Background:Lung cancer is one of the most lethal cancers worldwide,but studies have shown that the higher the expression of programmed cell death protein 1 ligand 1(PD-L1)in non-small cell lung cancer(NSCLC),the more ...Background:Lung cancer is one of the most lethal cancers worldwide,but studies have shown that the higher the expression of programmed cell death protein 1 ligand 1(PD-L1)in non-small cell lung cancer(NSCLC),the more likely it will benefit from anti-PD-L1 immunotherapy.The purpose of our study was to collect and analyze abundant clinical samples in order to provide evidence for clinicians and patients who might consider anti-PD-L1 immunotherapy while jointly formulating treatment plans.Methods:On the one hand,we obtained cases from The Cancer Genome Atlas(TCGA)database,including 498 lung squamous cell cancer(LUSC)patients and 515 lung adenocarcinoma(LUAD)patients.We studied the lung caner driver gene in LUSC and LUAD.On the other hand,PD-L1 expression was detected in lung cancer tissues of 1,008 NSCLC patients with immunohistochemistry staining(IHC),and we studied the correlation between PD-L1 protein expression and clinicopathological characteristics.Results:PD-L1 expression was higher in LUSC than in LUAD at the mRNA level.In univariate analysis,PD-L1 expression at the protein level was higher in patients who were males,were LUSC,were smokers,had a tumor diameter>3 cm,had poor differentiation,or had stages Ⅲ-Ⅳ disease.In multivariate analysis,PD-L1 expression was higher in patients who were LUSC or in poor differentiation.Conclusion:In term of protein level,PD-L1 expression was higher in NSCLC patients who were LUSC or in poor differentiation.We recommend that PD-L1 IHC detection can be routinely performed in such populations that are likely to benefit most from PD-L1 immunotherapy.展开更多
In the treatment of most malignancies,radiotherapy plays a significant role.However,the resistance of cancer cells to ionizing radiation(IR)is the main reason for the failure of radiotherapy,which causes tumor recurre...In the treatment of most malignancies,radiotherapy plays a significant role.However,the resistance of cancer cells to ionizing radiation(IR)is the main reason for the failure of radiotherapy,which causes tumor recurrence and metastasis.In this study,we confirmed that GPR162,an orphan receptor in the G-protein-coupled receptor family,acted as a novel radiotherapy sensitizer by interacting with the stimulator of interferon genes(STING),which targeted DNA damage responses,activated IRF3,accelerated the activation of type I interferon system,promoted the expression of chemokines including CXCL10 and CXCL4,and inhibited the occurrence and development of tumors.Interestingly,the activation of STING by overexpression of GPR162 was independent of the classical pathway of cGAS.STING inhibitors could resist the antitumor effect of overexpression of GPR162 in IR-induced mouse models.In addition,most solid tumors showed low expression of GPR162.And the higher expression of GPR162 indicated a better prognosis in patients with lung adenocarcinoma,liver cancer,breast cancer,etc.In summary,these results suggested that GPR162 may serve as a potential sensitizer of radiotherapy by promoting radiotherapy-induced STING-IFN production and increasing the expression of chemokines including CXCL10 and CXCL4 in DNA damage response,providing an alternative strategy for improving cancer radiotherapy.展开更多
A wide spectrum of metabolites(mainly,the three major nutrients and their derivatives)can be sensed by specific sensors,then trigger a series of signal transduction pathways and affect the expression levels of genes i...A wide spectrum of metabolites(mainly,the three major nutrients and their derivatives)can be sensed by specific sensors,then trigger a series of signal transduction pathways and affect the expression levels of genes in epigenetics,which is called metabolite sensing.Life body regulates metabolism,immunity,and inflammation by metabolite sensing,coordinating the pathophysiology of the host to achieve balance with the external environment.Metabolic reprogramming in cancers cause different phenotypic characteristics of cancer cell from normal cell,including cell proliferation,migration,invasion,angiogenesis,etc.Metabolic disorders in cancer cells further create a microenvironment including many kinds of oncometabolites that are conducive to the growth of cancer,thus forming a vicious circle.At the same time,exogenous metabolites can also affect the biological behavior of tumors.Here,we discuss the metabolite sensing mechanisms of the three major nutrients and their derivatives,as well as their abnormalities in the development of various cancers,and discuss the potential therapeutic targets based on metabolite-sensing signaling pathways to prevent the progression of cancer.展开更多
