Endocrine therapy that blocks estrogen signaling is the most effective treatment for patients with estrogen receptor positive(ER+)breast cancer.However,the efficacy of agents such as tamoxifen(Tam)is often compromised...Endocrine therapy that blocks estrogen signaling is the most effective treatment for patients with estrogen receptor positive(ER+)breast cancer.However,the efficacy of agents such as tamoxifen(Tam)is often compromised by the development of resistance.Here we report that cytokines-activated nuclear IKKαconfers Tam resistance to ER+breast cancer by inducing the expression of FAT10,and that the expression of FAT10 and nuclear IKKαin primary ER+human breast cancer was correlated with lymphotoxinβ(LTB)expression and significantly associated with relapse and metastasis in patients treated with adjuvant mono-Tam.IKKαactivation or enforced FAT10 expression promotes Tam-resistance while loss of IKKαor FAT10 augments Tam sensitivity.The induction of FAT10 by IKKαis mediated by the transcription factor Pax5,and coordinated via an IKKα-p53-miR-23a circuit in which activation of IKKαattenuates p53-directed repression of FAT10.Thus,our findings establish IKKα-to-FAT10 pathway as a new therapeutic target for the treatment of Tam-resistant ER+breast cancer.展开更多
目的初步了解PAX5缺失在无特殊重现染色体异常的B系急性淋巴细胞白血病(B-ALL)患儿中的发生情况,并进一步分析PAX5基因缺失与ALL预后的相关性。方法用多重连接探针扩增(MLPA)技术检测2008年4月至2013年4月初诊无特殊重现染色体异常的B-...目的初步了解PAX5缺失在无特殊重现染色体异常的B系急性淋巴细胞白血病(B-ALL)患儿中的发生情况,并进一步分析PAX5基因缺失与ALL预后的相关性。方法用多重连接探针扩增(MLPA)技术检测2008年4月至2013年4月初诊无特殊重现染色体异常的B-ALL患儿及对照组(同期非血液系统疾病及肿瘤儿童)的PAX5基因拷贝数情况。根据有无PAX5基因缺失分为缺失组和非缺失组。结果 86例患儿中18例(21%)发生了PAX5缺失。缺失组初诊时白细胞总数明显高于非缺失组(P=0.001)。Kaplan-Meier法分析显示:缺失组无病生存(DFS)率明显低于非缺失组(0.69±0.12 vs 0.90±0.04,P=0.017),但两组患儿的总生存(OS)率差异无统计学意义(P=0.128)。Cox法分析显示,PAX5缺失为影响DFS的不利因素(P=0.03)。结论 PAX5缺失为无特殊重现染色体异常B-ALL患儿DFS的独立危险因素。展开更多
Background:Gene promoter methylation is a major epigenetic change in cancers,which plays critical roles in carcinogenesis.As a crucial regulator in the early stages of B-cell differentiation and embryonic neurodevelop...Background:Gene promoter methylation is a major epigenetic change in cancers,which plays critical roles in carcinogenesis.As a crucial regulator in the early stages of B-cell differentiation and embryonic neurodevelopment,the paired box 5(PAX5)gene is downregulated by methylation in several kinds of tumors and the role of this downregulation in esophageal squamous cell carcinoma(ESCC)pathogenesis remains unclear.Methods:To elucidate the role of PAX5 in ESCC,eight ESCC cell lines,51 primary ESCC tissue samples,and eight normal esophageal mucosa samples were studied and The Cancer Genome Atlas(TCGA)was queried.PAX5 expression was examined by reverse transcription-polymerase chain reaction and western blotting.Cell apoptosis,proliferation,and chemosensitivity were detected by flow cytometry,colony formation assays,and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assays in ESCC cell lines with PAX5 overexpression or silencing.Tumor xenograft models were established for in vivo verification.Results:PAX5 methylation was found in 37.3%(19/51)of primary ESCC samples,which was significantly associated with age(P=0.007)and tumor-node-metastasis stage(P=0.014).TCGA data analysis indicated that PAX5 expression was inversely correlated with promoter region methylation(r=-0.189,P=0.011 for cg00464519 and r=-0.228,P=0.002 for cg02538199).Restoration of PAX5 expression suppressed cell proliferation,promoted apoptosis,and inhibited tumor growth of ESCC cell lines,which was verified in xenografted mice.Ectopic PAX5 expression significantly increased p53 reporter luciferase activity and increased p53 messenger RNA and protein levels.A direct interaction of PAX5 with the p53 promoter region was confirmed by chromatin immunoprecipitation assays.Re-expression of PAX5 sensitized ESCC cell lines KYSE150 and KYSE30 to fluorouracil and docetaxel.Silencing of PAX5 induced resistance of KYSE450 cells to these drugs.Conclusions:As a tumor suppressor gene regulated by promoter region methylation in human ESCC,PAX5 inhibit展开更多
基金supported by a postdoctoral trainee fellowship from the Frenchman's Creek Women for Cancer Research,a cancer research fellowship from UICC(ACS-10-003)the Natural Science Foundation of China(81974469 and 81672635)the Postgraduate Independent Exploration and Innovation Project of Central South University of China(2019zzts899)。
文摘Endocrine therapy that blocks estrogen signaling is the most effective treatment for patients with estrogen receptor positive(ER+)breast cancer.However,the efficacy of agents such as tamoxifen(Tam)is often compromised by the development of resistance.Here we report that cytokines-activated nuclear IKKαconfers Tam resistance to ER+breast cancer by inducing the expression of FAT10,and that the expression of FAT10 and nuclear IKKαin primary ER+human breast cancer was correlated with lymphotoxinβ(LTB)expression and significantly associated with relapse and metastasis in patients treated with adjuvant mono-Tam.IKKαactivation or enforced FAT10 expression promotes Tam-resistance while loss of IKKαor FAT10 augments Tam sensitivity.The induction of FAT10 by IKKαis mediated by the transcription factor Pax5,and coordinated via an IKKα-p53-miR-23a circuit in which activation of IKKαattenuates p53-directed repression of FAT10.Thus,our findings establish IKKα-to-FAT10 pathway as a new therapeutic target for the treatment of Tam-resistant ER+breast cancer.
