14-3-3σ基因甲基化失活与鼻咽癌侵袭转移关系及鼻咽癌血清蛋白质组学研究
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摘要
鼻咽癌(nasopharyngeal carcinoma,NPC)是我国南方及东南亚一种与遗传和环境因素密切相关的常见肿瘤。至今NPC发生发展机制仍然不清楚。NPC早期临床症状不明显,易早期发生颈部淋巴结和远处转移,绝大多数NPC病人就诊时已是中晚期,导致疗效不佳。因此,本研究一方面从NPC的甲基化失活基因着手,研究14-3-3σ基因甲基化与NPC侵袭转移的关系,以期能为揭示NPC的转移机制提供理论和科学依据;另一方面,采用血清蛋白质组学方法寻找NPC的血清标志物,以期能为NPC的诊治提供帮助。一、14-3-3σ基因甲基化与NPC侵袭转移的关系研究
14-3-3 sigma(σ)蛋白是一种潜在的肿瘤抑瘤蛋白,是细胞周期G2/M期检控点的负性调节子。我们前期的蛋白质组学研究发现14-3-3σ蛋白在NPC中表达下调,但14-3-3σ在NPC中表达水平下调的机制及意义尚不清楚,有待进一步研究。为揭示14-3-3σ在NPC中表达下调的机制及其作用,本研究以75例NPC组织、25例正常鼻咽黏膜组织、4株分化程度或转移潜能不同的NPC细胞系(CNE1、CNE2、5-8F、6-10B)和永生化的鼻咽上皮细胞系NP69为样本,(1)采用甲基化特异性PCR(MSP)、RT-PCR、Western blotting和免疫组化等方法检测14-3-3σ基因的甲基化状态和表达水平,分析14-3-3σ基因甲基化与其表达水平之间的关系及其临床病理意义;(2)采用MTT和流式细胞技术观察去甲基化药物5-杂氮-2-脱氧胞苷(5-aza-2dC)对NPC细胞增殖、凋亡和细胞周期分布的影响;(3)采用基因转染和Transwell小室实验分析14-3-3σ表达水平对NPC细胞体外侵袭能力的影响。主要结果如下:(1)4株NPC细胞系的14-3-3σ基因启动子均存在甲基化,而永生化人鼻咽上皮细胞株NP69的14-3-3σ基因启动子缺乏甲基化。5-aza-2dC处理后,4株NPC细胞系的14-3-3σ基因甲基化水平下降而其表达水平上调;(2)5-aza-2dC呈浓度依赖性地抑制4株NPC细胞系的生长,促进细胞凋亡,导致细胞周期阻滞,而且高分化CNE1和无转移6-10B细胞对药物的敏感性高于低分化CNE2和高转移5-8F细胞;(3)14-3-3σ启动子甲基化的频率在NPC组织显著高于正常鼻咽上皮组织(84%VS 28%),而且14-3-3σ基因完全甲基化只存在于NPC组织;(4)14-3-3σ基因在NPC组织中表达下调或丢失,且与14-3-3σ基因甲基化状态相关;(5)14-3-3σ甲基化的NPC患者有更高频率的淋巴结转移和远处转移以及更晚的临床分期;(6)上调14-3-3σ表达能够抑制高转移潜能NPC细胞株5-8F的体外侵袭能力。二、鼻咽癌血清蛋白质组学研究
以19例NPC组织及患者自身血清和19例健康人血清为样本,采用血清蛋白质组学方法筛选NPC抗原及自身抗体。首先,应用双向凝胶电泳(2-DE)分离NPC组织蛋白质,将胶中的蛋白质电转移至PVDF膜上,再分别与NPC患者自身血清及健康人对照血清进行Western blotting反应,获取Western blotting反应图谱,图像分析识别差异反应的蛋白质点,再用质谱技术并结合生物信息学方法对差异反应的蛋白质点进行鉴定,共鉴定了13个可以在多数NPC患者体内诱导产生自身抗体的抗原蛋白,其中CK19、EBP1和Rho-GDI-2抗体分别在47.4%、47.4%和36.8%的NPC患者血清中能检测到。
为验证血清蛋白质组学研究结果的可靠性,采用免疫共沉淀将CK19、EBP1和Rho-GDI-2蛋白从NPC细胞株CNE2的总蛋白中纯化出来,SDS-PAGE分离并转移至PVDF膜上,以它们作为抗原,采用Western blotting分析在新收集的30例NPC患者血清、23例其它肿瘤患者血清及20例健康人血清中的存在情况。结果显示:CK19、EBP1和Rho-GDI-2抗体在NPC患者血清中的阳性率明显高于其它肿瘤患者及健康人。结果表明:采用血清蛋白质组学筛选到的NPC抗原及其自身抗体结果可靠,CK19、EBP1和Rho-GDI-2抗体具有NPC特异性。
为探讨NPC组织CK19、EBP1和Rho-GDI-2蛋白产生免疫原性的机制,以30例NPC组织及30例正常鼻咽粘膜上皮组织为样本,采用Western blotting和免疫组织化学染色检测CK19、EBP1和Rho-GDI-2蛋白的表达和亚细胞定位情况。结果显示,CK19和EBP1在NPC组织中的表达比正常鼻咽粘膜上皮组织明显升高,而Rho-GDI-2在正常组织和NPC组织中的表达则没有明显差别,CK19、EBP1和Rho-GDI-2在肿瘤细胞与正常细胞中的亚细胞定位一致。结果提示,CK19和EBP1过表达可能是其产生免疫原性、诱导NPC患者体内产生自身抗体的原因之一,而NPC组织Rho-GDI-2的免疫原性可能与翻译后修饰有关。
为探讨分析CK19、Rho-GDI-2、HSP70和LAP3自身抗体诊断NPC的价值,采用ELISA方法检测CK19、Rho-GDI-2、HSP70和LAP3四个自身抗体在新收集的36例NPC患者、20例其它肿瘤患者和20例健康人血清中的水平,分析单个自身抗体以及自身抗体联合对NPC判别的特异性和敏感性。结果显示:4个自身抗体的血清水平在NPC患者和其他肿瘤患者均明显高于健康人,以单个自身抗体作为判别NPC的指标,Rho-GDI-2抗体具有更高的敏感性,而HSP70抗体的特异性最高;利用4个自身抗体组成的联合判别函数对NPC判别的敏感性为41.7%(15/36),特异性为95%(19/20)。
