Metabolic dysfunction-associated steatotic liver disease(MASLD)is a metabolic disease that can progress to metabolic dysfunction-associated steatohepatitis(MASH),cirrhosis,and cancer.The zonal distribution of biomolec...Metabolic dysfunction-associated steatotic liver disease(MASLD)is a metabolic disease that can progress to metabolic dysfunction-associated steatohepatitis(MASH),cirrhosis,and cancer.The zonal distribution of biomolecules in the liver is implicated in mediat-ing the disease progression.Recently,G-protein-coupled receptor 35(GPR35)has been highlighted to play a role in MASLD,but the precise mechanism is not fully understood,particularly,in a liver-zonal manner.Here,we aimed to identify spatially distributed specific genes and metabolites in different liver zonation that are regulated by GPR35 in MASLD,by combining lipid metabolomics,spatial transcriptomics(ST),and spatial metabolomics(SM).We found that GPR35 influenced lipid accumulation,inflammatory and metabolism-related factors in specific regions,notably affecting the anti-inflammation factor ELF4(E74 like E-twenty six(ETS)tran-scription factor 4),lipid homeostasis key factor CIDEA(cell death-inducing DNA fragmentation factor alpha(DFFA)-like effector A),and the injury response-related genes SAA1/2/3(serum amyloid A1/2/3),thereby impacting MASLD progression.Furthermore,SM elucidated specific metabolite distributions across different liver regions,such as C10H11N4O7P(3ʹ,5ʹ-cyclic inosine monophosphate(3ʹ,5ʹ-IMP))for the central vein,and this metabolite significantly decreased in the liver zones of GPR35-deficient mice during MASLD progression.Taken together,GPR35 regulates hepatocyte damage repair,controls inflammation,and prevents MASLD progression by influencing phospholipid homeostasis and gene expression in a zonal manner.展开更多
Background:Y-box binding protein 1(YB1 or YBX1)plays a critical role in tumorigenesis and cancer progression.However,whether YB1 affects malignant transformation by modulating non-codingRNAs remains largely unknown.Th...Background:Y-box binding protein 1(YB1 or YBX1)plays a critical role in tumorigenesis and cancer progression.However,whether YB1 affects malignant transformation by modulating non-codingRNAs remains largely unknown.This study aimed to investigate the relationship between YB1 and microRNAs and reveal the underlying mechanism by which YB1 impacts on tumor malignancy via miRNAs-mediated regulatory network.Methods:The biological functions of YB1 in hepatocellular carcinoma(HCC)cells were investigated by cell proliferation,wound healing,and transwell invasion assays.The miRNAs dysregulated by YB1 were screened by microarray analysis in HCC cell lines.The regulation of YB1 on miR-205 and miR-200b was determined by quantitative real-time PCR,dual-luciferase reporter assay,RNA immunoprecipitation,and pull-down assay.The relationships of YB1,DGCR8,Dicer,TUT4,and TUT1 were identified by pull-down and coimmunoprecipitation experiments.The cellular co-localization of YB1,DGCR8,and Dicer were detected by immunofluorescent staining.The in vivo effect of YB1 on tumor metastasis was determined by injecting MHCC97H cells transduced with YB1 shRNA or shControl via the tail vein in nude BALB/c mice.The expression levels of epithelial tomesenchymal transition markerswere detected by immunoblotting and immunohistochemistry assays.Results:YB1 promoted HCC cell migration and tumor metastasis by regulating miR-205/200b‒ZEB1 axis partially in a Snail-independent manner.YB1 suppressedmiR-205 and miR-200b maturation by interacting with the microprocessors DGCR8 and Dicer as well as TUT4 and TUT1 via the conserved cold shock domain.Subsequently,the downregulation of miR-205 and miR-200b enhanced ZEB1 expression,thus leading to increased cell migration and invasion.Furthermore,statistical analyses on gene expression data from HCC and normal liver tissues showed that YB1 expression was positively associated with ZEB1 expression and remarkably correlated with clinical prognosis.Conclusion:This study reveals a previously undescribed mechanism by which YB1 promotes cancer progression by regulating the miR-205/200b‒ZEB1 axis in HCC cells.Furthermore,these results highlight that YB1 may play biological functions via miRNAs-mediated gene regulation,and it can serve as a potential therapeutic target in human cancers.展开更多
