Background:The ORAI1 gene,central to store-operated calcium entry(SOCE),is increasingly recognized for its pivotal role in cancer progression and patient prognosis across a broad spectrum of malignancies.Despite its c...Background:The ORAI1 gene,central to store-operated calcium entry(SOCE),is increasingly recognized for its pivotal role in cancer progression and patient prognosis across a broad spectrum of malignancies.Despite its critical involvement in calcium signaling pathways that are essential for cellular functions such as proliferation,migration,and apoptosis,the comprehensive impacts of ORAI1 within the tumor microenvironment(TME)and its modulation across various cancers have not been fully elucidated.Methods:We conducted a pan-cancer analysis leveraging data from The Cancer Genome Atlas(TCGA)and Genotype-Tissue Expression(GTEx)to assess ORAI1 expression.Differential expression analyses were performed,complemented by correlative studies with tumor mutation burden(TMB),microsatellite instability(MSI),immune infiltration,and key biological processes and pathways.Results:Our results demonstrate that ORAI1 is consistently upregulated in a range of cancer types,associated with aggressive tumor characteristics and poor patient outcomes.Significantly,ORAI1 upregulation correlates with increased tumor mutation burden(TMB)and microsatellite instability(MSI),markers of genomic instability that are predictive of response to immunotherapy,underscoring its potential utility in clinical stratification and treatment decision-making.ORAI1's influence extended to the immune landscape,showing associations with immune cell infiltration and both immunosuppressive and immunostimulatory gene sets,thereby affecting the TME and possibly the efficacy of immunotherapeutic interventions.Conclusions:The multifaceted nature of ORAI1's involvement in cancer pathophysiology positions it as a prospective biomarker and therapeutic target.Its expression dynamics and correlative significance with prognostic and immune regulatory elements underscore its potential in guiding therapeutic strategies and improving clinical outcomes.This study lays a foundation for future research,aiming to leverage ORAI1's biological significance in cancer prognosis and therapy optimization.展开更多
Background:The ORAI family of proteins,comprising ORAI1,ORAI2,and ORAI3,plays a crucial role in the regulation of intracellular calcium signaling,which is essential for various cellular functions including proliferati...Background:The ORAI family of proteins,comprising ORAI1,ORAI2,and ORAI3,plays a crucial role in the regulation of intracellular calcium signaling,which is essential for various cellular functions including proliferation,differentiation,and apoptosis.Dysregulation of calcium signaling has been implicated in cancer pathogenesis,influencing tumor progression,metastasis,and resistance to therapy.This study aims to provide a comprehensive analysis of the ORAI family members across a broad spectrum of cancers.Methods:Publicly available datasets from The Cancer Genome Atlas and the Gene Expression Omnibus were utilized.RNA sequencing data,mutation profiles,copy number variation data,and methylation data across different cancer types were analyzed.Differential expression analysis,survival analysis,copy number variation analysis,mutation analysis,methylation analysis,immune cell infiltration analysis using the Cibersort algorithm,and gene set enrichment analysis were conducted using R software.Results:ORAI1 and ORAI3 were significantly upregulated in glioblastoma multiforme,whereas ORAI2 was notably downregulated in kidney chromophobe and pancreatic adenocarcinoma.ORAI2 exhibited higher mutation rates and copy number gains in multiple cancers compared to ORAI1 and ORAI3.The hypermethylation of ORAI2 in head and neck squamous cell carcinoma,esophageal carcinoma,and glioblastoma multiforme negatively correlated with its gene expression.ORAI1 and ORAI3 expression positively correlated with regulatory T cells infiltration,whereas ORAI2 showed a negative correlation with CD8^(+)T cell infiltration.Gene set enrichment analysis revealed that ORAI1 and ORAI2 are associated with immune-related pathways,while ORAI3 is linked to MYC targets and oxidative phosphorylation.Conclusion:Our pan-cancer analysis reveals significant differential expression,genomic alterations,and epigenetic regulation of ORAI family members across various cancers.ORAI1 and ORAI3 appear to promote an immunosuppressive environment,whereas ORAI2 may function as a tumor suppressor in certain contexts.These findings provide a foundation for future research targeting ORAI-mediated pathways in cancer therapy and highlight the therapeutic potential of ORAI proteins.展开更多
目的:研究乙型肝炎病毒x基因(hepatitis B virus x gene,HBx)蛋白调节细胞内钙离子可能分子机制,揭示乙型肝炎病毒(hepatitis B virus,HBV)诱导肝癌的可能途径.方法:培养HEK293细胞,取第2代HEK293细胞转染pcDNA-HBx质粒,培养12、24和48 ...目的:研究乙型肝炎病毒x基因(hepatitis B virus x gene,HBx)蛋白调节细胞内钙离子可能分子机制,揭示乙型肝炎病毒(hepatitis B virus,HBV)诱导肝癌的可能途径.方法:培养HEK293细胞,取第2代HEK293细胞转染pcDNA-HBx质粒,培养12、24和48 h后,细胞活力细胞毒性检测(cell counting kit-8,CCK-8)观察转染后细胞生长情况,Western b l o t检测H B x蛋白的表达情况,当共同转染HBx基因、Orai1基因或STIM1基因后co-IP实验、免疫荧光检测观察细胞内蛋白结合情况.结果:转染pcDNA-HBx质粒后HBx蛋白可以在HEK293细胞高表达,转染后的24 h后细胞增殖加快(P<0.05),co-IP实验及免疫荧光检测结果均显示,HBx蛋白在细胞内可以与Orai1蛋白结合.结论:HBx蛋白通过与细胞膜钙离子通道Orai1结合,来升高细胞内钙离子浓度,从而影响细胞增殖等活性.展开更多
基金grants from the Tianjin Health Technology Project(Grant no.2022QN106).