本研究结果表明,NPC存在高频14-3-3σ基因甲基化失活,14-3-3σ基因甲基化失活与NPC淋巴结转移和远处转移有关。CK19、EBP1、Rho-GDI-2、HSP70和LAP3抗原及其自身抗体可能有助于NPC的筛查、诊断及免疫治疗。
Nasopharyngeal carcinoma(NPC) is one of the most common malignant tumors in southern China,which closely correlates with genetic and environmental factors,and the mechanism underlying the pathogenesis of NPC remains unclear.Because of vague clinical symptoms and metastasis at the early stages of the disease,NPC is often difficult to early diagnose,and results in the strong decrease in the possibility of cure and the survival time in NPC patients.Therefore,in this study we first studied association of 14-3-3σgene methylation inactivation with invasion and metastasis in NPC to provide the basis for revealing the mechanisms of NPC metastasis,and on the other hand we carried out serological proteome analysis of NPC to provide the help for NPC diagnosis and treatment.
1.Inactivation of 14-3-3σgene by promoter methylation correlates with invasion and metastasis.
14-3-3σ,a potential tumor suppressor protein,is a negative regulator of cell cycle G2-M phase checkpoint in response to DNA damage and in 14-3-3 protein family.Our previous comparative proteomics study showed that expression of 14-3-3σwas downregulated in NPC tissue compared with normal nasopharyngeal epithelial tissue (NNET),but the mechanisms of its downregulation and significance remains unclear.
In order to reveal the mechanism and role of 14-3-3σdownregulation in the NPC,75 cases of NPC tissues,25 cases of NNET, 4 NPC cell lines(CNE1,CNE2,5-8F,6-10B) with the different differentiation degree or different metastatic potential as well as immortalization human nasopharyngeal epithelial cell line NP69 were used in this study.Methylation-specific PCR(MS-PCR),RT-PCR, Western blotting and immunohistochemistry were performed to detect the methylation status and expression level of 14-3-3σgene,and relationship between the methylation status and expression level of 14-3-3σgene as well as the clinicopathological significance of 14-3-3σmethylation inactivation were analysed;MTT assay and flow cytometry were used to detect the effects of demethylation agent 5-aza-2dC on cell growth,cell cycle distribution and apoptosis of NPC cells;and gene transfection and in vitro invasion assay were applied to determine the effect of 14-3-3σexpression levels on the invasive ability of NPC cells.
