Background:The regulatory mechanisms governing vasculogenic mimicry(VM)in oral squamous cell carcinoma(OSCC)remain largely undefined.This study aimed to identify critical factors and elucidate the epigenetic mechanism...Background:The regulatory mechanisms governing vasculogenic mimicry(VM)in oral squamous cell carcinoma(OSCC)remain largely undefined.This study aimed to identify critical factors and elucidate the epigenetic mechanisms underlying VM in OSCC.Methods:Bioinformatics analysis was performed utilizing single-cell RNA-seq,bulk RNA-seq,and histone H3 lysine 27 acetylation(H3K27ac)Chromatin Immunoprecipitation(ChIP)-seq data obtained from The Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)databases.ChIP-qPCR was used to validate the binding of ETS transcription factor ELK4(ELK4)to the dihydrofolate reductase(DHFR)enhancer.In vitro VM formation and invasion of OSCC cells were assessed using Matrigel-based tube formation and Transwell assays,respectively.Results:Elevated expression of VM-related genes predicts unfavorable prognosis in OSCC patients.High-dimensional weighted gene co-expression network analysis(hdWGCNA)identified epithelial subcluster C4 as most strongly associated with VM and metastasis.Three co-expression modules within this subcluster exhibited significant positive correlations with both phenotypic traits.Among the 30 eigengenes from the three modules,DHFR emerged as a key regulator of VM and metastasis.Knockdown or inhibition of DHFR significantly suppressed VM formation and invasion in OSCC cells.Mechanistically,ELK4 activated DHFR transcription through direct binding to its enhancer.DHFR overexpression rescued VM and invasion impairment induced by ELK4 knockdown.Conclusion:DHFR was a pivotal enhancer-regulated gene driving VM and metastasis in OSCC.ELK4 directly binds to DHFR enhancer regions to activate its transcription,thereby promoting these malignant phenotypes.These findings identified the ELK4/DHFR axis as a promising therapeutic target for anti-angiogenic intervention in OSCC.展开更多
Promotion of angiogenesis is crucial for bone tissue repair,and the poor activity of angiogenic cells and growth factors is the main problem in angiogenesis.New proangiogenic nanomaterials are urgently needed to be a ...Promotion of angiogenesis is crucial for bone tissue repair,and the poor activity of angiogenic cells and growth factors is the main problem in angiogenesis.New proangiogenic nanomaterials are urgently needed to be a promising strategy for this issue.Nb promotes bone formation and fracture healing,possibly by increasing vascular endothelial growth factor(VEGF)production.Nanoniobium particles(nNb)may promote angiogenesis.However,the effect of nNb on angiogenesis is unclear,limiting its application.This study confirmed that nNb significantly promoted angiogenesis.nNb increased and Ras-related C3 botulinum toxin substrate(Rac)family small guanosine triphosphatase(GTPase)1(Rac1)expression,inducing F-actin aggregation at the front edge of cells and the formation of pseudopodia to mediate cell migration,further promoting angiogenesis.We discovered that cyclin-dependent kinase-like 5(CDKL5)is a new signaling molecule that activates Rac1.V-ets erythroblastosis virus E26 oncogene homolog(ETS)domain-containing protein(ELK1),regulating CDKL5 and Rac1,plays an upstream regulatory role.When ELK1 was inhibited,CDKL5 and Rac1 levels were decreased.ELK1,CDKL5 or Rac1 are effective regulatory targets of angiogenesis.Inhibiting expression of ELK1,CDKL5 or Rac1 decreased angiogenesis.Thus,nNb has good angiogenic effects.The ELK1-CDKL5-Rac1 signaling pathway regulates the migration of endothelial cells to promote angiogenesis.nNb can be used in bone tissue engineering as a new nanomaterial,and it will promote the development of a new strategy for tissue engineering.展开更多
目的探讨核转录因子NF-κB(NF-κB)家族、信号转录与转录激活子1(STAT1)、调节转录因子1(ELK1)核表达对中晚期宫颈癌预后评估价值。方法78例宫颈癌患者组织标本,分为宫颈癌组(n=78)、正常组(n=30),行免疫组织化学检测,随访预后分为存活...目的探讨核转录因子NF-κB(NF-κB)家族、信号转录与转录激活子1(STAT1)、调节转录因子1(ELK1)核表达对中晚期宫颈癌预后评估价值。方法78例宫颈癌患者组织标本,分为宫颈癌组(n=78)、正常组(n=30),行免疫组织化学检测,随访预后分为存活组、死亡组,比较各组宫颈组织转录因子NF-κB家族(c-Rel、p50、p65)、STAT1、ELK1核表达。结果宫颈癌组c-Rel、NF-k B p50、NF-k B p65阳性表达率、ELK1阳性表达率均明显高于正常组,STAT1阳性表达率较正常组低(P<0.05)。78例患者,存活率41.03%,死亡组、存活组FIGO分期、病理类型、肿瘤大小、淋巴结转移、NF-κB家族c-Rel、NF-k B p50、NF-k B p65阳性表达率、ELK1阳性表达率、STAT1阳性表达率比较差异均有统计学意义(P<0.05)。FIGO分期、病理类型、肿瘤大小、淋巴结有无转移、NF-κB家族阳性表达、ELK1及STAT1阳性表达是宫颈癌患者预后的影响因素(P<0.05)。转录因子NF-κB家族、STAT1、ELK1核表达与宫颈癌患者预后密切相关(P<0.05)。结论转录因子NF-κB家族、STAT1、ELK1或可作为中晚期宫颈癌治疗及预后评估的潜在靶基因。展开更多
基金supported by Hebei Natural Science Foundation(H2024206476)Medical Science Research Project of Hebei(20240101).