文摘目的初步了解PAX5缺失在无特殊重现染色体异常的B系急性淋巴细胞白血病(B-ALL)患儿中的发生情况,并进一步分析PAX5基因缺失与ALL预后的相关性。方法用多重连接探针扩增(MLPA)技术检测2008年4月至2013年4月初诊无特殊重现染色体异常的B-ALL患儿及对照组(同期非血液系统疾病及肿瘤儿童)的PAX5基因拷贝数情况。根据有无PAX5基因缺失分为缺失组和非缺失组。结果 86例患儿中18例(21%)发生了PAX5缺失。缺失组初诊时白细胞总数明显高于非缺失组(P=0.001)。Kaplan-Meier法分析显示:缺失组无病生存(DFS)率明显低于非缺失组(0.69±0.12 vs 0.90±0.04,P=0.017),但两组患儿的总生存(OS)率差异无统计学意义(P=0.128)。Cox法分析显示,PAX5缺失为影响DFS的不利因素(P=0.03)。结论 PAX5缺失为无特殊重现染色体异常B-ALL患儿DFS的独立危险因素。
基金National Science Foundation of China(NSFC Nos.31671298,81802390,and 81672462)Natural Science Foundation of Beijing(No.7202187)+3 种基金National Key Research and Development Program of China(Nos.2016YFC0905200,2016YFC0905302,and 2017YFC 1308900)National Geriatrics Center Funding(No.NCRCG-PLAGH-2018002)Key Projects of Clinical Application and Promotion with Capital Characteristics(No.Z161100000516003)Military Medical Special Program for Youth of Chinese People's Liberation Army General Hospital(No.QNF19037)。
文摘Background:Gene promoter methylation is a major epigenetic change in cancers,which plays critical roles in carcinogenesis.As a crucial regulator in the early stages of B-cell differentiation and embryonic neurodevelopment,the paired box 5(PAX5)gene is downregulated by methylation in several kinds of tumors and the role of this downregulation in esophageal squamous cell carcinoma(ESCC)pathogenesis remains unclear.Methods:To elucidate the role of PAX5 in ESCC,eight ESCC cell lines,51 primary ESCC tissue samples,and eight normal esophageal mucosa samples were studied and The Cancer Genome Atlas(TCGA)was queried.PAX5 expression was examined by reverse transcription-polymerase chain reaction and western blotting.Cell apoptosis,proliferation,and chemosensitivity were detected by flow cytometry,colony formation assays,and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assays in ESCC cell lines with PAX5 overexpression or silencing.Tumor xenograft models were established for in vivo verification.Results:PAX5 methylation was found in 37.3%(19/51)of primary ESCC samples,which was significantly associated with age(P=0.007)and tumor-node-metastasis stage(P=0.014).TCGA data analysis indicated that PAX5 expression was inversely correlated with promoter region methylation(r=-0.189,P=0.011 for cg00464519 and r=-0.228,P=0.002 for cg02538199).Restoration of PAX5 expression suppressed cell proliferation,promoted apoptosis,and inhibited tumor growth of ESCC cell lines,which was verified in xenografted mice.Ectopic PAX5 expression significantly increased p53 reporter luciferase activity and increased p53 messenger RNA and protein levels.A direct interaction of PAX5 with the p53 promoter region was confirmed by chromatin immunoprecipitation assays.Re-expression of PAX5 sensitized ESCC cell lines KYSE150 and KYSE30 to fluorouracil and docetaxel.Silencing of PAX5 induced resistance of KYSE450 cells to these drugs.Conclusions:As a tumor suppressor gene regulated by promoter region methylation in human ESCC,PAX5 inhibit