Cancer is a major threat to human health and causes death worldwide.Research on the role of radiotherapy(RT)in the treatment of cancer is progressing;however,RT not only causes fatal DNA damage to tumor cells,but also...Cancer is a major threat to human health and causes death worldwide.Research on the role of radiotherapy(RT)in the treatment of cancer is progressing;however,RT not only causes fatal DNA damage to tumor cells,but also affects the interactions between tumor cells and different components of the tumor microenvironment(TME),including immune cells,fibroblasts,macrophages,extracellular matrix,and some soluble products.Some cancer cells can survive radiation and have shown strong resistance to radiation through interaction with the TME.Currently,the complex relationships between the tumor cells and cellular components that play major roles in various TMEs are poorly understood.This review explores the relationship between RT and cell-cell communication in the TME from the perspective of immunity and hypoxia and aims to identify new RT biomarkers and treatment methods in lung cancer to improve the current status of unstable RT effect and provide a theoretical basis for further lung cancer RT sensitization research in the future.展开更多
Since the publication of this article,we noticed a minor mistake in the article that needs to be corrected.We have checked the original data;the correct data are provided in this Corrigendum as follows.The key finding...Since the publication of this article,we noticed a minor mistake in the article that needs to be corrected.We have checked the original data;the correct data are provided in this Corrigendum as follows.The key findings of the article are not affected by these corrections.展开更多
Cancer stem cells(CSCs)exhibit highly aggressive and metastatic features and resistance to chemotherapy and radiotherapy.Aryl hydrocarbon receptor(AhR)expression varies among non-small cell lung cancers(NSCLCs),and th...Cancer stem cells(CSCs)exhibit highly aggressive and metastatic features and resistance to chemotherapy and radiotherapy.Aryl hydrocarbon receptor(AhR)expression varies among non-small cell lung cancers(NSCLCs),and the mechanisms that support abnormal AhR expression in CSCs remain elusive.Here,we identified ubiquitin carboxyl terminal hydrolase L3(UCHL3),a DUB enzyme in the UCH protease family,as a bona fide deubiquitylase of the AhR in NSCLC.UCHL3 was shown to interact with,deubiquitylate,and stabilize AhR in a manner dependent on its deubiquitylation activity.Moreover,we showed that UCHL3 promotes the stem-like characteristics and potent tumorigenic capacity of NSCLC cells.UCHL3 increased AhR stability and the binding of AhR to the promoter regions of the“stemness”genes ATP-binding cassette subfamily G member 2(ABCG2),KLF4,and c-Myc.Depletion of UCHL3 markedly downregulated the“stemness”genes ABCG2,KLF4,and c-Myc,leading to the loss of selfrenewal and tumorigenesis in NSCLCs.Furthermore,the UCHL3 inhibitor TCID induced AhR degradation and exhibited significantly attenuated efficacy in NSCLC cells with stem cell-like properties.Additionally,UCHL3 was shown to indicate poor prognosis in patients with lung adenocarcinoma.In general,our results reveal that the UCHL3 deubiquitylase is pivotal for AhR protein stability and a potential target for NSCLC-targeted therapy.展开更多
