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
Purpose:Triple-negative breast cancer(TNBC)is an aggressive subtype of breast cancer.It is still unclear that the mechanisms by which long non-coding RNA(lncRNA)regulates tumorigenesis of TNBC.In this study,we explore...Purpose:Triple-negative breast cancer(TNBC)is an aggressive subtype of breast cancer.It is still unclear that the mechanisms by which long non-coding RNA(lncRNA)regulates tumorigenesis of TNBC.In this study,we explored the function and regulation of lncRNA in TNBC.Methods:The diferentially expressed and overlapped lncRNAs were obtained from two microarray datasets of breast cancer.The cancer genome atlas(TCGA)data was applied to validate the roles of top diferentially expressed lncRNAs.The potential relationship among lncRNAs,miRNAs,and mRNAs and the efects of them on the TNBC tumorigenesis were further explored through multiple bioinformatic methods.Results:Long intergenic non-protein coding RNA 1351(LINC01351)was frst discovered to play an oncogenic role in TNBC.The highly expressed LINC01351 was signifcantly related to aggressive subtypes,advanced stages and metastasis of breast cancer.The overexpressed LINC01351 was associated with adverse prognosis of patients with TNBC.LINC01351 was found to negatively regulate ELK4 which was involved in the transcriptional regulation in cancer.The high expression of ELK4 showed favorable prognosis of patients with basal-like 1 subtype and luminal androgen receptor subtype of TNBC.Conclusion:The dysregulation of LINC01351 played an important role in triple-negative breast cancer.LINC01351 could be a poor prognostic marker and a potential target for patients with TNBC.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 the following grants:Foundation of Young Innovative Talents (Tianjin Medical University Cancer Institute and Hospital,2018-1-31)National Science Foundation of China (NSFC No.81401950)+2 种基金China Scholarship Council (File No.201706940019)Tianjin Key Medical Discipline (Specialty)Construction ProjectTianjin Medical University Cancer Hospital"14th Five-Year"Peak Discipline Support Program Project.
文摘Purpose:Triple-negative breast cancer(TNBC)is an aggressive subtype of breast cancer.It is still unclear that the mechanisms by which long non-coding RNA(lncRNA)regulates tumorigenesis of TNBC.In this study,we explored the function and regulation of lncRNA in TNBC.Methods:The diferentially expressed and overlapped lncRNAs were obtained from two microarray datasets of breast cancer.The cancer genome atlas(TCGA)data was applied to validate the roles of top diferentially expressed lncRNAs.The potential relationship among lncRNAs,miRNAs,and mRNAs and the efects of them on the TNBC tumorigenesis were further explored through multiple bioinformatic methods.Results:Long intergenic non-protein coding RNA 1351(LINC01351)was frst discovered to play an oncogenic role in TNBC.The highly expressed LINC01351 was signifcantly related to aggressive subtypes,advanced stages and metastasis of breast cancer.The overexpressed LINC01351 was associated with adverse prognosis of patients with TNBC.LINC01351 was found to negatively regulate ELK4 which was involved in the transcriptional regulation in cancer.The high expression of ELK4 showed favorable prognosis of patients with basal-like 1 subtype and luminal androgen receptor subtype of TNBC.Conclusion:The dysregulation of LINC01351 played an important role in triple-negative breast cancer.LINC01351 could be a poor prognostic marker and a potential target for patients with TNBC.
