malignancies has not yet been definitively clarified.In the literature,2 contradictory hypotheses on the function of BCL11B exist.One suggests that BCL11B functions as tumor suppressor gene,and the other suggests that BCL11B functions as oncogene.The aim of this review is to revise the current knowledge about the function of BCL11B in T-cell malignancies,confront these 2 hypotheses and present a new model of dual role of BCL11B in T-cell malignancies and potential new therapeutic approach,based on recent findings of the function of BCL11B in DNA damage repair.Decreased BCL11B expression,resulting in deficient DNA repair,may facilitate DNA mutations in rapidly proliferating T-cell progenitors that undergo gene rearrangements,thereby leading to malignant transformation.On the other hand,decreased BCL11B expression and inefficient DNA repair may result in accumulation of DNA damages in genes crucial for the cell survival and in apoptosis of malignant T cells.We hypothesize that T-cell malignancies expressing high levels of BCL11B might be dependent on it.In those cases,targeted inhibition of BCL11B expression may have a therapeutic effect.The antitumor effect of BCL11B suppression might be strengthened by generation of induced T to NK cells(ITNK).Therefore,there is an urgent need to develop a specific BCL11B inhibitor.
