Intestinal stem cells(ISCs)initiate intestinal epithelial regeneration and tumorigenesis,and they experi-ence rapid refilling upon various injuries for epithelial repair as well as tumor reoccurrence.It is crucial to ...Intestinal stem cells(ISCs)initiate intestinal epithelial regeneration and tumorigenesis,and they experi-ence rapid refilling upon various injuries for epithelial repair as well as tumor reoccurrence.It is crucial to reveal the mechanism underlying such plasticity for intestinal health.Recent studies have found that metabolic pathways control stem cell fate in homeostasis,but the role of metabolism in the regeneration of ISCs after damage has not been clarified.Here,we find that in a human colorectal cancer dataset,miR-29a and b(miR-29a/b)are metabolic regulators highly associated with intestinal tumorigenesis and worse prognostic value of radiotherapy.We also show that these two microRNAs are required for intesti-nal stemness maintenance in mice,and their expression is induced in regenerated ISCs after irradiation injury,resulting in skewed ISC fate from differentiation towards self-renewal.This upregulation of miR-29a/b expression in ISCs leads to suppression of fatty acid oxidation(FAO)and depression of oxidative phosphorylation,which in turn controls the balance between self-renewal and differentiation of ISCs.Deletion of miR-29a/b prevents these effects and thus impairs ISC-mediated epithelial recovery.Finally,we filter the potential targets of miR-29a/b and identify Hnf4g,a transcription factor,that drives this metabolic reprogramming through regulating FAO-related enzymes.Our work discovers an impor-tant metabolic mechanism of ISC-mediated regeneration and potentially pave the way for more targeted and effective therapeutic strategies for intestinal repair as well as tumor treatment.展开更多
目的探究外周miR-155、miR-181a在乙型肝炎病毒(hepatitis B virus,HBV)相关肝细胞癌(hepatocellular carcinoma,HCC)患者中的表达水平,分析两者对HBV HCC的诊断价值及与临床病理特征和生存预后的关系。方法选取2017年1月至2021年1月在...目的探究外周miR-155、miR-181a在乙型肝炎病毒(hepatitis B virus,HBV)相关肝细胞癌(hepatocellular carcinoma,HCC)患者中的表达水平,分析两者对HBV HCC的诊断价值及与临床病理特征和生存预后的关系。方法选取2017年1月至2021年1月在重庆市中医院接受治疗的HBV HCC患者117例作为肝细胞癌组,HBV相关良性肝病117例作为慢性肝病组,包括慢性乙型肝炎患者71例、乙型肝炎肝硬化患者46例,采集外周血,比较两组miR-155、miR-181a表达差异,分析miR-155、miR-181a表达与HBV相关HCC患者发病及临床病理特征的关系。绘制受试者操作特征(receiver operating characteristic,ROC)曲线评价外周血miR-155、miR-181a表达对HBV相关HCC的诊断价值。随访3年,Kaplan-Meier法分析miR-155、miR-181a对HBV相关HCC患者生存率的影响。结果肝细胞癌组外周血miR-155、miR-181a表达均较慢性肝病组高(P<0.05)。外周血miR-155、miR-181a表达与HBV相关HCC发病、HBV-DNA载量、门静脉侵袭、临床分期、淋巴结转移呈正相关,与分化程度呈负相关(P<0.05)。外周血miR-155、miR-181a诊断HBV相关HCC的曲线下面积(area under the curve,AUC)值分别为0.768、0.818,二者联合诊断AUC值0.923,明显高于各指标单独诊断,此时最佳敏感度、特异度分别为83.76%、88.03%。miR-155高表达亚组3年生存率为82.14%,明显低于低表达亚组的94.74%(P<0.05);miR-181a高表达亚组3年生存率为80.36%,明显低于低表达亚组的96.49%(P<0.05)。结论HBV相关HCC患者外周血miR-155、miR-181a表达异常升高,二者共同参与HBV相关HCC发病及恶性进展,检测其水平对于疾病诊断及预后预测具有一定价值。展开更多
基金supported by the National Natural Science Foundation of China(32372247)the National Key Research and Development Program of China(2023YFF1104501)to Huiyuan Guo.
文摘Intestinal stem cells(ISCs)initiate intestinal epithelial regeneration and tumorigenesis,and they experi-ence rapid refilling upon various injuries for epithelial repair as well as tumor reoccurrence.It is crucial to reveal the mechanism underlying such plasticity for intestinal health.Recent studies have found that metabolic pathways control stem cell fate in homeostasis,but the role of metabolism in the regeneration of ISCs after damage has not been clarified.Here,we find that in a human colorectal cancer dataset,miR-29a and b(miR-29a/b)are metabolic regulators highly associated with intestinal tumorigenesis and worse prognostic value of radiotherapy.We also show that these two microRNAs are required for intesti-nal stemness maintenance in mice,and their expression is induced in regenerated ISCs after irradiation injury,resulting in skewed ISC fate from differentiation towards self-renewal.This upregulation of miR-29a/b expression in ISCs leads to suppression of fatty acid oxidation(FAO)and depression of oxidative phosphorylation,which in turn controls the balance between self-renewal and differentiation of ISCs.Deletion of miR-29a/b prevents these effects and thus impairs ISC-mediated epithelial recovery.Finally,we filter the potential targets of miR-29a/b and identify Hnf4g,a transcription factor,that drives this metabolic reprogramming through regulating FAO-related enzymes.Our work discovers an impor-tant metabolic mechanism of ISC-mediated regeneration and potentially pave the way for more targeted and effective therapeutic strategies for intestinal repair as well as tumor treatment.
文摘目的探究外周miR-155、miR-181a在乙型肝炎病毒(hepatitis B virus,HBV)相关肝细胞癌(hepatocellular carcinoma,HCC)患者中的表达水平,分析两者对HBV HCC的诊断价值及与临床病理特征和生存预后的关系。方法选取2017年1月至2021年1月在重庆市中医院接受治疗的HBV HCC患者117例作为肝细胞癌组,HBV相关良性肝病117例作为慢性肝病组,包括慢性乙型肝炎患者71例、乙型肝炎肝硬化患者46例,采集外周血,比较两组miR-155、miR-181a表达差异,分析miR-155、miR-181a表达与HBV相关HCC患者发病及临床病理特征的关系。绘制受试者操作特征(receiver operating characteristic,ROC)曲线评价外周血miR-155、miR-181a表达对HBV相关HCC的诊断价值。随访3年,Kaplan-Meier法分析miR-155、miR-181a对HBV相关HCC患者生存率的影响。结果肝细胞癌组外周血miR-155、miR-181a表达均较慢性肝病组高(P<0.05)。外周血miR-155、miR-181a表达与HBV相关HCC发病、HBV-DNA载量、门静脉侵袭、临床分期、淋巴结转移呈正相关,与分化程度呈负相关(P<0.05)。外周血miR-155、miR-181a诊断HBV相关HCC的曲线下面积(area under the curve,AUC)值分别为0.768、0.818,二者联合诊断AUC值0.923,明显高于各指标单独诊断,此时最佳敏感度、特异度分别为83.76%、88.03%。miR-155高表达亚组3年生存率为82.14%,明显低于低表达亚组的94.74%(P<0.05);miR-181a高表达亚组3年生存率为80.36%,明显低于低表达亚组的96.49%(P<0.05)。结论HBV相关HCC患者外周血miR-155、miR-181a表达异常升高,二者共同参与HBV相关HCC发病及恶性进展,检测其水平对于疾病诊断及预后预测具有一定价值。
