目的探讨系统性ALK阴性间变性大细胞淋巴瘤(anaplastic large cell lymphoma,ALCL)的临床病理特点、分子特征、治疗和预后。方法回顾性分析18例系统性ALK^(-)ALCL的临床病理特征、免疫表型特点,行HE、免疫组化染色、FISH和NGS检测,并复...目的探讨系统性ALK阴性间变性大细胞淋巴瘤(anaplastic large cell lymphoma,ALCL)的临床病理特点、分子特征、治疗和预后。方法回顾性分析18例系统性ALK^(-)ALCL的临床病理特征、免疫表型特点,行HE、免疫组化染色、FISH和NGS检测,并复习相关文献。结果系统性ALK^(-)ALCL好发于老年男性,常位于进展期,以淋巴结病变为主,结外原发部位包括原发胰腺、原发胸椎;形态学显示17例呈普通型,1例呈“霍奇金样”型。免疫表型:肿瘤细胞中CD30均弥漫强阳性(>75%),CD2(16/17)、CD3(13/18)、CD5(4/18)、CD7(8/18)、CD4(14/18)、TIA-1(16/18)、CD8(2/16)、GATA-3(10/12)、EMA(3/5)、MUM1(12/12)、CD43(6/6)和CD56(2/8)不同程度阳性,Ki67增殖指数30%~90%,PD-L1(22C3)(TPS=0~100%),ALK、CD15、CD79α和CD20均阴性;FISH检测:5例TP63缺失,2例DUSP22缺失。NGS检测:16例发生基因突变,基因突变频率0~11个,平均4.2个基因突变;伴TP63重排的ALK^(-)ALCL更易发生于女性,多发于淋巴结,临床分期晚,易伴p53基因异常。结论伴TP63重排的系统性ALK^(-)ALCL与诸多不良因素相关,临床过程多呈侵袭性,预后不佳。展开更多
BACKGROUND Pancreatic cancer(PC)is one of the deadliest cancers worldwide.PC metastasis involves a complex set of events,including epithelial-mesenchymal transition(EMT),that increase tumor cell invasiveness.Recent ev...BACKGROUND Pancreatic cancer(PC)is one of the deadliest cancers worldwide.PC metastasis involves a complex set of events,including epithelial-mesenchymal transition(EMT),that increase tumor cell invasiveness.Recent evidence has shown that hypoxia is a major EMT regulator in pancreatic cancer cells and facilitates metastasis;however,the mechanisms remain elusive.AIM To investigate the role of miR-301a in hypoxia-induced EMT in PC cells.METHODS Real-time PCR and Western blot analysis were used to detect the expression of miR-301a and EMT markers in PDAC cells cultured in hypoxic and normoxic conditions.Western blot analysis was used to detect the expression of EMT markers in PDAC cells with miR-301a overexpression.Wound healing assay and Transwell assay were used to detect the migration capabilities of PDAC cells with miR-301a overexpression and knockout.Luciferase assay was used to detect the miR-301a promoter and the 3’untranslated region activity of TP63.Orthotopic PC mouse models were used to study the role of miR-301a in metastasis of PDAC cells in vivo.In situ hybridization assay was used to detect the expression of miR-301a in PDAC patient samples(adjacent paratumor and paired tumor tissues).RESULTS Hypoxic environment could directly promote the EMT of PC cells.The expression level of miR-301a was increased in a HIF2αdependent manner in hypoxia-cultured CFPAC-1 and BxPC-3 cells.Overexpression of miR-301a enhanced the hypoxia-induced EMT of PC cells,while knocking out miR-301a result in the suppression of hypoxia-induced EMT.TP63 was a direct target of miR-301a and involved in the metastatic process of PC cells.Furthermore,miR-301a upregulation facilitated PDAC distant metastasis and lymph node metastasis in vivo.Additionally,miR-301a overexpression was indicative of aggressive clinicopathological behaviors and poor prognosis.CONCLUSION The newly identified HIF-2α-miR301a-TP63 signaling pathway may play a crucial role in hypoxia-induced EMT in PDAC cells.展开更多
