目的探索铁自噬相关蛋白ELAV样RNA结合蛋白1(ELAV like RNA binding protein 1,ELAVL1)在多发性骨髓瘤(multiple myeloma,MM)中的表达,明确其在MM诊断及预后中的价值。方法首先利用GEO、TCGA数据库资料分析ELAVL1在健康对照及MM患者中...目的探索铁自噬相关蛋白ELAV样RNA结合蛋白1(ELAV like RNA binding protein 1,ELAVL1)在多发性骨髓瘤(multiple myeloma,MM)中的表达,明确其在MM诊断及预后中的价值。方法首先利用GEO、TCGA数据库资料分析ELAVL1在健康对照及MM患者中的表达,进一步用qRT-PCR在临床样本中进行验证。受试者工作特征(receiver operating characteristic,ROC)曲线及Kaplan-Meier法评估ELAVL1在MM患者诊断及预后中的价值;单因素及多因素COX分析探索影响MM预后的独立危险因素。最后,利用DAVID在线网站对差异基因进行功能富集分析。结果ELAVL1在初发MM及难治复发MM中表达增高(P<0.001),MM患者的ISS分期越高,ELAVL1的表达水平越高(P<0.01)。与20例健康对照相比,ELAVL1表达水平在28例初发MM患者标本中增高(P<0.001)。ROC曲线分析发现,ELAVL1的表达水平可以有效区分初发MM和健康对照(P<0.001)及单克隆免疫球蛋白增多症(monoclonal gammopathy of undetermined significance,MGUS)患者(P=0.0002)。生存分析发现,ELAVL1高表达组患者无进展生存时间(progression-free survival,PFS)(P=0.0141)及总体生存时间(overall survival time,OS)(P=0.0080)均短于ELAVL1低表达组患者。单因素分析及多因素分析发现,ELVAL1高表达是MM患者预后不良的独立危险因素(P=0.0050)。功能富集分析提示,差异基因主要富集于Hippo信号通路及MAPK信号通路。结论ELAVL1在MM中表达增高,其表达水平可以作为MM诊断及预后不良的标志物。ELAVL1可能通过Hippo信号通路及MAPK信号通路影响MM的发生发展。展开更多
Long noncoding RNAs(lncRNAs)modulate many aspects of biological and pathological processes.Recent studies have shown that host lncRNAs participate in the antiviral immune response,but functional lncRNAs in coxsackievi...Long noncoding RNAs(lncRNAs)modulate many aspects of biological and pathological processes.Recent studies have shown that host lncRNAs participate in the antiviral immune response,but functional lncRNAs in coxsackievirus B5(CVB5)infection remain unknown.Here,we identified a novel cytoplasmic lncRNA,LINC1392,which was highly inducible in CVB5 infected RD cells in a time-and dose-dependent manner,and also can be induced by the viral RNA and IFN-β.Further investigation showed that LINC1392 promoted several important interferon-stimulated genes(ISGs)expression,including IFIT1,IFIT2,and IFITM3 by activating MDA5,thereby inhibiting the replication of CVB5 in vitro.Mechanistically,LINC1392 bound to ELAV like RNA binding protein 1(ELAVL1)and blocked ELAVL1 interaction with MDA5.Functional study revealed that the 245–835 nt locus of LINC1392 exerted the antiviral effect and was also an important site for ELAVL1 binding.In mice,LINC1392 could inhibit CVB5 replication and alleviated the histopathological lesions of intestinal and brain tissues induced by viral infection.Our findings collectively reveal that the novel LINC1392 acts as a positive regulator in the IFN-I signaling pathway against CVB5 infection.Elucidating the underlying mechanisms on how lncRNA regulats the host innate immunity response towards CVB5 infection will lay the foundation for antiviral drug research.展开更多
The alteration of gene expression is not restricted to transcriptional regulation but includes a variety of posttranscriptional mechanisms;however,the role of the latter in many diseases remains relatively unknown.By ...The alteration of gene expression is not restricted to transcriptional regulation but includes a variety of posttranscriptional mechanisms;however,the role of the latter in many diseases remains relatively unknown.By using an RNA-Seq dataset of 1510 brain samples from individuals with autism spectrum disorder(ASD),bipolar disorder(BD),schizophrenia(SCZ),and controls,we assessed the contribution of post-transcriptional dysregulation and identified top perturbators accountable for transcriptomic alterations in neuropsychiatric disorders.Approximately 30%of the expression variability was attributed to post-transcriptional dysregulation.Interestingly,mature mRNA levels tended to be post-transcriptionally downregulated in SCZ and BD,leading to the inhibition of neurogenesis and neural differentiation,while they were upregulated in ASD,resulting in enhanced activity of apoptosis.These findings imply contrasting pathologies involving RNA metabolism across neuropsychiatric disorders.An RNA-binding protein,ELAVL3,was predicted to be significantly involved in the disruption of post-transcriptional regulation in all three disorders.To validate this,we knocked down its expression in cerebral organoids.Not only did the differentially expressed genes in ELAVL3 knockdown cover a considerable proportion of predicted targets in the three disorders,but we also found that neurogenesis was significantly affected,given the diminished proliferation and consequently reduced size of the organoids.The present study extends the current understanding of the link between post-transcriptional regulation and neuropsychiatric disorders and provides new potential therapeutic targets for early intervention.展开更多
