BACKGROUND Gastric cancer(GC)is a common malignancy of the digestive system.According to global 2018 cancer data,GC has the fifth-highest incidence and the thirdhighest fatality rate among malignant tumors.More than 6...BACKGROUND Gastric cancer(GC)is a common malignancy of the digestive system.According to global 2018 cancer data,GC has the fifth-highest incidence and the thirdhighest fatality rate among malignant tumors.More than 60%of GC are linked to infection with Helicobacter pylori(H.pylori),a gram-negative,active,microaerophilic,and helical bacterium.This parasite induces GC by producing toxic factors,such as cytotoxin-related gene A,vacuolar cytotoxin A,and outer membrane proteins.Ferroptosis,or iron-dependent programmed cell death,has been linked to GC,although there has been little research on the link between H.pylori infection-related GC and ferroptosis.AIM To identify coregulated differentially expressed genes among ferroptosis-related genes(FRGs)in GC patients and develop a ferroptosis-related prognostic model with discrimination ability.METHODS Gene expression profiles of GC patients and those with H.pylori-associated GC were obtained from The Cancer Genome Atlas and Gene Expression Omnibus(GEO)databases.The FRGs were acquired from the FerrDb database.A ferroptosis-related gene prognostic index(FRGPI)was created using least absolute shrinkage and selection operator–Cox regression.The predictive ability of the FRGPI was validated in the GEO cohort.Finally,we verified the expression of the hub genes and the activity of the ferroptosis inducer FIN56 in GC cell lines and tissues.RESULTS Four hub genes were identified(NOX4,MTCH1,GABARAPL2,and SLC2A3)and shown to accurately predict GC and H.pylori-associated GC.The FRGPI based on the hub genes could independently predict GC patient survival;GC patients in the high-risk group had considerably worse overall survival than did those in the low-risk group.The FRGPI was a significant predictor of GC prognosis and was strongly correlated with disease progression.Moreover,the gene expression levels of common immune checkpoint proteins dramatically increased in the highrisk subgroup of the FRGPI cohort.The hub genes were also confirmed to be highly overexpressed in GC cell lines and tissues and were found to be primarily localized at the cell membrane.The ferroptosis inducer FIN56 inhibited GC cell proliferation in a dose-dependent manner.CONCLUSION In this study,we developed a predictive model based on four FRGs that can accurately predict the prognosis of GC patients and the efficacy of immunotherapy in this population.展开更多
Ferroptosis is a pattern of iron-mediated regulatory cell death characterized by oxidative damage.The molecular regulatory mechanisms are related to iron metabolism,lipid peroxidation,and glutathione metabolism.Additi...Ferroptosis is a pattern of iron-mediated regulatory cell death characterized by oxidative damage.The molecular regulatory mechanisms are related to iron metabolism,lipid peroxidation,and glutathione metabolism.Additionally,some immunological signaling pathways,such as the cyclic GMP-AMP synthase-stimulator of the interferon gene axis,the Janus kinase-signal transducer and activator of transcription 1 axis,and the transforming growth factor beta 1-Smad3 axis,may also participate in the regulation of ferroptosis.Studies have shown that ferroptosis is significantly associated with many diseases such as cancer,neurodegenerative diseases,inflammatory diseases,and autoimmune diseases.Considering the pivotal role of ferroptosis-regulating signaling in the pathogenesis of diverse diseases,the development of ferroptosis inducers or inhibitors may have significant clinical potential for the treatment of aforementioned conditions.展开更多
Background and Aims:The growing knowledge of ferroptosis has suggested the regulatory role of ferroptosis in hepatocellular carcinoma(HCC),but the pertinent molecular mechanisms remain unclear.Herein,this study invest...Background and Aims:The growing knowledge of ferroptosis has suggested the regulatory role of ferroptosis in hepatocellular carcinoma(HCC),but the pertinent molecular mechanisms remain unclear.Herein,this study investigated the mechanistic basis of ferroptosis-related genes(ferrGenes)in the growth of HCC.Methods:Differentially expressed human ferrGenes and tumor-related transcription factors(TFs)were obtained from the The Cancer Genome Atlas(TCGA)dataset and the GTEx dataset.Spearman method-based correlation analysis were conducted to construct TF-ferrGene coexpression regulatory network.Key genes associated with prognosis were singled out with Lasso regression and multivariate Cox analysis to construct the prognostic risk model.Then the accuracy and independent prognostic ability of the model were evaluated.Expression of CENPA and STMN1 was determined in clinical HCC tissues and HCC cells,and their binding was analyzed with dual-luciferase and chromatin immunoprecipitation(ChIP)assays.Furthermore,ectopic expression and knockdown assays were performed in HCC cells to assess the effect of CENPA and STMN1 on ferroptosis and malignant phenotypes.Results:The prognostic risk model constructed based on the eight TF-ferrGene regulatory network-related genes accurately predicted the prognosis of HCC patients.It was strongly related to the clinical characteristics of HCC patients.Moreover,CENPA/STMN1 might be a key TF-ferrGene regulatory network in ferroptosis of HCC.CENPA and STMN1 were overexpressed in HCC tissues and cells.Additionally,CENPA facilitated STMN1 transcription by binding to STMN1 promoter,thus facilitating the malignant phenotypes and suppressing the ferroptosis of HCC cells.Conclusions:Taken together,CENPA curbs the ferroptosis of HCC cells by upregulating STMN1 transcription,thereby promoting HCC growth.展开更多
