Objective:Epithelial cancers often originate from progenitor cells,while the origin of hepatocellular carcinoma(HCC)is still controversial.HCC,one of the deadliest cancers,is closely linked with liver injuries and chr...Objective:Epithelial cancers often originate from progenitor cells,while the origin of hepatocellular carcinoma(HCC)is still controversial.HCC,one of the deadliest cancers,is closely linked with liver injuries and chronic inflammation,which trigger massive infiltration of bone marrow-derived cells(BMDCs)during liver repair.Methods:To address the possible roles of BMDCs in HCC origination,we established a diethylnitrosamine(DEN)-induced HCC model in bone marrow transplanted mice.Immunohistochemistry and frozen tissue immunofluorescence were used to verify DENinduced HCC in the pathology of the disease.The cellular origin of DEN-induced HCC was further studied by single cell sequencing,single-cell nested PCR,and immunofluorescence-fluorescence in situ hybridization.Results:Studies by using single cell sequencing and biochemical analysis revealed that HCC cells in these mice were coming from donor mice BMDCs,and not from recipient mice.Furthermore,the copy numbers of mouse orthologs of several HCC-related genes previously reported in human HCC were also altered in our mouse model.DEN-induced HCCs exhibited a similar histological phenotype and genomic profile as human HCCs.Conclusions:These results suggested that BMDCs are an important origin of HCC,which provide important clues to HCC prevention,detection,and treatments.展开更多
Histone acetyltransferase 1 serves as a succinyl transferase in tumors Protein post-translational modification(PTM)as an important research field has attracted increasing attention.Recently,our group has reported that...Histone acetyltransferase 1 serves as a succinyl transferase in tumors Protein post-translational modification(PTM)as an important research field has attracted increasing attention.Recently,our group has reported that histone acetyltransferase 1(HAT1)succinylated histones and non-histones and promoted tumorigenesis1.HAT1 plays a role in different biological processes,including cell cycle progression,glucose metabolism,histone production,and DNA damage repair2.We found that HAT1 succinylated histone H3 on K122.For a non-histone,HAT1 catalyzed the succinylation of phosphoglycerate mutase 1(PGAM1)on K99 to increase its enzyme activity,promoting glycolysis in cancer cells.Functionally,HAT1-mediated succinylation contributed to tumorigenesis.Our finding provided new insight into the mechanism of how a histone acetyltransferase HAT1 modulated succinylation during cancer development.展开更多
Metabolic reprogramming plays a central role in tumors.However,the key drivers modulating reprogramming of gluconeogenesis/lipogenesis are poorly understood.Here,we try to identify the mechanism by which histone acety...Metabolic reprogramming plays a central role in tumors.However,the key drivers modulating reprogramming of gluconeogenesis/lipogenesis are poorly understood.Here,we try to identify the mechanism by which histone acetyltransferase 1(HAT1)confers reprogramming of gluconeogenesis/lipogenesis in liver cancer.Diethylnitrosamine(DEN)/carbon tetrachloride(CCl4)-induced hepatocarcinogenesis was hardly observed in HAT1-knockout mice.Multi-omics identified that HAT1 modulated gluconeogenesis and lipogenesis in liver.Protein phosphatase 2 scaffold subunit alpha(PPP2R1A)promoted gluconeogenesis and inhibited lipogenesis by phosphoenolpyruvate carboxykinase 1(PCK1)serine 90 dephosphorylation to suppress the tumor growth.HAT1 succinylated PPP2R1A at lysine 541(K541)to block the assembly of protein phosphatase 2A(PP2A)holoenzyme and interaction with PCK1,resulting in the depression of dephosphorylation of PCK1.HAT1-succinylated PPP2R1A contributed to the remodeling of gluconeogenesis/lipogenesis by PCK1 serine 90 phosphorylation,leading to the inhibition of gluconeogenic enzyme activity and activating sterol regulatory element-binding protein 1(SREBP1)nuclear accumulation-induced lipogenesis gene expression,which enhanced the tumor growth.In conclusion,succinylation of PPP2R1A lysine 541 by HAT1 converses the role in modulation of gluconeogenesis/lipogenesis remodeling through PCK1 S90 phosphorylation to support liver cancer.Our finding provides new insights into the mechanism by which post-translational modifications(PTMs)confer the conversion of tumor suppressor function to oncogene.展开更多
