The international community has made significant efforts to flatten the COVID-19 curve,including predicting transmission[1,2],executing unprecedented global lockdowns and social distancing[3,4],promoting the wearing o...The international community has made significant efforts to flatten the COVID-19 curve,including predicting transmission[1,2],executing unprecedented global lockdowns and social distancing[3,4],promoting the wearing of facemasks and social distancing measures[5],and isolating confirmed cases and contacts[6].Because of the adverse consequences of these lockdown measures[7],many cities have reopened so they can rebuild their economies.However,as mobility has gradually returned towards normal,imported cases from unknown sources have disrupted the recovery situation,and cities are continually at high risk of new waves of infection[8,9]since airborne transmission is the dominant transmission route[10].展开更多
Background:Hepatocellular carcinoma(HCC)is one of the most prevalent cancers in the world,with a high likelihood of metastasis and a dismal prognosis.The reprogramming of glucosemetabolism is critical in the developme...Background:Hepatocellular carcinoma(HCC)is one of the most prevalent cancers in the world,with a high likelihood of metastasis and a dismal prognosis.The reprogramming of glucosemetabolism is critical in the development ofHCC.TheWarburg effect has recently been confirmed to occur in a variety of cancers,including HCC.However,little is known about the molecular biological mechanisms underlying the Warburg effect in HCC cells.In this study,we sought to better understand how methyltransferase 5,N6-adenosine(METTL5)controls the development of HCC and theWarburg effect.Methods:In the current study,quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of METTL5 in HCC tissues and cell lines.Several different cell models and animal models were established to determine the role of METTL5 in glucose metabolism reprogramming and the underlying molecularmechanism of HCC.Glutathione-S-transferase pulldown,coimmunoprecipitation,RNA sequencing,non-targeted metabolomics,polysome profiling,and luciferase reporter assays were performed to investigate the molecular mechanisms of METTL5 in HCC cells.Results:We discovered that METTL5 drove glucose metabolic reprogramming to promote the proliferation and metastasis of HCC.Mechanistically,upregulation of METTL5 promoted c-Myc stability and thus activated its downstream glycolytic genes lactate dehydrogenase A(LDHA),enolase 1(ENO1),triosephosphate isomerase 1(TPI1),solute carrier family 2 member 1(SLC2A1),and pyruvate kinase M2(PKM2).The c-Box and ubiquitin binding domain(UBA)regions of ubiquitin specific peptidase 5(USP5)binded to c-Myc protein and inhibited K48-linked polyubiquitination of c-Myc.Further study revealed that METTL5 controled the USP5 translation process,which in turn regulated the ubiquitination of c-Myc.Furthermore,we identified cAMP responsive element binding protein 1(CREB1)/P300 as a critical transcriptional regulator ofMETTL5 that promoted the transcription of METTL5 in HCC.In patient-derived tumor xenograft(PDX)models,adenovirus-mediated knockout of METTL5 had a good antitumor effect and prolonged the survival of PDX-bearing mice.Conclusions:These findings point to a novel mechanism by which CREB1/P300-METTL5-USP5-c-Myc controls abnormal glucose metabolism and promotes tumor growth,suggesting that METTL5 is a potential therapeutic target and prognostic biomarker for HCC.展开更多
Background and aim:Conventional hepatitis C treatment using pegylated interferon(PEG-IFN)and ribavirin is associated with significant side effects.IL28B polymorphism can predict response to treatment,with CC genotype ...Background and aim:Conventional hepatitis C treatment using pegylated interferon(PEG-IFN)and ribavirin is associated with significant side effects.IL28B polymorphism can predict response to treatment,with CC genotype having a better response.ITPA gene deficiency protects against clinically significant anaemia induced by treatment.The purpose of this study was to determine IL28B polymorphismand ITPA variation among hepatitis C genotype 1 patients who have undergone therapy with PEG-IFN and ribavirin and their association with sustained viral response(SVR).Methods:All hepatitis C genotype 1 patients who had been treated with PEG-IFN and ribavirin over the past 10 years were identified by available medical records and were contacted by letter of invitation to participate in the study.Blood samples for IL28B and ITPA genotyping were obtained.Medical records were reviewed for verification of treatment response,development of anaemia and if treatment reduction was required during the treatment.Results:A total of 61 patients with hepatitis C genotype 1 were treated with PEG-IFN and ribavirin,of whom 42 agreed to participate in the study.Mean age was 45.6±12.9 years at time of treatment,and 83.3%of patients weremales.Thirty-three(78.6%)had IL28B CC genotype,of whom 25(75.8%)obtained SVR compared with only 3 of 9(33.3%)non C/C genotype patients who achieved SVR(P=0.041).Eleven(26.1%)patients had ITPA AC genotype,and 30(71.4%)had CC genotype.There was no statistically significant difference between ITPA AC and CC genotypes in predicting clinically significant anaemia(45.5%vs 63.3%,P=0.302).Even among patients who developed anaemia,70.8%stillmanaged to achieve SVR.Treatment reduction also had no impact on SVR.Conclusion:Hepatitis C genotype 1 patients should be informed of the response rate for treatment with PEG-IFN and ribavirin in a population with favourable IL28B genotype before consideration of newer therapeutic options.展开更多
基金support from the National Research FoundationPrime Minister’s Office+7 种基金Singapore under its Campus for Research Excellence and Technological Enterprise(CREATE)programmeThe Hong Kong Polytechnic University Strategic Hiring Scheme(P0036221)support from the Key Program of National Natural Science Foundation of China(41930648)supports from the Hong Kong Research Grants Council(15602619,15603920,and C7064-18GF)supports from the Hong Kong Research Grants Council(14605920,14611621,and C4023-20GF)support from the National University of SingaporeMinistry of Education,Tier 1 under WBS R-109-000-270-133Ministry of Natural Resources of the People’s Republic of China(GS(2021)7327)。
文摘The international community has made significant efforts to flatten the COVID-19 curve,including predicting transmission[1,2],executing unprecedented global lockdowns and social distancing[3,4],promoting the wearing of facemasks and social distancing measures[5],and isolating confirmed cases and contacts[6].Because of the adverse consequences of these lockdown measures[7],many cities have reopened so they can rebuild their economies.However,as mobility has gradually returned towards normal,imported cases from unknown sources have disrupted the recovery situation,and cities are continually at high risk of new waves of infection[8,9]since airborne transmission is the dominant transmission route[10].