目的:探讨DNA甲基化影响TP63的表达及其与子宫颈癌的相关性。方法:收集宫颈癌患者40例(CC)和因子宫良性病变行全子宫切除术的45例患者的宫颈组织。采用全基因组DNA甲基化分析(WGBS)和RNA sequence联合筛查宫颈癌组织和正常宫颈组织(各3...目的:探讨DNA甲基化影响TP63的表达及其与子宫颈癌的相关性。方法:收集宫颈癌患者40例(CC)和因子宫良性病变行全子宫切除术的45例患者的宫颈组织。采用全基因组DNA甲基化分析(WGBS)和RNA sequence联合筛查宫颈癌组织和正常宫颈组织(各3例)的DNA甲基化度和mRNA表达。采用亚硫酸氢盐测序法(BSP)和实时定量PCR(qPCR)法检测TP63基因启动子区DNA甲基化和RUNX2、TP63、survivin的mRNA表达。CHIP法检测RUNX2在宫颈组织中与TP63基因启动子的结合情况,并分析TP63基因DNA甲基化状态与SCC病理参数的关系。结果: WGBS和RNA-seq联合筛查发现,TP63启动子DNA甲基化水平升高与其mRNA表达减少相关。BSP结果证实,与正常宫颈组织比较,宫颈癌组织中TP63基因启动子区-688 CpG位点DNA甲基化率显著升高,差异有统计学意义[77.5%(31/40)vs 31.1%(14/45), P <0.05]。qPCR结果显示,与对照组比较,宫颈癌组织中RUNX2和survivin的mRNA表达上调,TP63 mRNA表达下调( P 均<0.05)。染色质免疫共沉淀技术(ChIP)证实,宫颈癌组织中TP63基因启动子区存在转录因子RUNX2结合序列,且-688CpG位点DNA甲基化修饰影响RUNX2的结合。相关性分析显示,TP63基因DNA甲基化与肿瘤大小、病理分级、临床分期相关( P 均<0.05),与患者年龄无关( P >0.05)。结论: TP63基因启动子DNA甲基化抑制其表达,参与宫颈癌的发生发展。展开更多
Recent genome-wide association studies have identified lung cancer susceptibility loci, such as chromosome 5p15 (telomerase reverse transcriptase, TERT and cleft lip and palate transmembrane protein 1-like, CLPTM1L), ...Recent genome-wide association studies have identified lung cancer susceptibility loci, such as chromosome 5p15 (telomerase reverse transcriptase, TERT and cleft lip and palate transmembrane protein 1-like, CLPTM1L), 15q25 (nicotinic cholinergic receptor α, CHRNA3-CHRNA5), and 3q28 (tumor protein p63, TP63). Replication study was performed to confirm the association of the recently-identified susceptible loci (i.e., TERT-CLPTM1L, CHRNA3-CHRNA5, and TP63) in a total of 1460 male Japanese smokers (885 lung cancer cases and 575 healthy control subjects), which were previously studied for a low odds ratio of impaired or deletion polymorphism in cytochrome P450 2A6 (CYP2A6) for lung cancer risk. The minor allele frequency (0.442) of rs2736100 on 5p15 (TERT) was significantly higher in lung cancer cases than that (0.395) of controls, with an odds ratio of 1.27 (95% CI of 1.07 - 1.50, p = 0.00504). A series of subgroup analyses revealed the significant associations of rs4488809 (TP63, odds ratio of 1.21, p = 0.0422) and rs2736100 (TERT, odds ratio of 1.47, p = 6.40 × 10–5) with the risk of lung adenocarcinoma. No significant association of CHRNA3-CHRNA5 and CLPTM1L was found in this population. The present results support replication of the association of TERT and TP63 loci with lung adenocarcinomas and suggest subtype-specific effects of these loci on higher risk of lung cancer in smokers. The CYP2A6 including copy number polymorphism, uninvestigated in large-scale genome-wide association studies, may influence lower risk to heavy tobacco use-related lung cancer.展开更多
文摘目的探讨系统性ALK阴性间变性大细胞淋巴瘤(anaplastic large cell lymphoma,ALCL)的临床病理特点、分子特征、治疗和预后。方法回顾性分析18例系统性ALK^(-)ALCL的临床病理特征、免疫表型特点,行HE、免疫组化染色、FISH和NGS检测,并复习相关文献。结果系统性ALK^(-)ALCL好发于老年男性,常位于进展期,以淋巴结病变为主,结外原发部位包括原发胰腺、原发胸椎;形态学显示17例呈普通型,1例呈“霍奇金样”型。免疫表型:肿瘤细胞中CD30均弥漫强阳性(>75%),CD2(16/17)、CD3(13/18)、CD5(4/18)、CD7(8/18)、CD4(14/18)、TIA-1(16/18)、CD8(2/16)、GATA-3(10/12)、EMA(3/5)、MUM1(12/12)、CD43(6/6)和CD56(2/8)不同程度阳性,Ki67增殖指数30%~90%,PD-L1(22C3)(TPS=0~100%),ALK、CD15、CD79α和CD20均阴性;FISH检测:5例TP63缺失,2例DUSP22缺失。NGS检测:16例发生基因突变,基因突变频率0~11个,平均4.2个基因突变;伴TP63重排的ALK^(-)ALCL更易发生于女性,多发于淋巴结,临床分期晚,易伴p53基因异常。结论伴TP63重排的系统性ALK^(-)ALCL与诸多不良因素相关,临床过程多呈侵袭性,预后不佳。
基金Supported by National Natural Science Foundation of China,No.81372640.
