原发性眼眶MALT淋巴瘤患者VCP表达与患者预后的相关性及机制的研究
摘要
目的：探讨含缬酪肽蛋白(valosin-containing protein, VCP)表达水平与原发性眼眶MALT淋巴瘤患者预后的相关性,及VCP对人淋巴瘤细胞凋亡及增殖能力的影响。
方法：1.58例原发性眼眶MALT淋巴瘤患者眶内淋巴瘤组织石蜡标本,采用免疫组化法检测VCP表达水平,并对VCP表达水平与患者复发情况及生存率的相关性进行统计学分析,用X2检验及Fisher精确检验来分析VCP蛋白表达与各临床因素之间的关系；Kaplan-Meier法计算复发率、生存率,并绘制生存曲线；log-rank法计算组间差异,P<0.05为差异具有统计学意义；
2.根据免疫组化结果即VCP蛋白表达水平,选取10例患者眶内肿瘤石蜡组织(5例×2组)抽提总RNA,并应用实时荧光定量PCR(RT-qPCR)定量比较2组VCP基因表达水平的差异；
3.免疫细胞化学染色法检测人淋巴瘤细胞系Raji细胞及Daudi细胞VCP蛋白的表达。应用特异、高效并操作方便的RNAi技术,以VCP作为基因靶点,对Raji细胞建立有效的RNA干扰方法。利用脂质体介导基因si-VCP转染Raji细胞,RT-qPCR及Western blot分别从1nRNA水平及蛋白水平评估Raji细胞VCP基因沉默效果；
4.流式细胞术检测VCP基因沉默的人淋巴瘤Raji细胞凋亡率的变化；
5.MTS法检测VCP基因沉默对Raji细胞增殖能力的影响。
结果：1.58例眼眶MALT淋巴瘤患者中13例(22.4%)患者出现肿瘤复发。复发时间为10-56个月,其平均值为39.5个月。8例患者(13.8%)死于肿瘤,4例患者(6.9%)死于与肿瘤无关的其他原因。5年无瘤生存率及总生存率分别是70.7%、79.3%。5年无瘤生存时间为10-60个月,其平均值为54.7个月；5年总生存时间为24-60个月,其平均值为57.2个月。
2.58例原发性眼眶MALT淋巴瘤患者眶内肿瘤组织VCP表达阳性细胞百分率为32%到95%。VCP表达阳性细胞百分率的中位值为45%,低于或等于45%为VCP表达level
1,高于45%为VCP表达level2。58例原发性眼眶MALT淋巴瘤患者眶内肿瘤组织VCP表达水平与患者复发(P=0.003)及肿瘤大小(P=0.008)密切相关。VCP表达水平与患者年龄、性别、LDH水平、红细胞沉降率(ESR)、血清白蛋白水平、有无B症状等临床特征无明显相关性(P>0.05)。同时,VCP表达level1患者5年无瘤生存率及总生存率明显高于level2患者(P=0.001；P=0.032)。
3.10例患者眶内肿瘤组织VCPmRNA表达水平与VCP蛋白表达水平一致,根据免疫组化结果level2组患者肿瘤组织VCPmRNA表达明显高于level1组(P=0.009)。
4.人淋巴瘤细胞系Raji细胞及Daudi细胞VCP蛋白表达较强。利用脂质体进行细胞转染,VCPmRNA水平和蛋白表达水平分别被抑制65%和57%,基因沉默效果肯定。
5.流式细胞术结果显示,人淋巴瘤细胞系Raji细胞VCP基因沉默后,细胞凋亡明显增强。
6.MTS结果显示,人淋巴瘤细胞系Raji细胞VCP基因沉默后,细胞增殖能力明显受到抑制。
结论：1.VCP是评价原发性眼眶MALT淋巴瘤患者预后的良好指标。
2.利用脂质体介导si-VCP对人淋巴瘤Raji细胞靶基因VCP的抑制效果明显,VCPmRNA表达水平明显降低,从而使VCP蛋白表达量明显下降。
3.VCP基因沉默可明显促进体外培养人淋巴瘤细胞的凋亡,并降低细胞增殖能力。VCP在人淋巴瘤细胞凋亡及增殖过程中起重要作用,可能是原发性眼眶MALT淋巴瘤治疗的新的分子靶点。
Objective: To study the correlation of the valosin-containing protein (VCP) expression level and the prognosis of primary orbital MALT lymphoma patient, and the influence of VCP to the apoptosis and proliferation of human lymphoma cells.