文摘Background:The ORAI1 gene,central to store-operated calcium entry(SOCE),is increasingly recognized for its pivotal role in cancer progression and patient prognosis across a broad spectrum of malignancies.Despite its critical involvement in calcium signaling pathways that are essential for cellular functions such as proliferation,migration,and apoptosis,the comprehensive impacts of ORAI1 within the tumor microenvironment(TME)and its modulation across various cancers have not been fully elucidated.Methods:We conducted a pan-cancer analysis leveraging data from The Cancer Genome Atlas(TCGA)and Genotype-Tissue Expression(GTEx)to assess ORAI1 expression.Differential expression analyses were performed,complemented by correlative studies with tumor mutation burden(TMB),microsatellite instability(MSI),immune infiltration,and key biological processes and pathways.Results:Our results demonstrate that ORAI1 is consistently upregulated in a range of cancer types,associated with aggressive tumor characteristics and poor patient outcomes.Significantly,ORAI1 upregulation correlates with increased tumor mutation burden(TMB)and microsatellite instability(MSI),markers of genomic instability that are predictive of response to immunotherapy,underscoring its potential utility in clinical stratification and treatment decision-making.ORAI1's influence extended to the immune landscape,showing associations with immune cell infiltration and both immunosuppressive and immunostimulatory gene sets,thereby affecting the TME and possibly the efficacy of immunotherapeutic interventions.Conclusions:The multifaceted nature of ORAI1's involvement in cancer pathophysiology positions it as a prospective biomarker and therapeutic target.Its expression dynamics and correlative significance with prognostic and immune regulatory elements underscore its potential in guiding therapeutic strategies and improving clinical outcomes.This study lays a foundation for future research,aiming to leverage ORAI1's biological significance in cancer prognosis and therapy optimization.
基金supported by grants from the Tianjin Health Technology Project(Grant no.2022QN106).
文摘Background:The ORAI family of proteins,comprising ORAI1,ORAI2,and ORAI3,plays a crucial role in the regulation of intracellular calcium signaling,which is essential for various cellular functions including proliferation,differentiation,and apoptosis.Dysregulation of calcium signaling has been implicated in cancer pathogenesis,influencing tumor progression,metastasis,and resistance to therapy.This study aims to provide a comprehensive analysis of the ORAI family members across a broad spectrum of cancers.Methods:Publicly available datasets from The Cancer Genome Atlas and the Gene Expression Omnibus were utilized.RNA sequencing data,mutation profiles,copy number variation data,and methylation data across different cancer types were analyzed.Differential expression analysis,survival analysis,copy number variation analysis,mutation analysis,methylation analysis,immune cell infiltration analysis using the Cibersort algorithm,and gene set enrichment analysis were conducted using R software.Results:ORAI1 and ORAI3 were significantly upregulated in glioblastoma multiforme,whereas ORAI2 was notably downregulated in kidney chromophobe and pancreatic adenocarcinoma.ORAI2 exhibited higher mutation rates and copy number gains in multiple cancers compared to ORAI1 and ORAI3.The hypermethylation of ORAI2 in head and neck squamous cell carcinoma,esophageal carcinoma,and glioblastoma multiforme negatively correlated with its gene expression.ORAI1 and ORAI3 expression positively correlated with regulatory T cells infiltration,whereas ORAI2 showed a negative correlation with CD8^(+)T cell infiltration.Gene set enrichment analysis revealed that ORAI1 and ORAI2 are associated with immune-related pathways,while ORAI3 is linked to MYC targets and oxidative phosphorylation.Conclusion:Our pan-cancer analysis reveals significant differential expression,genomic alterations,and epigenetic regulation of ORAI family members across various cancers.ORAI1 and ORAI3 appear to promote an immunosuppressive environment,whereas ORAI2 may function as a tumor suppressor in certain contexts.These findings provide a foundation for future research targeting ORAI-mediated pathways in cancer therapy and highlight the therapeutic potential of ORAI proteins.
基金grants from Knowlodge Innovation Projectof The Chinese Academy of Sciences(KSCX2-SW- 224, Y2004018)National Basic Research Program of China(2004CB720000)~~
文摘目的:研究乙型肝炎病毒x基因(hepatitis B virus x gene,HBx)蛋白调节细胞内钙离子可能分子机制,揭示乙型肝炎病毒(hepatitis B virus,HBV)诱导肝癌的可能途径.方法:培养HEK293细胞,取第2代HEK293细胞转染pcDNA-HBx质粒,培养12、24和48 h后,细胞活力细胞毒性检测(cell counting kit-8,CCK-8)观察转染后细胞生长情况,Western b l o t检测H B x蛋白的表达情况,当共同转染HBx基因、Orai1基因或STIM1基因后co-IP实验、免疫荧光检测观察细胞内蛋白结合情况.结果:转染pcDNA-HBx质粒后HBx蛋白可以在HEK293细胞高表达,转染后的24 h后细胞增殖加快(P<0.05),co-IP实验及免疫荧光检测结果均显示,HBx蛋白在细胞内可以与Orai1蛋白结合.结论:HBx蛋白通过与细胞膜钙离子通道Orai1结合,来升高细胞内钙离子浓度,从而影响细胞增殖等活性.
