BACKGROUND Trastuzumab-targeted therapy is currently the standard of care for advanced human epidermal growth factor receptor 2(HER2)-positive gastric cancer.However,the emergence of resistance to trastuzumab poses si...BACKGROUND Trastuzumab-targeted therapy is currently the standard of care for advanced human epidermal growth factor receptor 2(HER2)-positive gastric cancer.However,the emergence of resistance to trastuzumab poses significant challenges.AIM To identify the key genes associated with trastuzumab resistance.These results provide a basis for the development of interventions to address drug resistance and improve patient outcomes.METHODS High-throughput sequencing and bioinformatics were used to identify the differentially expressed pivotal gene BIRC3 and delineate its potential function and pathway regulation.Tumor samples were collected from patients with HER2-positive gastric cancer to evaluate the correlation between BIRC3 expression and trastuzumab resistance.We established gastric cancer cell lines with both highly expressed and suppressed levels of BIRC3,followed by comprehensive in vitro and in vivo experiments to confirm the involvement of BIRC3 in trastuzumab resistance and to elucidate its underlying mechanisms.RESULTS In patients with HER2-positive gastric cancer,there is a significant correlation between elevated BIRC3 expression in tumor tissues and higher T stage,tumor node metastasis stage,as well as poor overall survival and progressionfree survival.BIRC3 is highly expressed in trastuzumab-resistant gastric cancer cell lines,where it inhibits tumor cell apoptosis and enhances trastuzumab resistance by promoting the phosphorylation and activation of the phosphoinositide 3-kinase-Akt(PI3K-AKT)pathway in HER2-positive gastric cancer cells,both in vivo and in vitro.CONCLUSION This study revealed a robust association between high BIRC3 expression and an unfavorable prognosis in patients with HER2-positive gastric cancer.Thus,the high expression of BIRC3 stimulated PI3K-AKT phosphorylation and activation,stimulating the proliferation of HER2-positive tumor cells and suppressing apoptosis,ultimately leading to trastuzumab resistance.展开更多
目的探讨含杆状病毒凋亡抑制蛋白重复序列蛋白5(baculoviral inhibitor of apoptosis protein repeat-containing protein 5,BIRC5)基因在胃癌(Gastric cancer,GC)中的表达和临床价值。方法采用GEPIA、BioGPS、Kaplan-Meier Plotter数...目的探讨含杆状病毒凋亡抑制蛋白重复序列蛋白5(baculoviral inhibitor of apoptosis protein repeat-containing protein 5,BIRC5)基因在胃癌(Gastric cancer,GC)中的表达和临床价值。方法采用GEPIA、BioGPS、Kaplan-Meier Plotter数据库分析胃癌组织与癌旁组织之间BIRC5基因表达差异,预测BIRC5的表达水平与胃癌患者生存及预后的关系;基于Coexpedia数据库构建BIRC5在胃癌中的共表达基因网络,使用String数据库取得与BIRC5相关蛋白质网络图和基因本体(GO)功能注释,分析京都基因和基因组百科全书(KEGG)相关通路。采用肿瘤免疫评估资源(TIMER)数据库,预测BIRC5在免疫浸润细胞中的表达。结果GEPIA、BioGPS、TIMER分析表明:与癌旁组织相比,BIRC5在胃癌组织中的表达较高(P<0.05)。Kaplan-Meier生存分析表明,BIRC5基因表达较低的胃癌患者总生存期(HR=1.28,P<0.05)及进展后生存期(HR=1.28,P<0.05)均延长。BIRC5的共表达基因主要有UBE2C、TPX2、BUB1B、PRC1、CCNB2、KIF2C、SPAG5、CKS1B、CCNB1、CDK1、CENPA、NUSAP1、ANLN、NEK2、PARP1、MAD2L1、CDC20、TCP1。通过String数据库收集BIRC5相关蛋白,参与7种信号传导通路,主要富集于86种生物学过程、5种分子功能和34种细胞学组分。TIMER数据库分析表明,在免疫微环境中,BIRC5mRNA水平较低的巨噬细胞和树突状细胞的胃癌患者生存较好。结论BIRC5基因在胃癌组织中高表达,BIRC5可能降低肿瘤免疫抑制,可作为评价胃癌患者预后的标志物。展开更多
Background:Fuzheng Huayu capsule(FZHY)combined with antiviral treatment has been shown to significantly reduce the risk of liver cancer in patients with hepatitis B cirrhosis.However,the potential of FZHY to directly ...Background:Fuzheng Huayu capsule(FZHY)combined with antiviral treatment has been shown to significantly reduce the risk of liver cancer in patients with hepatitis B cirrhosis.However,the potential of FZHY to directly treat liver cancer remains largely unknown.This study aims to investigate the molecular mechanism underlying the potential of FZHY in treating liver cancer.Methods:A network pharmacological