The results were as followings:(1) 14-3-3σpromoter methylation was detected in 100%NPC cell lines(4/4) but are not detected in NP69 cell line.Treatment of the 4 NPC cell lines with the methyltransferase inhibitor 5-aza-2'dC resulted in the demethylation and upregulation of 14-3-3σ;(2) 5-aza-2dC could inhibit cell proliferation,promote cell apoptosis,and block cell cycle progress in a dose-dependent manner in all of the four NPC cell lines.The chemosensitivity of NPC cell lines to 5-aza-2'dC is related to their differentiation degree and metastatic potential;(3) 14-3-3σpromoter methylation occurred at a higher frequency in NPC tissues,63/75(84%),compared to NNET,7/25(28%), and fully methylated 14-3-3σpromoter was detected in NPC but not in any of NNET;(4) 14-3-3σexpression was down-regulated or lost in NPC tissues with methylation,and there was a negative correlation between the expression levels and methylation statuses of 14-3-3σgene; (5) The NPC patients with methylated 14-3-3σpresented a higher frequency of lymph node and distant metastasis,and an advanced clinical stage;(6) Overexpression of 14-3-3σin NPC cell line 5-8F with high metastatic potential was able to inhibit its in vitro invasive ability.
2.serological proteome analysis of nasopharyngeal carcinoma
To discover novel NPC biomarkers,serological proteome analysis (SERPA) was used to identify proteins that commonly elicit a humoral immune response in NPC.Sera from 19 newly diagnosed NPC patients and 19 healthy individuals were analyzed for IgG autoantibodies against NPC proteins resolved by 2-DE.Protein spots that exhibited selective reactivity with sera from NPC patients were identified by MS.As a result, a total of 13 proteins that induced autoantibodies in the most of NPC patients were identified.Among the identified proteins,CK19,EBP 1,and Rho-GDI-2 induced autoantibodies in more than 36.8%of NPC patients.
To validate the findings of SERPA,occurrence of autoantibodies against the three proteins(CK19,EBP 1,and Rho-GDI-2) was detected by immunoprecipitation and Western blotting in additional 30 NPC patients, 23 other types of cancer patients and 20 healthy individuals.Results showed that frequency of autoantibodies against CK19,EBP1 and Rho-GDI-2 in NPC patients was significantly higher than that in other types of cancer patients and healthy individuals.The results not only validated the findings of SERPA,but also indicated that autoantibodies against these three proteins were specific in NPC patients.
To explore the mechanisms for autoantibody development of the three proteins(CK19,EBP1,and Rho-GDI-2) in NPC,Western blotting and immunohistochemical staining were performed to determine the expression and localization of CK19,EBP1,and Rho-GDI-2 in NPC tissues and NNET.Upregulation of CK19 and EBP1,but not Rho-GDI-2 were observed in NPC as compared with NNET,and subcellular localization of the three proteins in NPC tissue was same as that in the normal tissue.The results indicated that overexpression of CK19 and EBP 1 may be one of the mechanisms for their autoantibody development in NPC,and a protein translational modification may be related to Rho-GDI-2 autoantibody development in NPC.
To explore the value of autoantibodies against the four proteins (CK19,Rho-GDI-2,HSP70 and LAP3) for diagnosing NPC,we detect the serum levels of their autoantibodies in additional 36 NPC patients,20 other types of cancer patients and 20 healthy individuals by ELISA,and the sensitivity and specificity of individual autoantibody and four autoantibody combination for discriminating NPC patients and controls were analyzed.The results showed that the serum levels of four autoantibodies in NPC and other types of cancer patients were significantly higher than these in the healthy individuals.Using individual autoantibody as a judge marker for NPC patients,Rho-GDI-2 autoantibody had better sensitivity,and HSP70 autoantibody had the highest specificity.Using four autoantibody combination as a judge marker for NPC patients,the sensitivity was 41.7%(15/36),and the specificity was 95%(19/20).
