视网膜母细胞瘤中Legumain的表达及其对临床病理和预后的影响
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摘要
目的：Legumain是最近新发现的一个半胱氨酸内肽酶家族新成员,在恶性实体肿瘤中高表达,与恶性肿瘤的浸润、侵袭、转移和预后密切相关。目前国内外尚未见关于Legumain与视网膜母细胞瘤的相关研究报道。本研究利用分子生物学技术检测Legumain在视网膜母细胞瘤细胞系和视网膜母细胞瘤组织中的表达及其与视网膜母细胞瘤临床病理指标之间的关系和对预后生存的影响,旨在为视网膜母细胞瘤的临床预后判断寻找一个新的指标,帮助辨认高危瘤,以便更好的指导临床治疗。
材料与方法：应用RT-PCR、Western-Blot和免疫荧光技术对视网膜母细胞瘤Y79和WERI-Rb-1细胞系中Legumain的表达情况进行检测；应用免疫组化染色法对1999年1月-2009年12月在天津市眼科医院就诊并行眼球摘除术的106例视网膜母细胞瘤病理组织切片进行Legumain染色,同时收集患儿各项临床病理特征,进行病理切片复习,根据患儿的不同情况采取不同的方式进行预后随访,利用SPSS16.0软件,通过卡方检验分析Legumain表达情况与视网膜母细胞瘤患儿的临床病理特征之间的关系,用Kaplan-Meier法及Log-rank检验进行单因素生存分析初步筛选与视网膜母细胞瘤预后相关的风险因素。
结果：在(?)mRNA和蛋白水平上,Legumain在视网膜母细胞瘤Y79和WERI-Rb-1细胞系中均有表达,而Y79细胞系中Legumain在基因和蛋白水平上的表达均高于WERI-Rb-1细胞系。通过对106例视网膜母细胞瘤组织进行免疫组化染色发现,有26例切片Legumain呈阴性表达,42例呈弱阳性表达,38例呈强阳性表达,Legumain阳性表达率为75%,在视网膜母细胞瘤的肿瘤血管内皮细胞中可见Legumain强阳性表达。当肿瘤侵犯视神经时,视神经纤维的Legumain表达明显增高。通过统计学分析发现,Legumain表达水平与视网膜母细胞瘤患儿的病程、有无眼部组织浸润特别是视神经侵犯程度密切相关(p<0.05),而与性别、眼别、患儿的初诊年龄、临床分期、病理组织分化程度以及脉络膜浸润程度无关(p>0.05)；视网膜母细胞瘤患儿的预后与Legumain表达水平、患儿的初诊年龄、病程、临床分期以及视神经侵犯程度有关(p<0.05)。
结论：Legumain在视网膜母细胞瘤细胞系和组织中均有表达,Legumain表达水平与视网膜母细胞瘤眼部组织的浸润程度尤其是视神经侵犯程度密切相关,同时Legumain的表达水平与患儿的预后有关联性,Legumain的表达水平可以作为视网膜母细胞瘤预后评价的一个重要指标。Legumain如何通过新生血管形成和肿瘤相关巨噬细胞从而对视网膜母细胞瘤的浸润侵袭和转移发挥作用是未来研究的一个方向。由于Legumain与肿瘤新生血管形成和肿瘤相关巨噬细胞关系密切,在肿瘤的浸润、侵袭和转移中发挥着重要的作用,加之它在肿瘤中特异性的表达特点,提示Legumian在不久的将来能够成为视网膜母细胞瘤治疗的一个新的潜在靶点。
Objective:Legumain is a novel asparaginyl endopeptidase. It was found to be highly expressed in several types of solid tumors. Therefore, the overexpression of Legumain has been shown to be combined with increased migration, invasion and metastasis. However, there is no data available identifying the relationship of Legumain expression and clinicopathologic in retinobla-stoma. This research aims to investigate the expression of the Legumain in retinoblastoma cell lines and specimens, analyze the relationship between Legumain expression, the clinic pathological and prognosis significance.
Method:The expression of Legumain in retinoblastoma Y79 and WERI-Rb-1 cell lines was detected by RT-PCR, western-blot and immunofluorescence. The expression of Legumain in retinoblastoma paraffin-embedded tissues was determined by immunohistochemistry. The association between the expression of Legumain and the clinicopathological characteristics including invasion and differentiation was examined by theχ2 method. The association of staining for Legumain and clinicopathological features with patient outcome were evaluated using Kaplan-Meier plots. Comparisons between groups were performed using the log-rank test. Statistical significance was assumed if the P value was less than 0.05. The computer software Statistical Package for the Social Sciences, version 16.0 (SPSS Inc, Chicago, Illinois, USA), was used to run all statistical tests.
Results:Legumain mRNA and protein expression in retinoblastoma Y79 cell line was higher than WERI-Rb-1 cell line. Among the 106 tumors, there were 26(24.5%) tumors showed negative expression,42(39.6%) tumors showed weak expression and 38(35.9%) tumors with strong expression. We observed Legumain was highly expressed by tumor vascular endothelial cells in retinoblastoma specimens and highly expressed in optic nerve with invasion. Legumain expression was related to course of disease and invasion of retinoblastoma(p<0.05), especially with the optic nerve invasion(p=0.020). There was no significant change between Legumain expression and sex, age, clinical stage and differentiation (p>0.05). The patients with tumors that showed negative of the Legumain expression had a better prognosis.