analysis was performed using the Traditional Chinese Medicine Systems Pharmacology database to identify FZHY compounds and targets.Disease targets were searched using the Genecards database,and transcriptome data was downloaded from the NCBI database.Gene Ontology analysis was conducted using the DAVID database,and Kyoto Encyclopedia of Genes and Genomes analysis was based on KOBAS and bioinformatics methods.The Swissdock database was used for molecular docking.In cell experiments,the half inhibitory concentration(IC50)of FZHY was determined using the CCK8 method.The effects of FZHY on cell viability,apoptosis,and mitochondrial membrane potential were evaluated using a fluorescence microscope and flow cytometry.The molecular mechanism of FZHY in treating liver cancer was verified using quantitative polymerase chain reaction.Results:A total of 127 compounds and 184 proteins were identified as potential active ingredients and putative liver cancer-related targets.Additionally,1,899 liver cancer targets,279 transcriptome targets,and 3 pathways(p53 signaling pathway,apoptosis and PI3K-Akt pathway)were collected.The FZHY-targets-liver cancer interaction network was constructed.IC50 of FZHY lyophilized powder solution to liver cancer was 5.13 mg/mL(IC50=5.13 mg/mL).FZHY treatment led to an increase in the ratio of cell apoptosis and induced mitochondrial membrane potential damage,resulting in an increase in the number of dead cells.The expression levels of CCNB1 and BIRC5 were induced with FZHY treatment,while the expression levels of AKR1C3 and IGF2 were reduced.Conclusion:FZHY promotes apoptosis of liver cancer cells by acting on the p53 signaling pathway,apoptosis,and PI3K-Akt pathway.CCNB1,BIRC5,AKR1C3,and IGF2 are potential target proteins for FZHY in treating liver cancer.展开更多
文摘BACKGROUND Trastuzumab-targeted therapy is currently the standard of care for advanced human epidermal growth factor receptor 2(HER2)-positive gastric cancer.However,the emergence of resistance to trastuzumab poses significant challenges.AIM To identify the key genes associated with trastuzumab resistance.These results provide a basis for the development of interventions to address drug resistance and improve patient outcomes.METHODS High-throughput sequencing and bioinformatics were used to identify the differentially expressed pivotal gene BIRC3 and delineate its potential function and pathway regulation.Tumor samples were collected from patients with HER2-positive gastric cancer to evaluate the correlation between BIRC3 expression and trastuzumab resistance.We established gastric cancer cell lines with both highly expressed and suppressed levels of BIRC3,followed by comprehensive in vitro and in vivo experiments to confirm the involvement of BIRC3 in trastuzumab resistance and to elucidate its underlying mechanisms.RESULTS In patients with HER2-positive gastric cancer,there is a significant correlation between elevated BIRC3 expression in tumor tissues and higher T stage,tumor node metastasis stage,as well as poor overall survival and progressionfree survival.BIRC3 is highly expressed in trastuzumab-resistant gastric cancer cell lines,where it inhibits tumor cell apoptosis and enhances trastuzumab resistance by promoting the phosphorylation and activation of the phosphoinositide 3-kinase-Akt(PI3K-AKT)pathway in HER2-positive gastric cancer cells,both in vivo and in vitro.CONCLUSION This study revealed a robust association between high BIRC3 expression and an unfavorable prognosis in patients with HER2-positive gastric cancer.Thus,the high expression of BIRC3 stimulated PI3K-AKT phosphorylation and activation,stimulating the proliferation of HER2-positive tumor cells and suppressing apoptosis,ultimately leading to trastuzumab resistance.
