Background:Epigenetic regulation plays an important role in the development and progression of nasopharyngeal carcinoma(NPC).However,the epigenetic mechanisms underlying NPC metastasis remains poorly understood.We aim...Background:Epigenetic regulation plays an important role in the development and progression of nasopharyngeal carcinoma(NPC).However,the epigenetic mechanisms underlying NPC metastasis remains poorly understood.We aimed to find functional genes which regulate the metastasis of NPC and identify therapeutic targets for NPC treatment.Methods:Bisulfite pyrosequencing was used to analyze zinc finger protein 582(ZNF582)methylation in NPC tissues and cell lines.Quantitative reverse transcription-polymerase chain reaction(qRT-PCR)and Western blotting were used to determine the expression of ZNF582.In vitro and in vivo experiments were performed to evaluate the biological function of ZNF582 in NPC.ZNF582-targeting genes were identified by chromatin immunoprecipitation sequencing(ChIP-seq)and were confirmed by ChIP-qPCR and luciferase assay.Results:ZNF582 promoter was hypermethylated in NPC,and both the mRNA and protein levels of ZNF582 were down-regulated in NPC tissues and cell lines.The restoration of ZNF582 inhibited NPC migration,invasion,and metastasis,while the knockdown of ZNF582 promoted NPC migration,invasion,and metastasis in vitro and in vivo.ZNF582 directly regulated the transcription and expression of adhesion molecules Nectin-3 and NRXN3.Both Nectin-3 and NRXN3 were identified as functional targets of ZNF582,and the restoration or abrogation of these genes reversed the tumor suppressor effect of ZNF582 in NPC metastasis.Conclusions:ZNF582 acts as a tumor suppressor gene in NPC by regulating the transcription and expression of adhesion molecules Nectin-3 and NRXN3,which may provide novel therapeutic targets for NPC treatment.展开更多
The identification of predictors for immunotherapy is often hampered by the absence of control groups in many studies,making it difficult to distinguish between prognostic and predictive biomarkers.This study presents...The identification of predictors for immunotherapy is often hampered by the absence of control groups in many studies,making it difficult to distinguish between prognostic and predictive biomarkers.This study presents biomarker analyses from the phase 3 CONTINUUM trial(NCT03700476),the first to show that adding anti-PD-1(aPD1)to chemoradiotherapy(CRT)improves event-free survival(EFS)in patients with locoregionally advanced nasopharyngeal carcinoma.A dynamic single-cell atlas was profiled using mass cytometry on peripheral blood mononuclear cell samples from 12 pairs of matched relapsing and non-relapsing patients in the aPD1-CRT arm.Using a supervised representation learning algorithm,we identified a Ki67+proliferating regulatory T cells(Tregs)population expressing high levels of activated and immunosuppressive molecules including FOXP3,CD38,HLA-DR,CD39,and PD-1,whose abundance correlated with treatment outcome.The frequency of these Ki67+Tregs was significantly higher at baseline and increased during treatment in patients who relapsed compared to non-relapsers.Further validation through flow cytometry(n=120)confirmed the predictive value of this Treg subset.Multiplex immunohistochemistry(n=249)demonstrated that Ki67+Tregs in tumors could predict immunotherapy benefit,with aPD1 improving EFS only in patients with low baseline levels of Ki67+Tregs.These findings were further validated in the multicenter phase 3 DIPPER trial(n=262,NCT03427827)and the phase 3 OAK trial of anti-PD-L1 immunotherapy in NSCLC,underscoring the predictive value of Ki67+Treg frequency in identifying the beneficiaries of immunotherapy and potentially guiding personalized treatment strategies.展开更多
Following publication of this article[1],the authors noticed that the mismatched images were inadvertently included in Figure 5(migration assays of SUNE1-shNRXN3-#2 group in Figure 5I)and Figure 6(invasion assays of S...Following publication of this article[1],the authors noticed that the mismatched images were inadvertently included in Figure 5(migration assays of SUNE1-shNRXN3-#2 group in Figure 5I)and Figure 6(invasion assays of SUNE1-ZNF582+Nectin3 group in Figure 6A).This error has now been corrected online.展开更多
基金This study was supported by grants from the National Natural Science Foundation of China(81902962)the China Postdoctoral Science Foundation(2019M653224)+4 种基金the Planned Science and Technology Project of Guangdong Province(2019B020230002)the Natural Science Foundation of Guangdong Province(2017A030312003)the Health and Medical Collaborative Innovation Project of Guangzhou City,China(201803040003)the Innovation Team Development Plan of the Ministry of Education(IRT_17R110)the Overseas Expertise Introduction Project for Discipline Innovation(111 Project,B14035).