Vascular endothelial growth factor （VEGF） is a potent secreted mitogen critical for physiologic and tumor angiogenesis. Regulation of VEGF occurs at several levels, including transcription, mRNA stabilization, trans...Vascular endothelial growth factor （VEGF） is a potent secreted mitogen critical for physiologic and tumor angiogenesis. Regulation of VEGF occurs at several levels, including transcription, mRNA stabilization, translation, and differential cellular localization of various isoforms. Recent advances in our understanding of post-transcriptional regulation of VEGF include identification of the stabilizing mRNA binding protein, HuR, and the discovery of internal ribosomal entry sites in the 5＇UTR of the VEGF mRNA. Monoclonal anti-VEGF antibody was recently approved for use in humans, but suffers from the need for high systemic doses. RNA interference （RNAi） technology is being used in vitro and in animal models with promising results. Here, we review the literature on post-transcriptional regulation of VEGF and describe recent progress in targeting these mechanisms for therapeutic benefit.展开更多
Epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs)positively affect the initial control of non-small cell lung cancer(NSCLC).Rapidly acquired resistance to EGFR-TKIs is a major hurdle in successful...Epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs)positively affect the initial control of non-small cell lung cancer(NSCLC).Rapidly acquired resistance to EGFR-TKIs is a major hurdle in successful treatment.However,the mechanisms that control the resistance of EGFR-TKIs remain largely unknown.RNA structures have widespread and crucial functions in many biological regulations;however,the functions of RNA structures in regulating cancer drug resistance remain unclear.Here,the psoralen analysis of RNA interactions and structures(PARIS)method is used to establish the higher-order RNA structure maps of EGFRTKIs-resistant and-sensitive cells of NSCLC.Our results show that RNA structural regions are enriched in untranslated regions(UTRs)and correlate with translation efficiency(TE).Moreover,yrdC N6-threonylcarbamoyltransferase domain containing(YRDC)promotes resistance to EGFR-TKIs.RNA structure formation in YRDC 30 UTR suppresses embryonic lethal abnormal vision-like 1(ELAVL1)binding,leading to EGFR-TKI sensitivity by impairing YRDC translation.A potential therapeutic strategy for cancer treatment is provided using antisense oligonucleotide(ASO)to perturb the interaction between RNA and protein.Our study reveals an unprecedented mechanism through which the RNA structure switch modulates EGFR-TKI resistance by controlling YRDC mRNA translation in an ELAVL1-dependent manner.展开更多
基金This work was supported by the National Natural Science Foundation of China(No.81860357)the Young Talents Support Program of Yunnan Province,China(Ten Thousand People Plan,YNWR-QNBJ-2019-178).
文摘Long noncoding RNAs(lncRNAs)modulate many aspects of biological and pathological processes.Recent studies have shown that host lncRNAs participate in the antiviral immune response,but functional lncRNAs in coxsackievirus B5(CVB5)infection remain unknown.Here,we identified a novel cytoplasmic lncRNA,LINC1392,which was highly inducible in CVB5 infected RD cells in a time-and dose-dependent manner,and also can be induced by the viral RNA and IFN-β.Further investigation showed that LINC1392 promoted several important interferon-stimulated genes(ISGs)expression,including IFIT1,IFIT2,and IFITM3 by activating MDA5,thereby inhibiting the replication of CVB5 in vitro.Mechanistically,LINC1392 bound to ELAV like RNA binding protein 1(ELAVL1)and blocked ELAVL1 interaction with MDA5.Functional study revealed that the 245–835 nt locus of LINC1392 exerted the antiviral effect and was also an important site for ELAVL1 binding.In mice,LINC1392 could inhibit CVB5 replication and alleviated the histopathological lesions of intestinal and brain tissues induced by viral infection.Our findings collectively reveal that the novel LINC1392 acts as a positive regulator in the IFN-I signaling pathway against CVB5 infection.Elucidating the underlying mechanisms on how lncRNA regulats the host innate immunity response towards CVB5 infection will lay the foundation for antiviral drug research.