We conclude that(1)14-3-3σis frequently inactivated by promoter methylation in NPC,this aberrant methylation correlates with lymph node and distant metastasis,and 14-3-3σmay serve as the target molecule for treating NPC metastasis;(2) CK19,EBP1 and Rho-GDI-2 antigens and their autoantibodies may have utility in NPC screening,diagnosis and immunotherapy.
14-3-3 sigma(σ)蛋白是一种潜在的肿瘤抑瘤蛋白,是细胞周期G2/M期检控点的负性调节子。我们前期的蛋白质组学研究发现14-3-3σ蛋白在NPC中表达下调,但14-3-3σ在NPC中表达水平下调的机制及意义尚不清楚,有待进一步研究。为揭示14-3-3σ在NPC中表达下调的机制及其作用,本研究以75例NPC组织、25例正常鼻咽黏膜组织、4株分化程度或转移潜能不同的NPC细胞系(CNE1、CNE2、5-8F、6-10B)和永生化的鼻咽上皮细胞系NP69为样本,(1)采用甲基化特异性PCR(MSP)、RT-PCR、Western blotting和免疫组化等方法检测14-3-3σ基因的甲基化状态和表达水平,分析14-3-3σ基因甲基化与其表达水平之间的关系及其临床病理意义;(2)采用MTT和流式细胞技术观察去甲基化药物5-杂氮-2-脱氧胞苷(5-aza-2dC)对NPC细胞增殖、凋亡和细胞周期分布的影响;(3)采用基因转染和Transwell小室实验分析14-3-3σ表达水平对NPC细胞体外侵袭能力的影响。主要结果如下:(1)4株NPC细胞系的14-3-3σ基因启动子均存在甲基化,而永生化人鼻咽上皮细胞株NP69的14-3-3σ基因启动子缺乏甲基化。5-aza-2dC处理后,4株NPC细胞系的14-3-3σ基因甲基化水平下降而其表达水平上调;(2)5-aza-2dC呈浓度依赖性地抑制4株NPC细胞系的生长,促进细胞凋亡,导致细胞周期阻滞,而且高分化CNE1和无转移6-10B细胞对药物的敏感性高于低分化CNE2和高转移5-8F细胞;(3)14-3-3σ启动子甲基化的频率在NPC组织显著高于正常鼻咽上皮组织(84%VS 28%),而且14-3-3σ基因完全甲基化只存在于NPC组织;(4)14-3-3σ基因在NPC组织中表达下调或丢失,且与14-3-3σ基因甲基化状态相关;(5)14-3-3σ甲基化的NPC患者有更高频率的淋巴结转移和远处转移以及更晚的临床分期;(6)上调14-3-3σ表达能够抑制高转移潜能NPC细胞株5-8F的体外侵袭能力。二、鼻咽癌血清蛋白质组学研究
以19例NPC组织及患者自身血清和19例健康人血清为样本,采用血清蛋白质组学方法筛选NPC抗原及自身抗体。首先,应用双向凝胶电泳(2-DE)分离NPC组织蛋白质,将胶中的蛋白质电转移至PVDF膜上,再分别与NPC患者自身血清及健康人对照血清进行Western blotting反应,获取Western blotting反应图谱,图像分析识别差异反应的蛋白质点,再用质谱技术并结合生物信息学方法对差异反应的蛋白质点进行鉴定,共鉴定了13个可以在多数NPC患者体内诱导产生自身抗体的抗原蛋白,其中CK19、EBP1和Rho-GDI-2抗体分别在47.4%、47.4%和36.8%的NPC患者血清中能检测到。
为验证血清蛋白质组学研究结果的可靠性,采用免疫共沉淀将CK19、EBP1和Rho-GDI-2蛋白从NPC细胞株CNE2的总蛋白中纯化出来,SDS-PAGE分离并转移至PVDF膜上,以它们作为抗原,采用Western blotting分析在新收集的30例NPC患者血清、23例其它肿瘤患者血清及20例健康人血清中的存在情况。结果显示:CK19、EBP1和Rho-GDI-2抗体在NPC患者血清中的阳性率明显高于其它肿瘤患者及健康人。结果表明:采用血清蛋白质组学筛选到的NPC抗原及其自身抗体结果可靠,CK19、EBP1和Rho-GDI-2抗体具有NPC特异性。
为探讨NPC组织CK19、EBP1和Rho-GDI-2蛋白产生免疫原性的机制,以30例NPC组织及30例正常鼻咽粘膜上皮组织为样本,采用Western blotting和免疫组织化学染色检测CK19、EBP1和Rho-GDI-2蛋白的表达和亚细胞定位情况。结果显示,CK19和EBP1在NPC组织中的表达比正常鼻咽粘膜上皮组织明显升高,而Rho-GDI-2在正常组织和NPC组织中的表达则没有明显差别,CK19、EBP1和Rho-GDI-2在肿瘤细胞与正常细胞中的亚细胞定位一致。结果提示,CK19和EBP1过表达可能是其产生免疫原性、诱导NPC患者体内产生自身抗体的原因之一,而NPC组织Rho-GDI-2的免疫原性可能与翻译后修饰有关。
为探讨分析CK19、Rho-GDI-2、HSP70和LAP3自身抗体诊断NPC的价值,采用ELISA方法检测CK19、Rho-GDI-2、HSP70和LAP3四个自身抗体在新收集的36例NPC患者、20例其它肿瘤患者和20例健康人血清中的水平,分析单个自身抗体以及自身抗体联合对NPC判别的特异性和敏感性。结果显示:4个自身抗体的血清水平在NPC患者和其他肿瘤患者均明显高于健康人,以单个自身抗体作为判别NPC的指标,Rho-GDI-2抗体具有更高的敏感性,而HSP70抗体的特异性最高;利用4个自身抗体组成的联合判别函数对NPC判别的敏感性为41.7%(15/36),特异性为95%(19/20)。