Methods:1. VCP expression in58samples from primary orbital MALT lymphoma patients was determined by immunohistochemisty using monoclonal antibody of VCP. The correlation between VCP expression level and prognosis was clarified with the statistical analysis. We calculated the recurrence rate and survival rate, and drawed the survival curve using the Kaplan-Meier method. We calculated the difference between the groups using the log-rank method. P values lower than0.05were considered statistically significant.
2. According to the results of immunohistochemistry, which was VCP protein expression level, we chose10cases orbital tumor paraffin tissue (5cases×2groups) of primary orbital MALT lymphoma patients. Extract the total RNA, and compare the difference of VCP gene expression level between the2groups using the RT-qPCR.
3. Immune cell chemical dyeing method was used to detect VCP protein expression of human lymphoma cell line Raji cell and Daudi cell. We chose VCP as gene target and established the effective method of RNA interference to the human lymphoma cell line Raji cell, using the specific, efficient and convenient operation of RNAi technology. We used lipidosome to mediate gene si-VCP transfection Raji cell. Then real-time quantitative PCR and western blot were used to assess the silencing effect of VCP for Raji cells gene from the mRNA level and protein level.
4. Detected the change of apoptosis rate of human lymphoma Raji cell which the VCP gene was silenced using the flow cytometry.
5. Detected the change of proliferation of human lymphoma Raji cell which the VCP gene was silenced using the MTS method.
Results:1. According to the follow-up visit of all patients in this study, we found that13/58(22.4%) patients suffered from tumor recurrence. The mean value of recurrence time was39.5months (range from10to56months).8/58(13.8%) patients died of tumor,4/58(6.9%) patients died of other causes unrelated to the tumor. As shown in table1, the5-year disease-free and overall survival rates were70.7%and79.3%, respectively. The mean value of5-year disease-free survival was54.7months (range from10to60months). The mean value of overall survival in the series was57.2months (range from24to60months).
2. It was found that the percentage of VCP positive cells in samples of primary orbital MALT lymphoma was ranging from32%to95%. The samples were divided into two groups (level1and level2) according to the median value (45%) of the percentage of VCP positive cells. It was found that the expression level of VCP was significantly correlated with the recurrence (P=0.003) and the tumor size (P=0.008). There was no observed correlation between the expression level of VCP and other clinical features. Meanwhile, the5-year disease-free and overall survival rate of patients of level1was significantly better than that of level2(P=0.001; P=0.032).
3. In the orbital tumor tissue of10primary orbital MALT lymphoma patients, the expression level of VCP mRNA was consistent with the protein expression level of VCP. According to the results of immunohistochemical the VCP mRNA expression in tumor tissue of level2group was significantly higher than that of level1group (P=0.009).
4. VCP protein expression of human lymphoma cell line Raji cell and Daudi cell was stronge. After the use of liposomes for cell transfection, VCP mRNA and protein expression level were restrained65%and57%respectively. The gene silencing was effective.
5. Flow cytometry showed that the cell apoptosis enhanced obviously after the VCP gene was silence in human lymphoma cell line Raji cell.
6. MTS method showed that cell growth was significantly suppressed after the VCP gene was silence in human lymphoma cell line Raji cell.
Conclusion:1. VCP may serve as a novel prognostic marker for prediction of prognosis of patients with primary orbital MALT lymphoma.
2. The suppressive effection of Si-VCP is obvious to the human lymphoma Raji cells. VCP mRNA expression level decreased obviously, which made the amount of VCP protein expression decreased obviously.