Protein-metabolite interactions(PMIs)play important roles in various biological processes,especially in disease progression.However,due to the complexity of living cells,it is very difficult to identify specific PMIs....Protein-metabolite interactions(PMIs)play important roles in various biological processes,especially in disease progression.However,due to the complexity of living cells,it is very difficult to identify specific PMIs.Herein,we chose one oncogenic factor,metadherin(MTDH),as a bait to identify its in vivo interacting metabolites in cancer cells.Cholesterol is an important metabolite and essential structural component of cell membranes.It could also drive several diseases including cancer.Interestingly,we found that cholesterol robustly interacted with MTDH and downregulated the expression of MTDH in cancer cells.Furthermore,MTDH disturbed metabolite alterations under cholesterol treatment in MTDH transduced cancer cells.Collectively,our results uncover an undescribed PMI where MTDH,as an oncogenic factor,might positively regulate cancer progression by interacting with choleste rol.This study interprets the theoretical basis of PMI-oriented cancer progression and targeting therapies in clinic.展开更多
Pyruvate is an essential fuel for maintaining the tricarboxylic acid(TCA)cycle in the mitochondria.However,the precise mole-cular mechanism of pyruvate uptake by mitochondrial pyruvate carrier(MPC)is largely unknown.H...Pyruvate is an essential fuel for maintaining the tricarboxylic acid(TCA)cycle in the mitochondria.However,the precise mole-cular mechanism of pyruvate uptake by mitochondrial pyruvate carrier(MPC)is largely unknown.Here,we report that the DNA/RNA-binding protein Y-box binding protein 1(YBX1)is localized to the mitochondrial inter-membrane space by its C-terminal domain(CTD)in cancer cells.In mitochondria,YBX1 inhibits pyruvate uptake by associating with MPC1/2,thereby suppressing pyruvate-dependent TCA cycle flux.This association,in turn,promotes MPC-mediated glutaminolysis and histone lactylation.Our findings reveal that the YBX1-MPC axis exhibits a positive correlation with metastatic potential,while does not affect cell proliferation in both cultured cells and tumor xenografts.Therefore,the restricted pyruvate uptake into mitochondria potentially represents a hallmark of metastatic capacity,suggesting that the YBX1-MPC axis is a therapeutic target for combating cancer metastasis.展开更多
基金supported by the National Key Research and Development Program of China(2022YFA0806503)the National Natural Science Foundation of China(81972625 and 32201217)+3 种基金Liaoning Revitalization Talents Program(XLYC2002035)Liaoning Science and Technology Innovation Funding(20230101-JH2/1013)the Innovation Program of Science and Research from Dalian Institute of Chemical Physics,Chinese Academy of Sciences(DICP I202129 and DICP I202209)the Science and Technology Innovation Fund(Youth Science and Technology Star)of Dalian(2021RQ009 and 2023RQ040).
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD)is a metabolic disease that can progress to metabolic dysfunction-associated steatohepatitis(MASH),cirrhosis,and cancer.The zonal distribution of biomolecules in the liver is implicated in mediat-ing the disease progression.Recently,G-protein-coupled receptor 35(GPR35)has been highlighted to play a role in MASLD,but the precise mechanism is not fully understood,particularly,in a liver-zonal manner.Here,we aimed to identify spatially distributed specific genes and metabolites in different liver zonation that are regulated by GPR35 in MASLD,by combining lipid metabolomics,spatial transcriptomics(ST),and spatial metabolomics(SM).We found that GPR35 influenced lipid accumulation,inflammatory and metabolism-related factors in specific regions,notably affecting the anti-inflammation factor ELF4(E74 like E-twenty six(ETS)tran-scription factor 4),lipid homeostasis key factor CIDEA(cell death-inducing DNA fragmentation factor alpha(DFFA)-like effector A),and the injury response-related genes SAA1/2/3(serum amyloid A1/2/3),thereby impacting MASLD progression.Furthermore,SM elucidated specific metabolite distributions across different liver regions,such as C10H11N4O7P(3ʹ,5ʹ-cyclic inosine monophosphate(3ʹ,5ʹ-IMP))for the central vein,and this metabolite significantly decreased in the liver zones of GPR35-deficient mice during MASLD progression.Taken together,GPR35 regulates hepatocyte damage repair,controls inflammation,and prevents MASLD progression by influencing phospholipid homeostasis and gene expression in a zonal manner.