To explore the pharmacogenomic markers that affect the platinum-based chemotherapy response in non-small-cell lung carcinoma(NSCLC),we performed a two-cohort of genome-wide association studies(GWAS),including 34 for W...To explore the pharmacogenomic markers that affect the platinum-based chemotherapy response in non-small-cell lung carcinoma(NSCLC),we performed a two-cohort of genome-wide association studies(GWAS),including 34 for WES-based and 433 for microarray-based analyses,as well as two independent validation cohorts.After integrating the results of two studies,the genetic variations related to the platinum-based chemotherapy response were further determined by fine-mapping in 838 samples,and their potential functional impact were investigated by eQTL analysis and in vitro cell experiments.We found that a total of 68 variations were significant at P<1×10^(-3)in cohort 1 discovery stage,of which 3 SNPs were verified in 262 independent samples.A total of541 SNPs were significant at P<1×10^(-4)in cohort 2 discovery stage,of which 8 SNPs were verified in 347 independent samples.Comparing the validated SNPs in two GWAS,ADCY1 gene was verified in both independent studies.The results of fine-mapping showed that the G allele carriers of ADCY1rs2280496 and C allele carriers of rs189178649 were more likely to be resistant to platinum-based chemotherapy.In conclusion,our study found that rs2280496 and rs189178649 in ADCY1 gene were associated the sensitivity of platinum-based chemotherapy in NSCLC patients.展开更多
Posttranslational modifications(PTMs)of proteins,including chromatin modifiers,play crucial roles in the dynamic alteration of various protein properties and functions including stem-cell properties.However,the roles ...Posttranslational modifications(PTMs)of proteins,including chromatin modifiers,play crucial roles in the dynamic alteration of various protein properties and functions including stem-cell properties.However,the roles of Lymphoid-specific helicase(LSH),a DNA methylation modifier,in modulating stem-like properties in cancer are still not clearly clarified.Therefore,exploring PTMs modulation of LSH activity will be of great significance to further understand the function and activity of LSH.Here,we demonstrate that LSH is capable to undergo PTMs,including methylation and phosphorylation.The arginine methyltransferase PRMT5 can methylate LSH at R309 residue,meanwhile,LSH could as well be phosphorylated by MAPK1 kinase at S503 residue.We further show that the accumulation of phosphorylation of LSH at S503 site exhibits downregulation of LSH methylation at R309 residue,which eventually promoting stem-like properties in lung cancer.Whereas,phosphorylation-deficient LSH S503A mutant promotes the accumulation of LSH methylation at R309 residue and attenuates stem-like properties,indicating the critical roles of LSH PTMs in modulating stem-like properties.Thus,our study highlights the importance of the crosstalk between LSH PTMs in determining its activity and function in lung cancer stem-cell maintenance.展开更多
基金supported by the Fundamental Research Funds for the Central Universities of Central South University(Grant 2021zzts1026).
文摘Background:Lung cancer is one of the most lethal cancers worldwide,but studies have shown that the higher the expression of programmed cell death protein 1 ligand 1(PD-L1)in non-small cell lung cancer(NSCLC),the more likely it will benefit from anti-PD-L1 immunotherapy.The purpose of our study was to collect and analyze abundant clinical samples in order to provide evidence for clinicians and patients who might consider anti-PD-L1 immunotherapy while jointly formulating treatment plans.Methods:On the one hand,we obtained cases from The Cancer Genome Atlas(TCGA)database,including 498 lung squamous cell cancer(LUSC)patients and 515 lung adenocarcinoma(LUAD)patients.We studied the lung caner driver gene in LUSC and LUAD.On the other hand,PD-L1 expression was detected in lung cancer tissues of 1,008 NSCLC patients with immunohistochemistry staining(IHC),and we studied the correlation between PD-L1 protein expression and clinicopathological characteristics.Results:PD-L1 expression was higher in LUSC than in LUAD at the mRNA level.In univariate analysis,PD-L1 expression at the protein level was higher in patients who were males,were LUSC,were smokers,had a tumor diameter>3 cm,had poor differentiation,or had stages Ⅲ-Ⅳ disease.In multivariate analysis,PD-L1 expression was higher in patients who were LUSC or in poor differentiation.Conclusion:In term of protein level,PD-L1 expression was higher in NSCLC patients who were LUSC or in poor differentiation.We recommend that PD-L1 IHC detection can be routinely performed in such populations that are likely to benefit most from PD-L1 immunotherapy.
基金The Science and Technology Innovation Program of Hunan Province[2022RC3072(Y.Tao)].
