Approximately half of all cancers have p53 inactivating mutations,in addition to which most malignancies inactivate the p53 pathway by increasing p53 inhibitors,decreasing p53 activators,or inactivating p53 downstream...Approximately half of all cancers have p53 inactivating mutations,in addition to which most malignancies inactivate the p53 pathway by increasing p53 inhibitors,decreasing p53 activators,or inactivating p53 downstream targets.A growing number of researches have demonstrated that p53 can influence tumor progression through the tumor microenvironment(TME).TME is involved in the process of tumor development and metastasis and affects the clinical prognosis of patients.p53 participates in host immunity and engages in the immune landscape of the TME,but the specific mechanisms remain to be investigated.This review briefly explores the interactions between different states of p53 and TME components and their mechanisms,as well as their effects on tumor progression.To understand the progress of drug development and clinical studies related to p53 and tumor microenvironment.展开更多
目的:探讨在骨髓增生异常综合征(MDS)中TP53基因不同突变状态(野生型/突变型)对地西他滨(DAC)耐药性的影响,并筛选耐药相关调控基因。方法:选用2种TP53状态差异的MDS细胞:M-07e:野生型;SKM-1:突变型,用递增浓度(0、0.5、1、5和10μmol/L...目的:探讨在骨髓增生异常综合征(MDS)中TP53基因不同突变状态(野生型/突变型)对地西他滨(DAC)耐药性的影响,并筛选耐药相关调控基因。方法:选用2种TP53状态差异的MDS细胞:M-07e:野生型;SKM-1:突变型,用递增浓度(0、0.5、1、5和10μmol/L)的地西他滨干预0-72 h后,采用CCK-8法检测细胞活力。通过RNA-Seq转录组测序和甲基化组学分析,筛选与耐药相关的关键基因。结果:CCK-8实验结果显示DAC对M-07e和SKM-1细胞活力的抑制作用呈时间和剂量依赖性(SKM-1耐药性最强,IC_(50)=5μmol/L vs M-07e IC_(50)=0.5μmol/L,P<0.01)。基因表达分析结果显示,M-07e细胞经DAC处理后共鉴定到662个上调基因和452个下调基因;SKM-1细胞经DAC处理后共发现515个上调基因和73个下调基因。蛋白质组学检测显示:DAC处理的M-07e细胞中共鉴定117个上调蛋白和136个下调蛋白;DAC处理的SKM-1细胞中发现91个上调蛋白和46个下调蛋白。通过整合分析上调基因和蛋白表达谱,共筛选出181个候选基因。甲基化组学分析发现884个低甲基化基因中存在高敏感位点和高CpG密度区域,其中与上述181个候选基因存在交集的共31个基因,GO功能富集分析表明这31个基因主要参与细胞分化正调控、结合过程负调控以及细胞组分组织负调控等生物学过程。结论:TP53突变通过表观遗传重编程介导DAC耐药,靶向这些基因可能改善TP53突变型MDS的预后。展开更多
基金supported by the Natural Science Foundation of Hunan Province(No.2021JJ30589)Hunan Provincial Natural Science Foundation Sector Joint Fund(No.2023JJ60049).
文摘Approximately half of all cancers have p53 inactivating mutations,in addition to which most malignancies inactivate the p53 pathway by increasing p53 inhibitors,decreasing p53 activators,or inactivating p53 downstream targets.A growing number of researches have demonstrated that p53 can influence tumor progression through the tumor microenvironment(TME).TME is involved in the process of tumor development and metastasis and affects the clinical prognosis of patients.p53 participates in host immunity and engages in the immune landscape of the TME,but the specific mechanisms remain to be investigated.This review briefly explores the interactions between different states of p53 and TME components and their mechanisms,as well as their effects on tumor progression.To understand the progress of drug development and clinical studies related to p53 and tumor microenvironment.
文摘目的:探讨在骨髓增生异常综合征(MDS)中TP53基因不同突变状态(野生型/突变型)对地西他滨(DAC)耐药性的影响,并筛选耐药相关调控基因。方法:选用2种TP53状态差异的MDS细胞:M-07e:野生型;SKM-1:突变型,用递增浓度(0、0.5、1、5和10μmol/L)的地西他滨干预0-72 h后,采用CCK-8法检测细胞活力。通过RNA-Seq转录组测序和甲基化组学分析,筛选与耐药相关的关键基因。结果:CCK-8实验结果显示DAC对M-07e和SKM-1细胞活力的抑制作用呈时间和剂量依赖性(SKM-1耐药性最强,IC_(50)=5μmol/L vs M-07e IC_(50)=0.5μmol/L,P<0.01)。基因表达分析结果显示,M-07e细胞经DAC处理后共鉴定到662个上调基因和452个下调基因;SKM-1细胞经DAC处理后共发现515个上调基因和73个下调基因。蛋白质组学检测显示:DAC处理的M-07e细胞中共鉴定117个上调蛋白和136个下调蛋白;DAC处理的SKM-1细胞中发现91个上调蛋白和46个下调蛋白。通过整合分析上调基因和蛋白表达谱,共筛选出181个候选基因。甲基化组学分析发现884个低甲基化基因中存在高敏感位点和高CpG密度区域,其中与上述181个候选基因存在交集的共31个基因,GO功能富集分析表明这31个基因主要参与细胞分化正调控、结合过程负调控以及细胞组分组织负调控等生物学过程。结论:TP53突变通过表观遗传重编程介导DAC耐药,靶向这些基因可能改善TP53突变型MDS的预后。