基金NationalNatural Science Foundation of China,Grant/Award Numbers:81672440,31701156,81972625DICP,Grant/Award Number:ZZBS201803The Construction of Liaoning CancerResearch Center,Grant/Award Number:1564992449013。
文摘Background:Y-box binding protein 1(YB1 or YBX1)plays a critical role in tumorigenesis and cancer progression.However,whether YB1 affects malignant transformation by modulating non-codingRNAs remains largely unknown.This study aimed to investigate the relationship between YB1 and microRNAs and reveal the underlying mechanism by which YB1 impacts on tumor malignancy via miRNAs-mediated regulatory network.Methods:The biological functions of YB1 in hepatocellular carcinoma(HCC)cells were investigated by cell proliferation,wound healing,and transwell invasion assays.The miRNAs dysregulated by YB1 were screened by microarray analysis in HCC cell lines.The regulation of YB1 on miR-205 and miR-200b was determined by quantitative real-time PCR,dual-luciferase reporter assay,RNA immunoprecipitation,and pull-down assay.The relationships of YB1,DGCR8,Dicer,TUT4,and TUT1 were identified by pull-down and coimmunoprecipitation experiments.The cellular co-localization of YB1,DGCR8,and Dicer were detected by immunofluorescent staining.The in vivo effect of YB1 on tumor metastasis was determined by injecting MHCC97H cells transduced with YB1 shRNA or shControl via the tail vein in nude BALB/c mice.The expression levels of epithelial tomesenchymal transition markerswere detected by immunoblotting and immunohistochemistry assays.Results:YB1 promoted HCC cell migration and tumor metastasis by regulating miR-205/200b‒ZEB1 axis partially in a Snail-independent manner.YB1 suppressedmiR-205 and miR-200b maturation by interacting with the microprocessors DGCR8 and Dicer as well as TUT4 and TUT1 via the conserved cold shock domain.Subsequently,the downregulation of miR-205 and miR-200b enhanced ZEB1 expression,thus leading to increased cell migration and invasion.Furthermore,statistical analyses on gene expression data from HCC and normal liver tissues showed that YB1 expression was positively associated with ZEB1 expression and remarkably correlated with clinical prognosis.Conclusion:This study reveals a previously undescribed mechanism by which YB1 promotes cancer progression by regulating the miR-205/200b‒ZEB1 axis in HCC cells.Furthermore,these results highlight that YB1 may play biological functions via miRNAs-mediated gene regulation,and it can serve as a potential therapeutic target in human cancers.
基金the National Natural Science Foundation of China(Nos.81672440,21575142)Innovation Program of Science and Research from the DICP,CAS(No.DICP ZZBS201803)。
文摘Protein-metabolite interactions(PMIs)play important roles in various biological processes,especially in disease progression.However,due to the complexity of living cells,it is very difficult to identify specific PMIs.Herein,we chose one oncogenic factor,metadherin(MTDH),as a bait to identify its in vivo interacting metabolites in cancer cells.Cholesterol is an important metabolite and essential structural component of cell membranes.It could also drive several diseases including cancer.Interestingly,we found that cholesterol robustly interacted with MTDH and downregulated the expression of MTDH in cancer cells.Furthermore,MTDH disturbed metabolite alterations under cholesterol treatment in MTDH transduced cancer cells.Collectively,our results uncover an undescribed PMI where MTDH,as an oncogenic factor,might positively regulate cancer progression by interacting with choleste rol.This study interprets the theoretical basis of PMI-oriented cancer progression and targeting therapies in clinic.
基金This study was supported by the National Key Research and Development Program of China(2022YFA0806503)grants from the National Natural Science Foundation of China(No.81972625,No.21907093)+1 种基金Dalian Science and Technology Innovation Funding(2019J12SN52)Liaoning Revitalization Talents Program(XLYC2002035).
文摘Pyruvate is an essential fuel for maintaining the tricarboxylic acid(TCA)cycle in the mitochondria.However,the precise mole-cular mechanism of pyruvate uptake by mitochondrial pyruvate carrier(MPC)is largely unknown.Here,we report that the DNA/RNA-binding protein Y-box binding protein 1(YBX1)is localized to the mitochondrial inter-membrane space by its C-terminal domain(CTD)in cancer cells.In mitochondria,YBX1 inhibits pyruvate uptake by associating with MPC1/2,thereby suppressing pyruvate-dependent TCA cycle flux.This association,in turn,promotes MPC-mediated glutaminolysis and histone lactylation.Our findings reveal that the YBX1-MPC axis exhibits a positive correlation with metastatic potential,while does not affect cell proliferation in both cultured cells and tumor xenografts.Therefore,the restricted pyruvate uptake into mitochondria potentially represents a hallmark of metastatic capacity,suggesting that the YBX1-MPC axis is a therapeutic target for combating cancer metastasis.