文摘In the treatment of most malignancies,radiotherapy plays a significant role.However,the resistance of cancer cells to ionizing radiation(IR)is the main reason for the failure of radiotherapy,which causes tumor recurrence and metastasis.In this study,we confirmed that GPR162,an orphan receptor in the G-protein-coupled receptor family,acted as a novel radiotherapy sensitizer by interacting with the stimulator of interferon genes(STING),which targeted DNA damage responses,activated IRF3,accelerated the activation of type I interferon system,promoted the expression of chemokines including CXCL10 and CXCL4,and inhibited the occurrence and development of tumors.Interestingly,the activation of STING by overexpression of GPR162 was independent of the classical pathway of cGAS.STING inhibitors could resist the antitumor effect of overexpression of GPR162 in IR-induced mouse models.In addition,most solid tumors showed low expression of GPR162.And the higher expression of GPR162 indicated a better prognosis in patients with lung adenocarcinoma,liver cancer,breast cancer,etc.In summary,these results suggested that GPR162 may serve as a potential sensitizer of radiotherapy by promoting radiotherapy-induced STING-IFN production and increasing the expression of chemokines including CXCL10 and CXCL4 in DNA damage response,providing an alternative strategy for improving cancer radiotherapy.
基金supported by the National Natural Science Foundation of China[82072594(Y.T.),81874139,82073097(S.L.),81772496,82073136(D.X.)]Hunan Provincial Key Area R&D Programs[2019SK2253,2021SK2013,Y.T.]the Central South University Research Programme of Advanced Interdisciplinary Studies[2023QYJC030(Y.T.)].
文摘A wide spectrum of metabolites(mainly,the three major nutrients and their derivatives)can be sensed by specific sensors,then trigger a series of signal transduction pathways and affect the expression levels of genes in epigenetics,which is called metabolite sensing.Life body regulates metabolism,immunity,and inflammation by metabolite sensing,coordinating the pathophysiology of the host to achieve balance with the external environment.Metabolic reprogramming in cancers cause different phenotypic characteristics of cancer cell from normal cell,including cell proliferation,migration,invasion,angiogenesis,etc.Metabolic disorders in cancer cells further create a microenvironment including many kinds of oncometabolites that are conducive to the growth of cancer,thus forming a vicious circle.At the same time,exogenous metabolites can also affect the biological behavior of tumors.Here,we discuss the metabolite sensing mechanisms of the three major nutrients and their derivatives,as well as their abnormalities in the development of various cancers,and discuss the potential therapeutic targets based on metabolite-sensing signaling pathways to prevent the progression of cancer.
基金supported by the National Natural Science Foundation of China(No.82072594 to YT,Nos.82073097 and 81874139 to SL)Natural Science Foundation of Hunan Province,and Hunan Provincial Key Area Research&Development Programs(No.2021SK2013 to YT)
文摘Cancer is a major threat to human health and causes death worldwide.Research on the role of radiotherapy(RT)in the treatment of cancer is progressing;however,RT not only causes fatal DNA damage to tumor cells,but also affects the interactions between tumor cells and different components of the tumor microenvironment(TME),including immune cells,fibroblasts,macrophages,extracellular matrix,and some soluble products.Some cancer cells can survive radiation and have shown strong resistance to radiation through interaction with the TME.Currently,the complex relationships between the tumor cells and cellular components that play major roles in various TMEs are poorly understood.This review explores the relationship between RT and cell-cell communication in the TME from the perspective of immunity and hypoxia and aims to identify new RT biomarkers and treatment methods in lung cancer to improve the current status of unstable RT effect and provide a theoretical basis for further lung cancer RT sensitization research in the future.
文摘Since the publication of this article,we noticed a minor mistake in the article that needs to be corrected.We have checked the original data;the correct data are provided in this Corrigendum as follows.The key findings of the article are not affected by these corrections.
基金The National Natural Science Foundation of China(81672991 and 81874139[S.L.],81672787[Y.T.],81672308[X.W.])the National Basic Research Program of China(2015CB553903[Y.T.])supported this study.