文摘BACKGROUND Pancreatic cancer(PC)is one of the deadliest cancers worldwide.PC metastasis involves a complex set of events,including epithelial-mesenchymal transition(EMT),that increase tumor cell invasiveness.Recent evidence has shown that hypoxia is a major EMT regulator in pancreatic cancer cells and facilitates metastasis;however,the mechanisms remain elusive.AIM To investigate the role of miR-301a in hypoxia-induced EMT in PC cells.METHODS Real-time PCR and Western blot analysis were used to detect the expression of miR-301a and EMT markers in PDAC cells cultured in hypoxic and normoxic conditions.Western blot analysis was used to detect the expression of EMT markers in PDAC cells with miR-301a overexpression.Wound healing assay and Transwell assay were used to detect the migration capabilities of PDAC cells with miR-301a overexpression and knockout.Luciferase assay was used to detect the miR-301a promoter and the 3’untranslated region activity of TP63.Orthotopic PC mouse models were used to study the role of miR-301a in metastasis of PDAC cells in vivo.In situ hybridization assay was used to detect the expression of miR-301a in PDAC patient samples(adjacent paratumor and paired tumor tissues).RESULTS Hypoxic environment could directly promote the EMT of PC cells.The expression level of miR-301a was increased in a HIF2αdependent manner in hypoxia-cultured CFPAC-1 and BxPC-3 cells.Overexpression of miR-301a enhanced the hypoxia-induced EMT of PC cells,while knocking out miR-301a result in the suppression of hypoxia-induced EMT.TP63 was a direct target of miR-301a and involved in the metastatic process of PC cells.Furthermore,miR-301a upregulation facilitated PDAC distant metastasis and lymph node metastasis in vivo.Additionally,miR-301a overexpression was indicative of aggressive clinicopathological behaviors and poor prognosis.CONCLUSION The newly identified HIF-2α-miR301a-TP63 signaling pathway may play a crucial role in hypoxia-induced EMT in PDAC cells.
文摘目的:探讨DNA甲基化影响TP63的表达及其与子宫颈癌的相关性。方法:收集宫颈癌患者40例(CC)和因子宫良性病变行全子宫切除术的45例患者的宫颈组织。采用全基因组DNA甲基化分析(WGBS)和RNA sequence联合筛查宫颈癌组织和正常宫颈组织(各3例)的DNA甲基化度和mRNA表达。采用亚硫酸氢盐测序法(BSP)和实时定量PCR(qPCR)法检测TP63基因启动子区DNA甲基化和RUNX2、TP63、survivin的mRNA表达。CHIP法检测RUNX2在宫颈组织中与TP63基因启动子的结合情况,并分析TP63基因DNA甲基化状态与SCC病理参数的关系。结果: WGBS和RNA-seq联合筛查发现,TP63启动子DNA甲基化水平升高与其mRNA表达减少相关。BSP结果证实,与正常宫颈组织比较,宫颈癌组织中TP63基因启动子区-688 CpG位点DNA甲基化率显著升高,差异有统计学意义[77.5%(31/40)vs 31.1%(14/45), P <0.05]。qPCR结果显示,与对照组比较,宫颈癌组织中RUNX2和survivin的mRNA表达上调,TP63 mRNA表达下调( P 均<0.05)。染色质免疫共沉淀技术(ChIP)证实,宫颈癌组织中TP63基因启动子区存在转录因子RUNX2结合序列,且-688CpG位点DNA甲基化修饰影响RUNX2的结合。相关性分析显示,TP63基因DNA甲基化与肿瘤大小、病理分级、临床分期相关( P 均<0.05),与患者年龄无关( P >0.05)。结论: TP63基因启动子DNA甲基化抑制其表达,参与宫颈癌的发生发展。
文摘Recent genome-wide association studies have identified lung cancer susceptibility loci, such as chromosome 5p15 (telomerase reverse transcriptase, TERT and cleft lip and palate transmembrane protein 1-like, CLPTM1L), 15q25 (nicotinic cholinergic receptor α, CHRNA3-CHRNA5), and 3q28 (tumor protein p63, TP63). Replication study was performed to confirm the association of the recently-identified susceptible loci (i.e., TERT-CLPTM1L, CHRNA3-CHRNA5, and TP63) in a total of 1460 male Japanese smokers (885 lung cancer cases and 575 healthy control subjects), which were previously studied for a low odds ratio of impaired or deletion polymorphism in cytochrome P450 2A6 (CYP2A6) for lung cancer risk. The minor allele frequency (0.442) of rs2736100 on 5p15 (TERT) was significantly higher in lung cancer cases than that (0.395) of controls, with an odds ratio of 1.27 (95% CI of 1.07 - 1.50, p = 0.00504). A series of subgroup analyses revealed the significant associations of rs4488809 (TP63, odds ratio of 1.21, p = 0.0422) and rs2736100 (TERT, odds ratio of 1.47, p = 6.40 × 10–5) with the risk of lung adenocarcinoma. No significant association of CHRNA3-CHRNA5 and CLPTM1L was found in this population. The present results support replication of the association of TERT and TP63 loci with lung adenocarcinomas and suggest subtype-specific effects of these loci on higher risk of lung cancer in smokers. The CYP2A6 including copy number polymorphism, uninvestigated in large-scale genome-wide association studies, may influence lower risk to heavy tobacco use-related lung cancer.