文摘目的探讨含杆状病毒凋亡抑制蛋白重复序列蛋白5(baculoviral inhibitor of apoptosis protein repeat-containing protein 5,BIRC5)基因在胃癌(Gastric cancer,GC)中的表达和临床价值。方法采用GEPIA、BioGPS、Kaplan-Meier Plotter数据库分析胃癌组织与癌旁组织之间BIRC5基因表达差异,预测BIRC5的表达水平与胃癌患者生存及预后的关系;基于Coexpedia数据库构建BIRC5在胃癌中的共表达基因网络,使用String数据库取得与BIRC5相关蛋白质网络图和基因本体(GO)功能注释,分析京都基因和基因组百科全书(KEGG)相关通路。采用肿瘤免疫评估资源(TIMER)数据库,预测BIRC5在免疫浸润细胞中的表达。结果GEPIA、BioGPS、TIMER分析表明:与癌旁组织相比,BIRC5在胃癌组织中的表达较高(P<0.05)。Kaplan-Meier生存分析表明,BIRC5基因表达较低的胃癌患者总生存期(HR=1.28,P<0.05)及进展后生存期(HR=1.28,P<0.05)均延长。BIRC5的共表达基因主要有UBE2C、TPX2、BUB1B、PRC1、CCNB2、KIF2C、SPAG5、CKS1B、CCNB1、CDK1、CENPA、NUSAP1、ANLN、NEK2、PARP1、MAD2L1、CDC20、TCP1。通过String数据库收集BIRC5相关蛋白,参与7种信号传导通路,主要富集于86种生物学过程、5种分子功能和34种细胞学组分。TIMER数据库分析表明,在免疫微环境中,BIRC5mRNA水平较低的巨噬细胞和树突状细胞的胃癌患者生存较好。结论BIRC5基因在胃癌组织中高表达,BIRC5可能降低肿瘤免疫抑制,可作为评价胃癌患者预后的标志物。
文摘Background:Fuzheng Huayu capsule(FZHY)combined with antiviral treatment has been shown to significantly reduce the risk of liver cancer in patients with hepatitis B cirrhosis.However,the potential of FZHY to directly treat liver cancer remains largely unknown.This study aims to investigate the molecular mechanism underlying the potential of FZHY in treating liver cancer.Methods:A network pharmacological analysis was performed using the Traditional Chinese Medicine Systems Pharmacology database to identify FZHY compounds and targets.Disease targets were searched using the Genecards database,and transcriptome data was downloaded from the NCBI database.Gene Ontology analysis was conducted using the DAVID database,and Kyoto Encyclopedia of Genes and Genomes analysis was based on KOBAS and bioinformatics methods.The Swissdock database was used for molecular docking.In cell experiments,the half inhibitory concentration(IC50)of FZHY was determined using the CCK8 method.The effects of FZHY on cell viability,apoptosis,and mitochondrial membrane potential were evaluated using a fluorescence microscope and flow cytometry.The molecular mechanism of FZHY in treating liver cancer was verified using quantitative polymerase chain reaction.Results:A total of 127 compounds and 184 proteins were identified as potential active ingredients and putative liver cancer-related targets.Additionally,1,899 liver cancer targets,279 transcriptome targets,and 3 pathways(p53 signaling pathway,apoptosis and PI3K-Akt pathway)were collected.The FZHY-targets-liver cancer interaction network was constructed.IC50 of FZHY lyophilized powder solution to liver cancer was 5.13 mg/mL(IC50=5.13 mg/mL).FZHY treatment led to an increase in the ratio of cell apoptosis and induced mitochondrial membrane potential damage,resulting in an increase in the number of dead cells.The expression levels of CCNB1 and BIRC5 were induced with FZHY treatment,while the expression levels of AKR1C3 and IGF2 were reduced.Conclusion:FZHY promotes apoptosis of liver cancer cells by acting on the p53 signaling pathway,apoptosis,and PI3K-Akt pathway.CCNB1,BIRC5,AKR1C3,and IGF2 are potential target proteins for FZHY in treating liver cancer.