基金the Ethics Committee of Zhongnan Hospital ofWuhan University(permit number:KELUN2017082 and KELUN2020100)The tissue samples were obtained with written informed consent from each patient.All animal experiments were approved in accordance with the guidelines of the Animal Ethics and Welfare Committee of Wuhan University of Zhongnan Hospital(permit number:ZN2022005).
文摘Background:Hepatocellular carcinoma(HCC)is one of the most prevalent cancers in the world,with a high likelihood of metastasis and a dismal prognosis.The reprogramming of glucosemetabolism is critical in the development ofHCC.TheWarburg effect has recently been confirmed to occur in a variety of cancers,including HCC.However,little is known about the molecular biological mechanisms underlying the Warburg effect in HCC cells.In this study,we sought to better understand how methyltransferase 5,N6-adenosine(METTL5)controls the development of HCC and theWarburg effect.Methods:In the current study,quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of METTL5 in HCC tissues and cell lines.Several different cell models and animal models were established to determine the role of METTL5 in glucose metabolism reprogramming and the underlying molecularmechanism of HCC.Glutathione-S-transferase pulldown,coimmunoprecipitation,RNA sequencing,non-targeted metabolomics,polysome profiling,and luciferase reporter assays were performed to investigate the molecular mechanisms of METTL5 in HCC cells.Results:We discovered that METTL5 drove glucose metabolic reprogramming to promote the proliferation and metastasis of HCC.Mechanistically,upregulation of METTL5 promoted c-Myc stability and thus activated its downstream glycolytic genes lactate dehydrogenase A(LDHA),enolase 1(ENO1),triosephosphate isomerase 1(TPI1),solute carrier family 2 member 1(SLC2A1),and pyruvate kinase M2(PKM2).The c-Box and ubiquitin binding domain(UBA)regions of ubiquitin specific peptidase 5(USP5)binded to c-Myc protein and inhibited K48-linked polyubiquitination of c-Myc.Further study revealed that METTL5 controled the USP5 translation process,which in turn regulated the ubiquitination of c-Myc.Furthermore,we identified cAMP responsive element binding protein 1(CREB1)/P300 as a critical transcriptional regulator ofMETTL5 that promoted the transcription of METTL5 in HCC.In patient-derived tumor xenograft(PDX)models,adenovirus-mediated knockout of METTL5 had a good antitumor effect and prolonged the survival of PDX-bearing mice.Conclusions:These findings point to a novel mechanism by which CREB1/P300-METTL5-USP5-c-Myc controls abnormal glucose metabolism and promotes tumor growth,suggesting that METTL5 is a potential therapeutic target and prognostic biomarker for HCC.
文摘Background and aim:Conventional hepatitis C treatment using pegylated interferon(PEG-IFN)and ribavirin is associated with significant side effects.IL28B polymorphism can predict response to treatment,with CC genotype having a better response.ITPA gene deficiency protects against clinically significant anaemia induced by treatment.The purpose of this study was to determine IL28B polymorphismand ITPA variation among hepatitis C genotype 1 patients who have undergone therapy with PEG-IFN and ribavirin and their association with sustained viral response(SVR).Methods:All hepatitis C genotype 1 patients who had been treated with PEG-IFN and ribavirin over the past 10 years were identified by available medical records and were contacted by letter of invitation to participate in the study.Blood samples for IL28B and ITPA genotyping were obtained.Medical records were reviewed for verification of treatment response,development of anaemia and if treatment reduction was required during the treatment.Results:A total of 61 patients with hepatitis C genotype 1 were treated with PEG-IFN and ribavirin,of whom 42 agreed to participate in the study.Mean age was 45.6±12.9 years at time of treatment,and 83.3%of patients weremales.Thirty-three(78.6%)had IL28B CC genotype,of whom 25(75.8%)obtained SVR compared with only 3 of 9(33.3%)non C/C genotype patients who achieved SVR(P=0.041).Eleven(26.1%)patients had ITPA AC genotype,and 30(71.4%)had CC genotype.There was no statistically significant difference between ITPA AC and CC genotypes in predicting clinically significant anaemia(45.5%vs 63.3%,P=0.302).Even among patients who developed anaemia,70.8%stillmanaged to achieve SVR.Treatment reduction also had no impact on SVR.Conclusion:Hepatitis C genotype 1 patients should be informed of the response rate for treatment with PEG-IFN and ribavirin in a population with favourable IL28B genotype before consideration of newer therapeutic options.