文摘The alteration of gene expression is not restricted to transcriptional regulation but includes a variety of posttranscriptional mechanisms;however,the role of the latter in many diseases remains relatively unknown.By using an RNA-Seq dataset of 1510 brain samples from individuals with autism spectrum disorder(ASD),bipolar disorder(BD),schizophrenia(SCZ),and controls,we assessed the contribution of post-transcriptional dysregulation and identified top perturbators accountable for transcriptomic alterations in neuropsychiatric disorders.Approximately 30%of the expression variability was attributed to post-transcriptional dysregulation.Interestingly,mature mRNA levels tended to be post-transcriptionally downregulated in SCZ and BD,leading to the inhibition of neurogenesis and neural differentiation,while they were upregulated in ASD,resulting in enhanced activity of apoptosis.These findings imply contrasting pathologies involving RNA metabolism across neuropsychiatric disorders.An RNA-binding protein,ELAVL3,was predicted to be significantly involved in the disruption of post-transcriptional regulation in all three disorders.To validate this,we knocked down its expression in cerebral organoids.Not only did the differentially expressed genes in ELAVL3 knockdown cover a considerable proportion of predicted targets in the three disorders,but we also found that neurogenesis was significantly affected,given the diminished proliferation and consequently reduced size of the organoids.The present study extends the current understanding of the link between post-transcriptional regulation and neuropsychiatric disorders and provides new potential therapeutic targets for early intervention.
文摘Vascular endothelial growth factor （VEGF） is a potent secreted mitogen critical for physiologic and tumor angiogenesis. Regulation of VEGF occurs at several levels, including transcription, mRNA stabilization, translation, and differential cellular localization of various isoforms. Recent advances in our understanding of post-transcriptional regulation of VEGF include identification of the stabilizing mRNA binding protein, HuR, and the discovery of internal ribosomal entry sites in the 5＇UTR of the VEGF mRNA. Monoclonal anti-VEGF antibody was recently approved for use in humans, but suffers from the need for high systemic doses. RNA interference （RNAi） technology is being used in vitro and in animal models with promising results. Here, we review the literature on post-transcriptional regulation of VEGF and describe recent progress in targeting these mechanisms for therapeutic benefit.
基金supported by grants from the Province and Ministry Coconstruction Major Program of Medical Science and Technique Foundation of Henan Province,China(Grant No.SBGJ202001007)the National Natural Science Foundation of China(Grant Nos.31870809 and 32121001)the Special Fund for Young and Middle School Leaders of Henan Health Commission,China(Grant No.HNSWJW-2020017).
文摘Epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs)positively affect the initial control of non-small cell lung cancer(NSCLC).Rapidly acquired resistance to EGFR-TKIs is a major hurdle in successful treatment.However,the mechanisms that control the resistance of EGFR-TKIs remain largely unknown.RNA structures have widespread and crucial functions in many biological regulations;however,the functions of RNA structures in regulating cancer drug resistance remain unclear.Here,the psoralen analysis of RNA interactions and structures(PARIS)method is used to establish the higher-order RNA structure maps of EGFRTKIs-resistant and-sensitive cells of NSCLC.Our results show that RNA structural regions are enriched in untranslated regions(UTRs)and correlate with translation efficiency(TE).Moreover,yrdC N6-threonylcarbamoyltransferase domain containing(YRDC)promotes resistance to EGFR-TKIs.RNA structure formation in YRDC 30 UTR suppresses embryonic lethal abnormal vision-like 1(ELAVL1)binding,leading to EGFR-TKI sensitivity by impairing YRDC translation.A potential therapeutic strategy for cancer treatment is provided using antisense oligonucleotide(ASO)to perturb the interaction between RNA and protein.Our study reveals an unprecedented mechanism through which the RNA structure switch modulates EGFR-TKI resistance by controlling YRDC mRNA translation in an ELAVL1-dependent manner.