本研究结果表明,NPC存在高频14-3-3σ基因甲基化失活,14-3-3σ基因甲基化失活与NPC淋巴结转移和远处转移有关。CK19、EBP1、Rho-GDI-2、HSP70和LAP3抗原及其自身抗体可能有助于NPC的筛查、诊断及免疫治疗。
Nasopharyngeal carcinoma(NPC) is one of the most common malignant tumors in southern China,which closely correlates with genetic and environmental factors,and the mechanism underlying the pathogenesis of NPC remains unclear.Because of vague clinical symptoms and metastasis at the early stages of the disease,NPC is often difficult to early diagnose,and results in the strong decrease in the possibility of cure and the survival time in NPC patients.Therefore,in this study we first studied association of 14-3-3σgene methylation inactivation with invasion and metastasis in NPC to provide the basis for revealing the mechanisms of NPC metastasis,and on the other hand we carried out serological proteome analysis of NPC to provide the help for NPC diagnosis and treatment.
1.Inactivation of 14-3-3σgene by promoter methylation correlates with invasion and metastasis.
14-3-3σ,a potential tumor suppressor protein,is a negative regulator of cell cycle G2-M phase checkpoint in response to DNA damage and in 14-3-3 protein family.Our previous comparative proteomics study showed that expression of 14-3-3σwas downregulated in NPC tissue compared with normal nasopharyngeal epithelial tissue (NNET),but the mechanisms of its downregulation and significance remains unclear.
In order to reveal the mechanism and role of 14-3-3σdownregulation in the NPC,75 cases of NPC tissues,25 cases of NNET, 4 NPC cell lines(CNE1,CNE2,5-8F,6-10B) with the different differentiation degree or different metastatic potential as well as immortalization human nasopharyngeal epithelial cell line NP69 were used in this study.Methylation-specific PCR(MS-PCR),RT-PCR, Western blotting and immunohistochemistry were performed to detect the methylation status and expression level of 14-3-3σgene,and relationship between the methylation status and expression level of 14-3-3σgene as well as the clinicopathological significance of 14-3-3σmethylation inactivation were analysed;MTT assay and flow cytometry were used to detect the effects of demethylation agent 5-aza-2dC on cell growth,cell cycle distribution and apoptosis of NPC cells;and gene transfection and in vitro invasion assay were applied to determine the effect of 14-3-3σexpression levels on the invasive ability of NPC cells.
