The epithelial-mesenchymal transition(EMT),in which cells undergo a switch from a polarized,epithelial phenotype to a highly motile fibroblastic or mesenchymal phenotype is fundamental during embryonic development and...The epithelial-mesenchymal transition(EMT),in which cells undergo a switch from a polarized,epithelial phenotype to a highly motile fibroblastic or mesenchymal phenotype is fundamental during embryonic development and can be reactivated in a variety of diseases including cancer.Spatio-temporally-regulated mechanisms are constantly orchestrated to allow cells to adapt to their constantly changing environments when disseminating to distant organs.Although numerous transcriptional regulatory factors are currently well-characterized,the post-transcriptional control of EMT requires continued investigation.The hnRNP E1 protein displays a major role in the control of tumor cell plasticity by regulating the translatome through multiple non-redundant mechanisms,and this role is exemplified when E1 is absent.hnRNP E1 binding to RNA molecules leads to direct or indirect translational regulation of specific sets of proteins:(1)hnRNP E1 binding to specific targets has a direct role in translation by preventing elongation of translation;(2)hnRNP E1-dependent alternative splicing can prevent the generation of a competing long non-coding RNA that acts as a decoy for microRNAs(miRNAs)involved in translational inhibition of EMT master regulators;(3)hnRNP E1 binding to the 3'untranslated region of transcripts can also positively regulate the stability of certain mRNAs to improve their translation.Globally,hnRNP E1 appears to control proteome reprogramming during cell plasticity,either by direct or indirect regulation of protein translation.展开更多
Impairment of glucose(Glu)uptake and storage by skeletal muscle is a prime risk factor for the development of metabolic diseases.Heterogeneous nuclear ribonucleoprotein A1(hnRNP Al)is a highly abundant RNA-binding pro...Impairment of glucose(Glu)uptake and storage by skeletal muscle is a prime risk factor for the development of metabolic diseases.Heterogeneous nuclear ribonucleoprotein A1(hnRNP Al)is a highly abundant RNA-binding protein that has been implicated in diverse cellular functions.The aim of this study was to investigate the function of hnRNP A1 on muscle tissue insulin sensitivity and systemic Glu homeostasis.Our results showed that conditional deletion of hnRNP Al in the muscle gave rise to a severe insulin resistance phenotype in mice fed a high-fat diet(HFD).Conditional knockout mice fed a HFD showed exacerbated obesity,insulin resistance,and hepatic steatosis.In vitro interference of hnRNP Al in C2C12 myotubes impaired insulin signal transduction and inhibited Glu uptake,whereas hnRNP Al overexpression in C2C12 myotubes protected against insulin resistance induced by supraphysiological concentrations of insulin.The expression and stability of glycogen synthase(gysl)mRNA were also decreased in the absence of hnRNP A l.Mechanistically,hnRNP Al interacted with gys l and stabilized its mRNA,thereby promoting glycogen synthesis and maintaining the insulin sensitivity in muscle tissue.Taken together,our findings are the first to show that reduced expression of hnRNP Al in skeletal muscle affects the metabolic properties and systemic insulin sensitivity by inhibiting glycogen synthesis.展开更多