文摘Background:The regulatory mechanisms governing vasculogenic mimicry(VM)in oral squamous cell carcinoma(OSCC)remain largely undefined.This study aimed to identify critical factors and elucidate the epigenetic mechanisms underlying VM in OSCC.Methods:Bioinformatics analysis was performed utilizing single-cell RNA-seq,bulk RNA-seq,and histone H3 lysine 27 acetylation(H3K27ac)Chromatin Immunoprecipitation(ChIP)-seq data obtained from The Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)databases.ChIP-qPCR was used to validate the binding of ETS transcription factor ELK4(ELK4)to the dihydrofolate reductase(DHFR)enhancer.In vitro VM formation and invasion of OSCC cells were assessed using Matrigel-based tube formation and Transwell assays,respectively.Results:Elevated expression of VM-related genes predicts unfavorable prognosis in OSCC patients.High-dimensional weighted gene co-expression network analysis(hdWGCNA)identified epithelial subcluster C4 as most strongly associated with VM and metastasis.Three co-expression modules within this subcluster exhibited significant positive correlations with both phenotypic traits.Among the 30 eigengenes from the three modules,DHFR emerged as a key regulator of VM and metastasis.Knockdown or inhibition of DHFR significantly suppressed VM formation and invasion in OSCC cells.Mechanistically,ELK4 activated DHFR transcription through direct binding to its enhancer.DHFR overexpression rescued VM and invasion impairment induced by ELK4 knockdown.Conclusion:DHFR was a pivotal enhancer-regulated gene driving VM and metastasis in OSCC.ELK4 directly binds to DHFR enhancer regions to activate its transcription,thereby promoting these malignant phenotypes.These findings identified the ELK4/DHFR axis as a promising therapeutic target for anti-angiogenic intervention in OSCC.
基金supported by Guangzhou Science and Technology Plan Project(No.2023A03J0328)the National Natural Science Foundation of China(No.81600904)。
文摘Promotion of angiogenesis is crucial for bone tissue repair,and the poor activity of angiogenic cells and growth factors is the main problem in angiogenesis.New proangiogenic nanomaterials are urgently needed to be a promising strategy for this issue.Nb promotes bone formation and fracture healing,possibly by increasing vascular endothelial growth factor(VEGF)production.Nanoniobium particles(nNb)may promote angiogenesis.However,the effect of nNb on angiogenesis is unclear,limiting its application.This study confirmed that nNb significantly promoted angiogenesis.nNb increased and Ras-related C3 botulinum toxin substrate(Rac)family small guanosine triphosphatase(GTPase)1(Rac1)expression,inducing F-actin aggregation at the front edge of cells and the formation of pseudopodia to mediate cell migration,further promoting angiogenesis.We discovered that cyclin-dependent kinase-like 5(CDKL5)is a new signaling molecule that activates Rac1.V-ets erythroblastosis virus E26 oncogene homolog(ETS)domain-containing protein(ELK1),regulating CDKL5 and Rac1,plays an upstream regulatory role.When ELK1 was inhibited,CDKL5 and Rac1 levels were decreased.ELK1,CDKL5 or Rac1 are effective regulatory targets of angiogenesis.Inhibiting expression of ELK1,CDKL5 or Rac1 decreased angiogenesis.Thus,nNb has good angiogenic effects.The ELK1-CDKL5-Rac1 signaling pathway regulates the migration of endothelial cells to promote angiogenesis.nNb can be used in bone tissue engineering as a new nanomaterial,and it will promote the development of a new strategy for tissue engineering.
文摘目的探讨核转录因子NF-κB(NF-κB)家族、信号转录与转录激活子1(STAT1)、调节转录因子1(ELK1)核表达对中晚期宫颈癌预后评估价值。方法78例宫颈癌患者组织标本,分为宫颈癌组(n=78)、正常组(n=30),行免疫组织化学检测,随访预后分为存活组、死亡组,比较各组宫颈组织转录因子NF-κB家族(c-Rel、p50、p65)、STAT1、ELK1核表达。结果宫颈癌组c-Rel、NF-k B p50、NF-k B p65阳性表达率、ELK1阳性表达率均明显高于正常组,STAT1阳性表达率较正常组低(P<0.05)。78例患者,存活率41.03%,死亡组、存活组FIGO分期、病理类型、肿瘤大小、淋巴结转移、NF-κB家族c-Rel、NF-k B p50、NF-k B p65阳性表达率、ELK1阳性表达率、STAT1阳性表达率比较差异均有统计学意义(P<0.05)。FIGO分期、病理类型、肿瘤大小、淋巴结有无转移、NF-κB家族阳性表达、ELK1及STAT1阳性表达是宫颈癌患者预后的影响因素(P<0.05)。转录因子NF-κB家族、STAT1、ELK1核表达与宫颈癌患者预后密切相关(P<0.05)。结论转录因子NF-κB家族、STAT1、ELK1或可作为中晚期宫颈癌治疗及预后评估的潜在靶基因。