Soil nematodes regulate belowground ecological processes,yet their community composition and energy structure responses to Chinese herbal medicine planting are largely unknown.Here,four Euphorbiaceae plants—Phyllanth...Soil nematodes regulate belowground ecological processes,yet their community composition and energy structure responses to Chinese herbal medicine planting are largely unknown.Here,four Euphorbiaceae plants—Phyllanthus emblica,Excoecaria acerifolia,Baccaurea ramiflora,and Aporosa yunnanensis—were selected and cultivated in the Xishuangbanna Tropical Botanical Garden.After two years of cultivation,we assessed soil physicochemical properties,plant traits,microbial diversity,nematode diversity and community composition,and nematode energy flux.Our results revealed that the cultivation of these four medicinal plants significantly reduced soil nematode abundance and diversity and altered the community composition.Total nematode abundance was positively correlated with soil pH,aboveground biomass,and microbial richness,but negatively correlated with soil moisture,soil total phosphorus,and leaf thickness.Additionally,the energy flux within the soil nematode food web decreased by 40%−71%after the cultivation of medicinal plants,which was attributed to the reduction in nematode diversity and abundance.Our findings suggest that the cultivation of medicinal plants can influence soil resource availability and alter soil nematode communities,with diverse nematode species playing a key role in energy transfer within the belowground ecosystem.展开更多
Protein arginine methyltransferase 5(PRMT5)acts as an oncogene in liver cancer,yet its roles and in-depth molecular mechanisms within the liver cancer immune microenvironment remain mostly undefined.Here,we demonstrat...Protein arginine methyltransferase 5(PRMT5)acts as an oncogene in liver cancer,yet its roles and in-depth molecular mechanisms within the liver cancer immune microenvironment remain mostly undefined.Here,we demonstrated that disruption of tumor-intrinsic PRMT5 enhances CD8^(+)T-cell-mediated antitumor immunity both in vivo and in vitro.Further experiments verified that this effect is achieved through downregulation of the inhibitory immune checkpoint molecule,fibrinogen-like protein 1(FGL1).Mechanistically,PRMT5 catalyzed symmetric dimethylation of transcription factor 12(TCF12)at arginine 554(R554),prompting the binding of TCF12 to FGL1 promoter region,which transcriptionally activated FGL1 in tumor cells.Methylation deficiency at TCF12-R554 residue downregulated FGL1 expression,which promoted CD8^(+)T-cell-mediated antitumor immunity.Notably,combining the PRMT5 methyltransferase inhibitor GSK591 with PD-L1 blockade efficiently inhibited liver cancer growth and improved overall survival in mice.Collectively,our findings reveal the immunosuppressive role and mechanism of PRMT5 in liver cancer and highlight that targeting PRMT5 could boost checkpoint immunotherapy efficacy.展开更多
Al-driven genetic engineering,as a burgeoning diagnostic tool,can offer predictive information on the five-year survival rate(FYSR)in the setup of a prognostic therapeutic schedule.This approach provides the individua...Al-driven genetic engineering,as a burgeoning diagnostic tool,can offer predictive information on the five-year survival rate(FYSR)in the setup of a prognostic therapeutic schedule.This approach provides the individuality and accuracy of prognosis for FYSR of gastric cancer(GC).Unlike traditional neoplasm staging criteria,our technique ensures accuracy and individuality without relying on statistical data and empirical study.展开更多
基金supported by the grants from the National Natural Science Foundation of China(Grant No.81902401,81972656,31671421,81970107,81600083)the National 135 Major Project of China(Grant No.2018ZX10723204,2018ZX10302205)+3 种基金the Natural Science Foundation of Tianjin(Grant No.19JCQNJC09000)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2018PT32034)CAMS Innovation Fund for Medical Sciences(Grant No.2016-12M-1-003)supported by the China Scholarship Council(Grant No.201906940003)。
文摘Objective:Epithelial cancers often originate from progenitor cells,while the origin of hepatocellular carcinoma(HCC)is still controversial.HCC,one of the deadliest cancers,is closely linked with liver injuries and chronic inflammation,which trigger massive infiltration of bone marrow-derived cells(BMDCs)during liver repair.Methods:To address the possible roles of BMDCs in HCC origination,we established a diethylnitrosamine(DEN)-induced HCC model in bone marrow transplanted mice.Immunohistochemistry and frozen tissue immunofluorescence were used to verify DENinduced HCC in the pathology of the disease.The cellular origin of DEN-induced HCC was further studied by single cell sequencing,single-cell nested PCR,and immunofluorescence-fluorescence in situ hybridization.Results:Studies by using single cell sequencing and biochemical analysis revealed that HCC cells in these mice were coming from donor mice BMDCs,and not from recipient mice.Furthermore,the copy numbers of mouse orthologs of several HCC-related genes previously reported in human HCC were also altered in our mouse model.DEN-induced HCCs exhibited a similar histological phenotype and genomic profile as human HCCs.Conclusions:These results suggested that BMDCs are an important origin of HCC,which provide important clues to HCC prevention,detection,and treatments.