Owing to incurable castration-resistant prostate cancer(CRPC)ultimately developing after treating with androgen deprivation therapy(ADT),it is vital to devise new therapeutic strategies to treat CRPC.Treatments that t...Owing to incurable castration-resistant prostate cancer(CRPC)ultimately developing after treating with androgen deprivation therapy(ADT),it is vital to devise new therapeutic strategies to treat CRPC.Treatments that target programmed cell death protein 1(PD-1)and programmed death ligand-1(PD-L1)have been approved for human cancers with clinical benefit.However,many patients,especially prostate cancer,fail to respond to anti-PD-1/PD-L1 treatment,so it is an urgent need to seek a support strategy for improving the traditional PD-1/PD-L1 targeting immunotherapy.In the present study,analyzing the data from our prostate cancer tissue microarray,we found that PD-L1 expression was positively correlated with the expression of heterogeneous nuclear ribonucleoprotein L(Hn RNP L).Hence,we further investigated the potential role of Hn RNP L on the PD-L1 expression,the sensitivity of cancer cells to T-cell killing and the synergistic effect with anti-PD-1 therapy in CRPC.Indeed,Hn RNP L knockdown effectively decreased PD-L1 expression and recovered the sensitivity of cancer cells to T-cell killing in vitro and in vivo,on the contrary,Hn RNP L overexpression led to the opposite effect in CRPC cells.In addition,consistent with the previous study,we revealed that ferroptosis played a critical role in T-cell-induced cancer cell death,and Hn RNP L promoted the cancer immune escape partly through targeting YY1/PD-L1 axis and inhibiting ferroptosis in CRPC cells.Furthermore,Hn RNP L knockdown enhanced antitumor immunity by recruiting infiltrating CD8^(+)T cells and synergized with anti-PD-1 therapy in CRPC tumors.This study provided biological evidence that Hn RNP L knockdown might be a novel therapeutic agent in PD-L1/PD-1 blockade strategy that enhanced anti-tumor immune response in CRPC.展开更多
目的探讨核不均一核糖核蛋白(heterogeneous nuclear ribonul leoprotins,hnRNPs)E 1和E 2与宫颈癌变及其预后的关系。方法收集2013年6月至2018年6月辽阳市中心医院收治的112例宫颈癌患者肿瘤组织标本为宫颈癌组,同期100例宫颈上皮内瘤...目的探讨核不均一核糖核蛋白(heterogeneous nuclear ribonul leoprotins,hnRNPs)E 1和E 2与宫颈癌变及其预后的关系。方法收集2013年6月至2018年6月辽阳市中心医院收治的112例宫颈癌患者肿瘤组织标本为宫颈癌组,同期100例宫颈上皮内瘤变(cervical intraepithelial,CIN)患者为CIN组,100例子宫良性疾病的正常宫颈组织标本为正常对照组。采用免疫组化法检测不同宫颈病变组中hnRNP E 1和E 2蛋白的表达情况。使用Kaplan-Meier和Log-Rank检验分别绘制生存曲线以及比较生存率来分析预后情况。结果hnRNP E 1、hnRNP E 2蛋白在宫颈癌组的阳性表达显著低于CIN组和正常对照组(P<0.05);hnRNP E 1、hnRNP E 2蛋白在3组中的表达两两比较发现,宫颈癌组与CIN组、正常对照组比较,差异均有统计学意义(P<0.05);CIN组和正常对照组比较,差异无统计学意义(P>0.05)。不同CIN分级中宫颈组织中hnRNP E 1、hnRNP E 2蛋白阳性率表达比较,差异有统计学意义(P<0.05);CIN I级组织中hnRNP E 1、hnRNP E 2蛋白阳性率表达高于CIN III级(P<0.05)。将hnRNP E 1、hnRNP E 2蛋白表达与宫颈癌患者临床病理特征相关分析得出,hnRNP E 1的蛋白阳性表达率与FIGO分期、宫颈癌分化程度、术后辅助治疗及淋巴结转移有关(P<0.05),与患者的年龄、病理组织类型、肿瘤直径、肌层浸润深度均不相关(P>0.05);hnRNP E 2的蛋白阳性表达率与FIGO分期、术后辅助治疗及淋巴结转移有关(P<0.05),与患者的年龄、病理组织类型、肿瘤直径、宫颈癌分化程度、肌层浸润深度均不相关(P>0.05)。分析112例宫颈癌患者随访情况,其中9例失访,15例死亡,hnRNP E 1蛋白表达阳性患者死亡率为4.5%(5/112),表达为阴性患者死亡率为14.3%(16/112),两者生存率比较差异有统计学意义(χ~2=4.535,P=0.033)。hnRNP E 2蛋白表达阳性患者死亡率为3.6%(4/112),表达为阴性患者死亡率为15.2%(17/112),两者生存率比较差异有统计学意义展开更多