3. The VCP gene silencing which was used lipidosome mediated gene si-VCP transfection can obviously promote the training of lymphoma cells apoptosis and reduce the cell proliferation ability. VCP plays an important role in the process of apoptosis and proliferation in human lymphoma cells. VCP might create new therapeutic targets to primary orbital MALT lymphoma.
方法：1.58例原发性眼眶MALT淋巴瘤患者眶内淋巴瘤组织石蜡标本,采用免疫组化法检测VCP表达水平,并对VCP表达水平与患者复发情况及生存率的相关性进行统计学分析,用X2检验及Fisher精确检验来分析VCP蛋白表达与各临床因素之间的关系；Kaplan-Meier法计算复发率、生存率,并绘制生存曲线；log-rank法计算组间差异,P<0.05为差异具有统计学意义；
2.根据免疫组化结果即VCP蛋白表达水平,选取10例患者眶内肿瘤石蜡组织(5例×2组)抽提总RNA,并应用实时荧光定量PCR(RT-qPCR)定量比较2组VCP基因表达水平的差异；
3.免疫细胞化学染色法检测人淋巴瘤细胞系Raji细胞及Daudi细胞VCP蛋白的表达。应用特异、高效并操作方便的RNAi技术,以VCP作为基因靶点,对Raji细胞建立有效的RNA干扰方法。利用脂质体介导基因si-VCP转染Raji细胞,RT-qPCR及Western blot分别从1nRNA水平及蛋白水平评估Raji细胞VCP基因沉默效果；
4.流式细胞术检测VCP基因沉默的人淋巴瘤Raji细胞凋亡率的变化；
5.MTS法检测VCP基因沉默对Raji细胞增殖能力的影响。
结果：1.58例眼眶MALT淋巴瘤患者中13例(22.4%)患者出现肿瘤复发。复发时间为10-56个月,其平均值为39.5个月。8例患者(13.8%)死于肿瘤,4例患者(6.9%)死于与肿瘤无关的其他原因。5年无瘤生存率及总生存率分别是70.7%、79.3%。5年无瘤生存时间为10-60个月,其平均值为54.7个月；5年总生存时间为24-60个月,其平均值为57.2个月。
2.58例原发性眼眶MALT淋巴瘤患者眶内肿瘤组织VCP表达阳性细胞百分率为32%到95%。VCP表达阳性细胞百分率的中位值为45%,低于或等于45%为VCP表达level
1,高于45%为VCP表达level2。58例原发性眼眶MALT淋巴瘤患者眶内肿瘤组织VCP表达水平与患者复发(P=0.003)及肿瘤大小(P=0.008)密切相关。VCP表达水平与患者年龄、性别、LDH水平、红细胞沉降率(ESR)、血清白蛋白水平、有无B症状等临床特征无明显相关性(P>0.05)。同时,VCP表达level1患者5年无瘤生存率及总生存率明显高于level2患者(P=0.001；P=0.032)。
3.10例患者眶内肿瘤组织VCPmRNA表达水平与VCP蛋白表达水平一致,根据免疫组化结果level2组患者肿瘤组织VCPmRNA表达明显高于level1组(P=0.009)。
4.人淋巴瘤细胞系Raji细胞及Daudi细胞VCP蛋白表达较强。利用脂质体进行细胞转染,VCPmRNA水平和蛋白表达水平分别被抑制65%和57%,基因沉默效果肯定。
5.流式细胞术结果显示,人淋巴瘤细胞系Raji细胞VCP基因沉默后,细胞凋亡明显增强。
6.MTS结果显示,人淋巴瘤细胞系Raji细胞VCP基因沉默后,细胞增殖能力明显受到抑制。
结论：1.VCP是评价原发性眼眶MALT淋巴瘤患者预后的良好指标。
2.利用脂质体介导si-VCP对人淋巴瘤Raji细胞靶基因VCP的抑制效果明显,VCPmRNA表达水平明显降低,从而使VCP蛋白表达量明显下降。
3.VCP基因沉默可明显促进体外培养人淋巴瘤细胞的凋亡,并降低细胞增殖能力。VCP在人淋巴瘤细胞凋亡及增殖过程中起重要作用,可能是原发性眼眶MALT淋巴瘤治疗的新的分子靶点。
Objective: To study the correlation of the valosin-containing protein (VCP) expression level and the prognosis of primary orbital MALT lymphoma patient, and the influence of VCP to the apoptosis and proliferation of human lymphoma cells.