文摘Histone acetyltransferase 1 serves as a succinyl transferase in tumors Protein post-translational modification(PTM)as an important research field has attracted increasing attention.Recently,our group has reported that histone acetyltransferase 1(HAT1)succinylated histones and non-histones and promoted tumorigenesis1.HAT1 plays a role in different biological processes,including cell cycle progression,glucose metabolism,histone production,and DNA damage repair2.We found that HAT1 succinylated histone H3 on K122.For a non-histone,HAT1 catalyzed the succinylation of phosphoglycerate mutase 1(PGAM1)on K99 to increase its enzyme activity,promoting glycolysis in cancer cells.Functionally,HAT1-mediated succinylation contributed to tumorigenesis.Our finding provided new insight into the mechanism of how a histone acetyltransferase HAT1 modulated succinylation during cancer development.
基金supported by the National Natural Science Foundation of China(Nos.82103066,82372818,82303210,and 82302887)Tianjin Key Medical Discipline(Specialty)Construction Project(TJYXZDXK-009A,China).
文摘Metabolic reprogramming plays a central role in tumors.However,the key drivers modulating reprogramming of gluconeogenesis/lipogenesis are poorly understood.Here,we try to identify the mechanism by which histone acetyltransferase 1(HAT1)confers reprogramming of gluconeogenesis/lipogenesis in liver cancer.Diethylnitrosamine(DEN)/carbon tetrachloride(CCl4)-induced hepatocarcinogenesis was hardly observed in HAT1-knockout mice.Multi-omics identified that HAT1 modulated gluconeogenesis and lipogenesis in liver.Protein phosphatase 2 scaffold subunit alpha(PPP2R1A)promoted gluconeogenesis and inhibited lipogenesis by phosphoenolpyruvate carboxykinase 1(PCK1)serine 90 dephosphorylation to suppress the tumor growth.HAT1 succinylated PPP2R1A at lysine 541(K541)to block the assembly of protein phosphatase 2A(PP2A)holoenzyme and interaction with PCK1,resulting in the depression of dephosphorylation of PCK1.HAT1-succinylated PPP2R1A contributed to the remodeling of gluconeogenesis/lipogenesis by PCK1 serine 90 phosphorylation,leading to the inhibition of gluconeogenic enzyme activity and activating sterol regulatory element-binding protein 1(SREBP1)nuclear accumulation-induced lipogenesis gene expression,which enhanced the tumor growth.In conclusion,succinylation of PPP2R1A lysine 541 by HAT1 converses the role in modulation of gluconeogenesis/lipogenesis remodeling through PCK1 S90 phosphorylation to support liver cancer.Our finding provides new insights into the mechanism by which post-translational modifications(PTMs)confer the conversion of tumor suppressor function to oncogene.
基金supported by the National Key R&D Program of China(Grant No.2023YFC2604502)the Project for Talent and Platform of Science and Technology in Yunnan Province Science and Technology Department(Grant No.202205AM070005)+1 种基金the Scientific Research and Innovation Project of Postgraduate Students in the Academic Degree of Yunnan University(Grant Nos.KC-23235386,KC-23234008)the Xingdian Scholar Fund of Yunnan,and the Double Top University Fund of Yunnan University.