基金Hollings Cancer Center Postdoctoral Fellowship to Grelet S and the National Cancer Institute(CA154663)to Howe PH
文摘The epithelial-mesenchymal transition(EMT),in which cells undergo a switch from a polarized,epithelial phenotype to a highly motile fibroblastic or mesenchymal phenotype is fundamental during embryonic development and can be reactivated in a variety of diseases including cancer.Spatio-temporally-regulated mechanisms are constantly orchestrated to allow cells to adapt to their constantly changing environments when disseminating to distant organs.Although numerous transcriptional regulatory factors are currently well-characterized,the post-transcriptional control of EMT requires continued investigation.The hnRNP E1 protein displays a major role in the control of tumor cell plasticity by regulating the translatome through multiple non-redundant mechanisms,and this role is exemplified when E1 is absent.hnRNP E1 binding to RNA molecules leads to direct or indirect translational regulation of specific sets of proteins:(1)hnRNP E1 binding to specific targets has a direct role in translation by preventing elongation of translation;(2)hnRNP E1-dependent alternative splicing can prevent the generation of a competing long non-coding RNA that acts as a decoy for microRNAs(miRNAs)involved in translational inhibition of EMT master regulators;(3)hnRNP E1 binding to the 3'untranslated region of transcripts can also positively regulate the stability of certain mRNAs to improve their translation.Globally,hnRNP E1 appears to control proteome reprogramming during cell plasticity,either by direct or indirect regulation of protein translation.
基金This work was supported by the National Natural Science Foundation of China(81673436,91853109,81872877,and 91229109)the open fund of State Key Laboratory of Drug Research(SIMM1903KF-10)the Mountain-Climbing Talents Project of Nanjing University to Y.S.
文摘Impairment of glucose(Glu)uptake and storage by skeletal muscle is a prime risk factor for the development of metabolic diseases.Heterogeneous nuclear ribonucleoprotein A1(hnRNP Al)is a highly abundant RNA-binding protein that has been implicated in diverse cellular functions.The aim of this study was to investigate the function of hnRNP A1 on muscle tissue insulin sensitivity and systemic Glu homeostasis.Our results showed that conditional deletion of hnRNP Al in the muscle gave rise to a severe insulin resistance phenotype in mice fed a high-fat diet(HFD).Conditional knockout mice fed a HFD showed exacerbated obesity,insulin resistance,and hepatic steatosis.In vitro interference of hnRNP Al in C2C12 myotubes impaired insulin signal transduction and inhibited Glu uptake,whereas hnRNP Al overexpression in C2C12 myotubes protected against insulin resistance induced by supraphysiological concentrations of insulin.The expression and stability of glycogen synthase(gysl)mRNA were also decreased in the absence of hnRNP A l.Mechanistically,hnRNP Al interacted with gys l and stabilized its mRNA,thereby promoting glycogen synthesis and maintaining the insulin sensitivity in muscle tissue.Taken together,our findings are the first to show that reduced expression of hnRNP Al in skeletal muscle affects the metabolic properties and systemic insulin sensitivity by inhibiting glycogen synthesis.