Methods:1. VCP expression in58samples from primary orbital MALT lymphoma patients was determined by immunohistochemisty using monoclonal antibody of VCP. The correlation between VCP expression level and prognosis was clarified with the statistical analysis. We calculated the recurrence rate and survival rate, and drawed the survival curve using the Kaplan-Meier method. We calculated the difference between the groups using the log-rank method. P values lower than0.05were considered statistically significant.
2. According to the results of immunohistochemistry, which was VCP protein expression level, we chose10cases orbital tumor paraffin tissue (5cases×2groups) of primary orbital MALT lymphoma patients. Extract the total RNA, and compare the difference of VCP gene expression level between the2groups using the RT-qPCR.
3. Immune cell chemical dyeing method was used to detect VCP protein expression of human lymphoma cell line Raji cell and Daudi cell. We chose VCP as gene target and established the effective method of RNA interference to the human lymphoma cell line Raji cell, using the specific, efficient and convenient operation of RNAi technology. We used lipidosome to mediate gene si-VCP transfection Raji cell. Then real-time quantitative PCR and western blot were used to assess the silencing effect of VCP for Raji cells gene from the mRNA level and protein level.
4. Detected the change of apoptosis rate of human lymphoma Raji cell which the VCP gene was silenced using the flow cytometry.
5. Detected the change of proliferation of human lymphoma Raji cell which the VCP gene was silenced using the MTS method.
Results:1. According to the follow-up visit of all patients in this study, we found that13/58(22.4%) patients suffered from tumor recurrence. The mean value of recurrence time was39.5months (range from10to56months).8/58(13.8%) patients died of tumor,4/58(6.9%) patients died of other causes unrelated to the tumor. As shown in table1, the5-year disease-free and overall survival rates were70.7%and79.3%, respectively. The mean value of5-year disease-free survival was54.7months (range from10to60months). The mean value of overall survival in the series was57.2months (range from24to60months).
2. It was found that the percentage of VCP positive cells in samples of primary orbital MALT lymphoma was ranging from32%to95%. The samples were divided into two groups (level1and level2) according to the median value (45%) of the percentage of VCP positive cells. It was found that the expression level of VCP was significantly correlated with the recurrence (P=0.003) and the tumor size (P=0.008). There was no observed correlation between the expression level of VCP and other clinical features. Meanwhile, the5-year disease-free and overall survival rate of patients of level1was significantly better than that of level2(P=0.001; P=0.032).
3. In the orbital tumor tissue of10primary orbital MALT lymphoma patients, the expression level of VCP mRNA was consistent with the protein expression level of VCP. According to the results of immunohistochemical the VCP mRNA expression in tumor tissue of level2group was significantly higher than that of level1group (P=0.009).
4. VCP protein expression of human lymphoma cell line Raji cell and Daudi cell was stronge. After the use of liposomes for cell transfection, VCP mRNA and protein expression level were restrained65%and57%respectively. The gene silencing was effective.
5. Flow cytometry showed that the cell apoptosis enhanced obviously after the VCP gene was silence in human lymphoma cell line Raji cell.
6. MTS method showed that cell growth was significantly suppressed after the VCP gene was silence in human lymphoma cell line Raji cell.
Conclusion:1. VCP may serve as a novel prognostic marker for prediction of prognosis of patients with primary orbital MALT lymphoma.
2. The suppressive effection of Si-VCP is obvious to the human lymphoma Raji cells. VCP mRNA expression level decreased obviously, which made the amount of VCP protein expression decreased obviously.
3. The VCP gene silencing which was used lipidosome mediated gene si-VCP transfection can obviously promote the training of lymphoma cells apoptosis and reduce the cell proliferation ability. VCP plays an important role in the process of apoptosis and proliferation in human lymphoma cells. VCP might create new therapeutic targets to primary orbital MALT lymphoma.
引文
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