文摘Cancer stem cells(CSCs)exhibit highly aggressive and metastatic features and resistance to chemotherapy and radiotherapy.Aryl hydrocarbon receptor(AhR)expression varies among non-small cell lung cancers(NSCLCs),and the mechanisms that support abnormal AhR expression in CSCs remain elusive.Here,we identified ubiquitin carboxyl terminal hydrolase L3(UCHL3),a DUB enzyme in the UCH protease family,as a bona fide deubiquitylase of the AhR in NSCLC.UCHL3 was shown to interact with,deubiquitylate,and stabilize AhR in a manner dependent on its deubiquitylation activity.Moreover,we showed that UCHL3 promotes the stem-like characteristics and potent tumorigenic capacity of NSCLC cells.UCHL3 increased AhR stability and the binding of AhR to the promoter regions of the“stemness”genes ATP-binding cassette subfamily G member 2(ABCG2),KLF4,and c-Myc.Depletion of UCHL3 markedly downregulated the“stemness”genes ABCG2,KLF4,and c-Myc,leading to the loss of selfrenewal and tumorigenesis in NSCLCs.Furthermore,the UCHL3 inhibitor TCID induced AhR degradation and exhibited significantly attenuated efficacy in NSCLC cells with stem cell-like properties.Additionally,UCHL3 was shown to indicate poor prognosis in patients with lung adenocarcinoma.In general,our results reveal that the UCHL3 deubiquitylase is pivotal for AhR protein stability and a potential target for NSCLC-targeted therapy.
基金supported by the National Key Research and Development Programs(2016YFC1306900 and 2017ZX09304014,China)National Natural Science Foundation of China(81573508,81874327,81773823,81803640 and 82073943,China)+3 种基金Fundamental Research Funds for the Central Universities of Central South University(2018zzts251,China)The StrategyOriented Special Project of Central South University in China(ZLXD2017003)Youth Science Foundation of Xiangya Hospital,Central South University(2017Q02,China)Hunan Cancer Hospital Climb Plan(YF2020011,China)。
文摘To explore the pharmacogenomic markers that affect the platinum-based chemotherapy response in non-small-cell lung carcinoma(NSCLC),we performed a two-cohort of genome-wide association studies(GWAS),including 34 for WES-based and 433 for microarray-based analyses,as well as two independent validation cohorts.After integrating the results of two studies,the genetic variations related to the platinum-based chemotherapy response were further determined by fine-mapping in 838 samples,and their potential functional impact were investigated by eQTL analysis and in vitro cell experiments.We found that a total of 68 variations were significant at P<1×10^(-3)in cohort 1 discovery stage,of which 3 SNPs were verified in 262 independent samples.A total of541 SNPs were significant at P<1×10^(-4)in cohort 2 discovery stage,of which 8 SNPs were verified in 347 independent samples.Comparing the validated SNPs in two GWAS,ADCY1 gene was verified in both independent studies.The results of fine-mapping showed that the G allele carriers of ADCY1rs2280496 and C allele carriers of rs189178649 were more likely to be resistant to platinum-based chemotherapy.In conclusion,our study found that rs2280496 and rs189178649 in ADCY1 gene were associated the sensitivity of platinum-based chemotherapy in NSCLC patients.
基金supported by the National Natural Science Foundation of China[81672991 and 81874139 to S.L.,81872285 to Y.S.,81728014 to Y.T.,81672787 to Y.T.,81672307 to X.W,81772927 to D.X.]the National Basic Research Program of China[2015CB553903 to Y.T.]+1 种基金the Overseas Expertise Introduction Project for Discipline Innovation(111 Project,No.111-2-12)the Fundamental Research Funds for the Central Universities[2017zzts206 to N.L.].
文摘Posttranslational modifications(PTMs)of proteins,including chromatin modifiers,play crucial roles in the dynamic alteration of various protein properties and functions including stem-cell properties.However,the roles of Lymphoid-specific helicase(LSH),a DNA methylation modifier,in modulating stem-like properties in cancer are still not clearly clarified.Therefore,exploring PTMs modulation of LSH activity will be of great significance to further understand the function and activity of LSH.Here,we demonstrate that LSH is capable to undergo PTMs,including methylation and phosphorylation.The arginine methyltransferase PRMT5 can methylate LSH at R309 residue,meanwhile,LSH could as well be phosphorylated by MAPK1 kinase at S503 residue.We further show that the accumulation of phosphorylation of LSH at S503 site exhibits downregulation of LSH methylation at R309 residue,which eventually promoting stem-like properties in lung cancer.Whereas,phosphorylation-deficient LSH S503A mutant promotes the accumulation of LSH methylation at R309 residue and attenuates stem-like properties,indicating the critical roles of LSH PTMs in modulating stem-like properties.Thus,our study highlights the importance of the crosstalk between LSH PTMs in determining its activity and function in lung cancer stem-cell maintenance.