The results were as followings:(1) 14-3-3σpromoter methylation was detected in 100%NPC cell lines(4/4) but are not detected in NP69 cell line.Treatment of the 4 NPC cell lines with the methyltransferase inhibitor 5-aza-2'dC resulted in the demethylation and upregulation of 14-3-3σ;(2) 5-aza-2dC could inhibit cell proliferation,promote cell apoptosis,and block cell cycle progress in a dose-dependent manner in all of the four NPC cell lines.The chemosensitivity of NPC cell lines to 5-aza-2'dC is related to their differentiation degree and metastatic potential;(3) 14-3-3σpromoter methylation occurred at a higher frequency in NPC tissues,63/75(84%),compared to NNET,7/25(28%), and fully methylated 14-3-3σpromoter was detected in NPC but not in any of NNET;(4) 14-3-3σexpression was down-regulated or lost in NPC tissues with methylation,and there was a negative correlation between the expression levels and methylation statuses of 14-3-3σgene; (5) The NPC patients with methylated 14-3-3σpresented a higher frequency of lymph node and distant metastasis,and an advanced clinical stage;(6) Overexpression of 14-3-3σin NPC cell line 5-8F with high metastatic potential was able to inhibit its in vitro invasive ability.
2.serological proteome analysis of nasopharyngeal carcinoma
To discover novel NPC biomarkers,serological proteome analysis (SERPA) was used to identify proteins that commonly elicit a humoral immune response in NPC.Sera from 19 newly diagnosed NPC patients and 19 healthy individuals were analyzed for IgG autoantibodies against NPC proteins resolved by 2-DE.Protein spots that exhibited selective reactivity with sera from NPC patients were identified by MS.As a result, a total of 13 proteins that induced autoantibodies in the most of NPC patients were identified.Among the identified proteins,CK19,EBP 1,and Rho-GDI-2 induced autoantibodies in more than 36.8%of NPC patients.
To validate the findings of SERPA,occurrence of autoantibodies against the three proteins(CK19,EBP 1,and Rho-GDI-2) was detected by immunoprecipitation and Western blotting in additional 30 NPC patients, 23 other types of cancer patients and 20 healthy individuals.Results showed that frequency of autoantibodies against CK19,EBP1 and Rho-GDI-2 in NPC patients was significantly higher than that in other types of cancer patients and healthy individuals.The results not only validated the findings of SERPA,but also indicated that autoantibodies against these three proteins were specific in NPC patients.
To explore the mechanisms for autoantibody development of the three proteins(CK19,EBP1,and Rho-GDI-2) in NPC,Western blotting and immunohistochemical staining were performed to determine the expression and localization of CK19,EBP1,and Rho-GDI-2 in NPC tissues and NNET.Upregulation of CK19 and EBP1,but not Rho-GDI-2 were observed in NPC as compared with NNET,and subcellular localization of the three proteins in NPC tissue was same as that in the normal tissue.The results indicated that overexpression of CK19 and EBP 1 may be one of the mechanisms for their autoantibody development in NPC,and a protein translational modification may be related to Rho-GDI-2 autoantibody development in NPC.
To explore the value of autoantibodies against the four proteins (CK19,Rho-GDI-2,HSP70 and LAP3) for diagnosing NPC,we detect the serum levels of their autoantibodies in additional 36 NPC patients,20 other types of cancer patients and 20 healthy individuals by ELISA,and the sensitivity and specificity of individual autoantibody and four autoantibody combination for discriminating NPC patients and controls were analyzed.The results showed that the serum levels of four autoantibodies in NPC and other types of cancer patients were significantly higher than these in the healthy individuals.Using individual autoantibody as a judge marker for NPC patients,Rho-GDI-2 autoantibody had better sensitivity,and HSP70 autoantibody had the highest specificity.Using four autoantibody combination as a judge marker for NPC patients,the sensitivity was 41.7%(15/36),and the specificity was 95%(19/20).
We conclude that(1)14-3-3σis frequently inactivated by promoter methylation in NPC,this aberrant methylation correlates with lymph node and distant metastasis,and 14-3-3σmay serve as the target molecule for treating NPC metastasis;(2) CK19,EBP1 and Rho-GDI-2 antigens and their autoantibodies may have utility in NPC screening,diagnosis and immunotherapy.
引文
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