文摘Soil nematodes regulate belowground ecological processes,yet their community composition and energy structure responses to Chinese herbal medicine planting are largely unknown.Here,four Euphorbiaceae plants—Phyllanthus emblica,Excoecaria acerifolia,Baccaurea ramiflora,and Aporosa yunnanensis—were selected and cultivated in the Xishuangbanna Tropical Botanical Garden.After two years of cultivation,we assessed soil physicochemical properties,plant traits,microbial diversity,nematode diversity and community composition,and nematode energy flux.Our results revealed that the cultivation of these four medicinal plants significantly reduced soil nematode abundance and diversity and altered the community composition.Total nematode abundance was positively correlated with soil pH,aboveground biomass,and microbial richness,but negatively correlated with soil moisture,soil total phosphorus,and leaf thickness.Additionally,the energy flux within the soil nematode food web decreased by 40%−71%after the cultivation of medicinal plants,which was attributed to the reduction in nematode diversity and abundance.Our findings suggest that the cultivation of medicinal plants can influence soil resource availability and alter soil nematode communities,with diverse nematode species playing a key role in energy transfer within the belowground ecosystem.
基金supported by the National Natural Science Foundation of China(Nos.82372818 to Xiaodong Zhang,82103066 to Guang Yang,82302887 to Hongfeng Yuan,82303210 to Yufei Wang)The China Postdoctoral Science Foundation(No.2022M712389 to Hongfeng Yuan,No.2023M732624 to Yufei Wang,No.2023M742621 to Lina Zhao)+1 种基金Tianjin Key Medical Discipline(Specialty)Construction Project(TJYXZDXK-009A to W.Lu,China)“14th Five-Year Plan”Tumor Prevention and Treatment Research Project of Tianjin Medical University Cancer Institute and Hospital(No.YZ-03,China).
文摘Protein arginine methyltransferase 5(PRMT5)acts as an oncogene in liver cancer,yet its roles and in-depth molecular mechanisms within the liver cancer immune microenvironment remain mostly undefined.Here,we demonstrated that disruption of tumor-intrinsic PRMT5 enhances CD8^(+)T-cell-mediated antitumor immunity both in vivo and in vitro.Further experiments verified that this effect is achieved through downregulation of the inhibitory immune checkpoint molecule,fibrinogen-like protein 1(FGL1).Mechanistically,PRMT5 catalyzed symmetric dimethylation of transcription factor 12(TCF12)at arginine 554(R554),prompting the binding of TCF12 to FGL1 promoter region,which transcriptionally activated FGL1 in tumor cells.Methylation deficiency at TCF12-R554 residue downregulated FGL1 expression,which promoted CD8^(+)T-cell-mediated antitumor immunity.Notably,combining the PRMT5 methyltransferase inhibitor GSK591 with PD-L1 blockade efficiently inhibited liver cancer growth and improved overall survival in mice.Collectively,our findings reveal the immunosuppressive role and mechanism of PRMT5 in liver cancer and highlight that targeting PRMT5 could boost checkpoint immunotherapy efficacy.
基金supported by the Science and Technology Planning Project of Guangzhou,Guangdong,China(No.006259497026)the Young Creative Talents of Department Education of Guangdong,China(Natural Science,No.2019KQNCX067)+3 种基金the National Natural Science Foundation of China(No.52172083)International Science&Technology CooperationProgramnofGuangdong,China(No.2021A0505030078)Guangzhou Key Research and Development Program(China)(No.2023B03J1239)Program for Innovative Research Team inUniversityof Education Systemof Guangzhou,China(No.202235404).
文摘Al-driven genetic engineering,as a burgeoning diagnostic tool,can offer predictive information on the five-year survival rate(FYSR)in the setup of a prognostic therapeutic schedule.This approach provides the individuality and accuracy of prognosis for FYSR of gastric cancer(GC).Unlike traditional neoplasm staging criteria,our technique ensures accuracy and individuality without relying on statistical data and empirical study.