文摘Background:Epigenetic regulation plays an important role in the development and progression of nasopharyngeal carcinoma(NPC).However,the epigenetic mechanisms underlying NPC metastasis remains poorly understood.We aimed to find functional genes which regulate the metastasis of NPC and identify therapeutic targets for NPC treatment.Methods:Bisulfite pyrosequencing was used to analyze zinc finger protein 582(ZNF582)methylation in NPC tissues and cell lines.Quantitative reverse transcription-polymerase chain reaction(qRT-PCR)and Western blotting were used to determine the expression of ZNF582.In vitro and in vivo experiments were performed to evaluate the biological function of ZNF582 in NPC.ZNF582-targeting genes were identified by chromatin immunoprecipitation sequencing(ChIP-seq)and were confirmed by ChIP-qPCR and luciferase assay.Results:ZNF582 promoter was hypermethylated in NPC,and both the mRNA and protein levels of ZNF582 were down-regulated in NPC tissues and cell lines.The restoration of ZNF582 inhibited NPC migration,invasion,and metastasis,while the knockdown of ZNF582 promoted NPC migration,invasion,and metastasis in vitro and in vivo.ZNF582 directly regulated the transcription and expression of adhesion molecules Nectin-3 and NRXN3.Both Nectin-3 and NRXN3 were identified as functional targets of ZNF582,and the restoration or abrogation of these genes reversed the tumor suppressor effect of ZNF582 in NPC metastasis.Conclusions:ZNF582 acts as a tumor suppressor gene in NPC by regulating the transcription and expression of adhesion molecules Nectin-3 and NRXN3,which may provide novel therapeutic targets for NPC treatment.
基金supported by grants from the National Natural Science Foundation of China(81930072,82101750,82172870,82202943,82373312,and 82403896)Natural Science Foundation of Guangdong Province(2024B1515020114)+2 种基金Science and Technology Plan Project of Guangzhou(2024A04J3943)Cancer Innovative Research Program of Sun Yat-sen University Cancer Center(CIRP-SYSUCC-0005)Chih Kuang Scholarship for Outstanding Young Physician-Scientists of Sun Yat-sen University Cancer Center(CKS-SYSUCC-2023004).
文摘The identification of predictors for immunotherapy is often hampered by the absence of control groups in many studies,making it difficult to distinguish between prognostic and predictive biomarkers.This study presents biomarker analyses from the phase 3 CONTINUUM trial(NCT03700476),the first to show that adding anti-PD-1(aPD1)to chemoradiotherapy(CRT)improves event-free survival(EFS)in patients with locoregionally advanced nasopharyngeal carcinoma.A dynamic single-cell atlas was profiled using mass cytometry on peripheral blood mononuclear cell samples from 12 pairs of matched relapsing and non-relapsing patients in the aPD1-CRT arm.Using a supervised representation learning algorithm,we identified a Ki67+proliferating regulatory T cells(Tregs)population expressing high levels of activated and immunosuppressive molecules including FOXP3,CD38,HLA-DR,CD39,and PD-1,whose abundance correlated with treatment outcome.The frequency of these Ki67+Tregs was significantly higher at baseline and increased during treatment in patients who relapsed compared to non-relapsers.Further validation through flow cytometry(n=120)confirmed the predictive value of this Treg subset.Multiplex immunohistochemistry(n=249)demonstrated that Ki67+Tregs in tumors could predict immunotherapy benefit,with aPD1 improving EFS only in patients with low baseline levels of Ki67+Tregs.These findings were further validated in the multicenter phase 3 DIPPER trial(n=262,NCT03427827)and the phase 3 OAK trial of anti-PD-L1 immunotherapy in NSCLC,underscoring the predictive value of Ki67+Treg frequency in identifying the beneficiaries of immunotherapy and potentially guiding personalized treatment strategies.
文摘Following publication of this article[1],the authors noticed that the mismatched images were inadvertently included in Figure 5(migration assays of SUNE1-shNRXN3-#2 group in Figure 5I)and Figure 6(invasion assays of SUNE1-ZNF582+Nectin3 group in Figure 6A).This error has now been corrected online.