基金supported by the National Natural Science Foundation of China(Grant No.81773277)Science and Technology Program of Guangzhou,China(Grant No.201803010014)+3 种基金Guangdong Basic and Applied Basic Research Foundation(Grant Nos.2020A1515110922 and 2019A1515110033,China)China Postdoctoral Science Foundation funded project(Grant Nos.2018M643126 and 2019M662865)Distinguished Young Talents in Higher Education Foundation of Guangdong Province(Grant No.2019KQNCX115,China)Achievement Cultivation and Clinical Transformation Application Cultivation Projects of the First Affiliated Hospital of Guangzhou Medical University(Grant No.ZH201908,China)。
文摘Owing to incurable castration-resistant prostate cancer(CRPC)ultimately developing after treating with androgen deprivation therapy(ADT),it is vital to devise new therapeutic strategies to treat CRPC.Treatments that target programmed cell death protein 1(PD-1)and programmed death ligand-1(PD-L1)have been approved for human cancers with clinical benefit.However,many patients,especially prostate cancer,fail to respond to anti-PD-1/PD-L1 treatment,so it is an urgent need to seek a support strategy for improving the traditional PD-1/PD-L1 targeting immunotherapy.In the present study,analyzing the data from our prostate cancer tissue microarray,we found that PD-L1 expression was positively correlated with the expression of heterogeneous nuclear ribonucleoprotein L(Hn RNP L).Hence,we further investigated the potential role of Hn RNP L on the PD-L1 expression,the sensitivity of cancer cells to T-cell killing and the synergistic effect with anti-PD-1 therapy in CRPC.Indeed,Hn RNP L knockdown effectively decreased PD-L1 expression and recovered the sensitivity of cancer cells to T-cell killing in vitro and in vivo,on the contrary,Hn RNP L overexpression led to the opposite effect in CRPC cells.In addition,consistent with the previous study,we revealed that ferroptosis played a critical role in T-cell-induced cancer cell death,and Hn RNP L promoted the cancer immune escape partly through targeting YY1/PD-L1 axis and inhibiting ferroptosis in CRPC cells.Furthermore,Hn RNP L knockdown enhanced antitumor immunity by recruiting infiltrating CD8^(+)T cells and synergized with anti-PD-1 therapy in CRPC tumors.This study provided biological evidence that Hn RNP L knockdown might be a novel therapeutic agent in PD-L1/PD-1 blockade strategy that enhanced anti-tumor immune response in CRPC.
文摘目的探讨核不均一核糖核蛋白(heterogeneous nuclear ribonul leoprotins,hnRNPs)E 1和E 2与宫颈癌变及其预后的关系。方法收集2013年6月至2018年6月辽阳市中心医院收治的112例宫颈癌患者肿瘤组织标本为宫颈癌组,同期100例宫颈上皮内瘤变(cervical intraepithelial,CIN)患者为CIN组,100例子宫良性疾病的正常宫颈组织标本为正常对照组。采用免疫组化法检测不同宫颈病变组中hnRNP E 1和E 2蛋白的表达情况。使用Kaplan-Meier和Log-Rank检验分别绘制生存曲线以及比较生存率来分析预后情况。结果hnRNP E 1、hnRNP E 2蛋白在宫颈癌组的阳性表达显著低于CIN组和正常对照组(P<0.05);hnRNP E 1、hnRNP E 2蛋白在3组中的表达两两比较发现,宫颈癌组与CIN组、正常对照组比较,差异均有统计学意义(P<0.05);CIN组和正常对照组比较,差异无统计学意义(P>0.05)。不同CIN分级中宫颈组织中hnRNP E 1、hnRNP E 2蛋白阳性率表达比较,差异有统计学意义(P<0.05);CIN I级组织中hnRNP E 1、hnRNP E 2蛋白阳性率表达高于CIN III级(P<0.05)。将hnRNP E 1、hnRNP E 2蛋白表达与宫颈癌患者临床病理特征相关分析得出,hnRNP E 1的蛋白阳性表达率与FIGO分期、宫颈癌分化程度、术后辅助治疗及淋巴结转移有关(P<0.05),与患者的年龄、病理组织类型、肿瘤直径、肌层浸润深度均不相关(P>0.05);hnRNP E 2的蛋白阳性表达率与FIGO分期、术后辅助治疗及淋巴结转移有关(P<0.05),与患者的年龄、病理组织类型、肿瘤直径、宫颈癌分化程度、肌层浸润深度均不相关(P>0.05)。分析112例宫颈癌患者随访情况,其中9例失访,15例死亡,hnRNP E 1蛋白表达阳性患者死亡率为4.5%(5/112),表达为阴性患者死亡率为14.3%(16/112),两者生存率比较差异有统计学意义(χ~2=4.535,P=0.033)。hnRNP E 2蛋白表达阳性患者死亡率为3.6%(4/112),表达为阴性患者死亡率为15.2%(17/112),两者生存率比较差异有统计学意义