Conclusion:Legumian were expressed in retinoblastoma cell lines and specimens, The expression levels of Legumain was related to retinoblastoma invasion especially to the degree of optic nerve invasion and have a prognostic value in retinoblastoma. How Legumain have effect on retinoblastoma invasion by angiogenesis and tumor associated macrophages needs further study. Since Legumain and tumor angiogenesis and tumor associated macrophages are closely related to invasion and metastasis of tumor, coupled with its unique restricted specificity, Legumain may represent a potential candidate target for retinoblastoma therapy.
材料与方法：应用RT-PCR、Western-Blot和免疫荧光技术对视网膜母细胞瘤Y79和WERI-Rb-1细胞系中Legumain的表达情况进行检测；应用免疫组化染色法对1999年1月-2009年12月在天津市眼科医院就诊并行眼球摘除术的106例视网膜母细胞瘤病理组织切片进行Legumain染色,同时收集患儿各项临床病理特征,进行病理切片复习,根据患儿的不同情况采取不同的方式进行预后随访,利用SPSS16.0软件,通过卡方检验分析Legumain表达情况与视网膜母细胞瘤患儿的临床病理特征之间的关系,用Kaplan-Meier法及Log-rank检验进行单因素生存分析初步筛选与视网膜母细胞瘤预后相关的风险因素。
结果：在(?)mRNA和蛋白水平上,Legumain在视网膜母细胞瘤Y79和WERI-Rb-1细胞系中均有表达,而Y79细胞系中Legumain在基因和蛋白水平上的表达均高于WERI-Rb-1细胞系。通过对106例视网膜母细胞瘤组织进行免疫组化染色发现,有26例切片Legumain呈阴性表达,42例呈弱阳性表达,38例呈强阳性表达,Legumain阳性表达率为75%,在视网膜母细胞瘤的肿瘤血管内皮细胞中可见Legumain强阳性表达。当肿瘤侵犯视神经时,视神经纤维的Legumain表达明显增高。通过统计学分析发现,Legumain表达水平与视网膜母细胞瘤患儿的病程、有无眼部组织浸润特别是视神经侵犯程度密切相关(p<0.05),而与性别、眼别、患儿的初诊年龄、临床分期、病理组织分化程度以及脉络膜浸润程度无关(p>0.05)；视网膜母细胞瘤患儿的预后与Legumain表达水平、患儿的初诊年龄、病程、临床分期以及视神经侵犯程度有关(p<0.05)。
结论：Legumain在视网膜母细胞瘤细胞系和组织中均有表达,Legumain表达水平与视网膜母细胞瘤眼部组织的浸润程度尤其是视神经侵犯程度密切相关,同时Legumain的表达水平与患儿的预后有关联性,Legumain的表达水平可以作为视网膜母细胞瘤预后评价的一个重要指标。Legumain如何通过新生血管形成和肿瘤相关巨噬细胞从而对视网膜母细胞瘤的浸润侵袭和转移发挥作用是未来研究的一个方向。由于Legumain与肿瘤新生血管形成和肿瘤相关巨噬细胞关系密切,在肿瘤的浸润、侵袭和转移中发挥着重要的作用,加之它在肿瘤中特异性的表达特点,提示Legumian在不久的将来能够成为视网膜母细胞瘤治疗的一个新的潜在靶点。
Objective:Legumain is a novel asparaginyl endopeptidase. It was found to be highly expressed in several types of solid tumors. Therefore, the overexpression of Legumain has been shown to be combined with increased migration, invasion and metastasis. However, there is no data available identifying the relationship of Legumain expression and clinicopathologic in retinobla-stoma. This research aims to investigate the expression of the Legumain in retinoblastoma cell lines and specimens, analyze the relationship between Legumain expression, the clinic pathological and prognosis significance.
Method:The expression of Legumain in retinoblastoma Y79 and WERI-Rb-1 cell lines was detected by RT-PCR, western-blot and immunofluorescence. The expression of Legumain in retinoblastoma paraffin-embedded tissues was determined by immunohistochemistry. The association between the expression of Legumain and the clinicopathological characteristics including invasion and differentiation was examined by theχ2 method. The association of staining for Legumain and clinicopathological features with patient outcome were evaluated using Kaplan-Meier plots. Comparisons between groups were performed using the log-rank test. Statistical significance was assumed if the P value was less than 0.05. The computer software Statistical Package for the Social Sciences, version 16.0 (SPSS Inc, Chicago, Illinois, USA), was used to run all statistical tests.
Results:Legumain mRNA and protein expression in retinoblastoma Y79 cell line was higher than WERI-Rb-1 cell line. Among the 106 tumors, there were 26(24.5%) tumors showed negative expression,42(39.6%) tumors showed weak expression and 38(35.9%) tumors with strong expression. We observed Legumain was highly expressed by tumor vascular endothelial cells in retinoblastoma specimens and highly expressed in optic nerve with invasion. Legumain expression was related to course of disease and invasion of retinoblastoma(p<0.05), especially with the optic nerve invasion(p=0.020). There was no significant change between Legumain expression and sex, age, clinical stage and differentiation (p>0.05). The patients with tumors that showed negative of the Legumain expression had a better prognosis.
Conclusion:Legumian were expressed in retinoblastoma cell lines and specimens, The expression levels of Legumain was related to retinoblastoma invasion especially to the degree of optic nerve invasion and have a prognostic value in retinoblastoma. How Legumain have effect on retinoblastoma invasion by angiogenesis and tumor associated macrophages needs further study. Since Legumain and tumor angiogenesis and tumor associated macrophages are closely related to invasion and metastasis of tumor, coupled with its unique restricted specificity, Legumain may represent a potential candidate target for retinoblastoma therapy.
引文
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