文摘BACKGROUND Gastric cancer(GC)is a common malignancy of the digestive system.According to global 2018 cancer data,GC has the fifth-highest incidence and the thirdhighest fatality rate among malignant tumors.More than 60%of GC are linked to infection with Helicobacter pylori(H.pylori),a gram-negative,active,microaerophilic,and helical bacterium.This parasite induces GC by producing toxic factors,such as cytotoxin-related gene A,vacuolar cytotoxin A,and outer membrane proteins.Ferroptosis,or iron-dependent programmed cell death,has been linked to GC,although there has been little research on the link between H.pylori infection-related GC and ferroptosis.AIM To identify coregulated differentially expressed genes among ferroptosis-related genes(FRGs)in GC patients and develop a ferroptosis-related prognostic model with discrimination ability.METHODS Gene expression profiles of GC patients and those with H.pylori-associated GC were obtained from The Cancer Genome Atlas and Gene Expression Omnibus(GEO)databases.The FRGs were acquired from the FerrDb database.A ferroptosis-related gene prognostic index(FRGPI)was created using least absolute shrinkage and selection operator–Cox regression.The predictive ability of the FRGPI was validated in the GEO cohort.Finally,we verified the expression of the hub genes and the activity of the ferroptosis inducer FIN56 in GC cell lines and tissues.RESULTS Four hub genes were identified(NOX4,MTCH1,GABARAPL2,and SLC2A3)and shown to accurately predict GC and H.pylori-associated GC.The FRGPI based on the hub genes could independently predict GC patient survival;GC patients in the high-risk group had considerably worse overall survival than did those in the low-risk group.The FRGPI was a significant predictor of GC prognosis and was strongly correlated with disease progression.Moreover,the gene expression levels of common immune checkpoint proteins dramatically increased in the highrisk subgroup of the FRGPI cohort.The hub genes were also confirmed to be highly overexpressed in GC cell lines and tissues and were found to be primarily localized at the cell membrane.The ferroptosis inducer FIN56 inhibited GC cell proliferation in a dose-dependent manner.CONCLUSION In this study,we developed a predictive model based on four FRGs that can accurately predict the prognosis of GC patients and the efficacy of immunotherapy in this population.
基金supported by the National Key Research and Development Program of China(Grant No.2022YFA1303900 to S.Y.)the National Natural Science Foundation of China(Grant Nos.32270921 and 82070567 to S.Y.,and 82204354 to Y.H.)+4 种基金the Open Project of State Key Laboratory of Reproductive Medicine of Nanjing Medical University(Grant No.SKLRM-2021B3 to S.Y.)'the Talent Cultivation Project of"Organized Scientific Research"of Nanjing Medical University(Grant No.NJMURC20220014 to S.Y.)the Natural Science Foundation of Jiangsu Province(Grant No.BK20221352 to B.W.)the Jiangsu Provincial Outstanding Postdoctoral Program(Grant No.2022ZB419 to Y.H.)the Postdoctoral Research Funding Project of Gusu School(Grant No.GSBSHKY202104 to Y.H.)the China Postdoctoral Science Foundation(Grant No.2023T160329 to Y.H.).
文摘Ferroptosis is a pattern of iron-mediated regulatory cell death characterized by oxidative damage.The molecular regulatory mechanisms are related to iron metabolism,lipid peroxidation,and glutathione metabolism.Additionally,some immunological signaling pathways,such as the cyclic GMP-AMP synthase-stimulator of the interferon gene axis,the Janus kinase-signal transducer and activator of transcription 1 axis,and the transforming growth factor beta 1-Smad3 axis,may also participate in the regulation of ferroptosis.Studies have shown that ferroptosis is significantly associated with many diseases such as cancer,neurodegenerative diseases,inflammatory diseases,and autoimmune diseases.Considering the pivotal role of ferroptosis-regulating signaling in the pathogenesis of diverse diseases,the development of ferroptosis inducers or inhibitors may have significant clinical potential for the treatment of aforementioned conditions.
基金supported by Hunan Provincial Natural Science Foundation(2019JJ50321)Hunan Provincial Graduate Scientific Research Innovation Project(QL20220133).
文摘Background and Aims:The growing knowledge of ferroptosis has suggested the regulatory role of ferroptosis in hepatocellular carcinoma(HCC),but the pertinent molecular mechanisms remain unclear.Herein,this study investigated the mechanistic basis of ferroptosis-related genes(ferrGenes)in the growth of HCC.Methods:Differentially expressed human ferrGenes and tumor-related transcription factors(TFs)were obtained from the The Cancer Genome Atlas(TCGA)dataset and the GTEx dataset.Spearman method-based correlation analysis were conducted to construct TF-ferrGene coexpression regulatory network.Key genes associated with prognosis were singled out with Lasso regression and multivariate Cox analysis to construct the prognostic risk model.Then the accuracy and independent prognostic ability of the model were evaluated.Expression of CENPA and STMN1 was determined in clinical HCC tissues and HCC cells,and their binding was analyzed with dual-luciferase and chromatin immunoprecipitation(ChIP)assays.Furthermore,ectopic expression and knockdown assays were performed in HCC cells to assess the effect of CENPA and STMN1 on ferroptosis and malignant phenotypes.Results:The prognostic risk model constructed based on the eight TF-ferrGene regulatory network-related genes accurately predicted the prognosis of HCC patients.It was strongly related to the clinical characteristics of HCC patients.Moreover,CENPA/STMN1 might be a key TF-ferrGene regulatory network in ferroptosis of HCC.CENPA and STMN1 were overexpressed in HCC tissues and cells.Additionally,CENPA facilitated STMN1 transcription by binding to STMN1 promoter,thus facilitating the malignant phenotypes and suppressing the ferroptosis of HCC cells.Conclusions:Taken together,CENPA curbs the ferroptosis of HCC cells by upregulating STMN1 transcription,thereby promoting HCC growth.
