TGF-β1在滑膜肉瘤中的作用及其促转移机制的研究
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摘要
目的：
检测TGF-β1在滑膜肉瘤中的表达,分析它在滑膜肉瘤发生发展中的作用,并探讨其促进滑膜肉瘤转移的可能机制。
方法：
1.分析滑膜肉瘤中TGF-β1的表达及其与SYT-SSX融合基因的关系。
收集天津医科大学附属肿瘤医院2005-2009年冻存的新鲜滑膜肉瘤组织标本35例,利用RT-PCR技术检测滑膜肉瘤的SYT-SSX亚型,应用Real-time PCR技术检测TGF-β1 mRNA的表达,分析TGF-β1 mRNA表达与SYT-SSX亚型的关系。
筛选1974-2005年经手术切除石蜡包埋的滑膜肉瘤组织标本140例,使用免疫组化技术检测TGF-β1蛋白的表达,RT-PCR检测SYT-SSX亚型,分析TGF-β1蛋白表达与SYT-SSX亚型的关系。
2.收集140例滑膜肉瘤的临床病理资料和随访资料,回顾性分析TGF-β1表达与患者临床病理参数及总体生存、无转移生存之间的关系,探讨TGF-β1在滑膜肉瘤发生发展中的作用。
3.在滑膜肉瘤石蜡包埋组织中,使用免疫组化方法检测CD31、MMP-2、TIMP-2、MMP-9、TIMP-1的表达,分析微血管密度(MVD)、基质金属蛋白酶及其抑制剂与肿瘤转移及患者总体生存、无转移生存的关系,进而分析它们与TGF-β1的关系,探讨TGF-β1促进滑膜肉瘤转移的作用机制。
结果：
1.TGF-β1在滑膜肉瘤中的表达及其与SYT-SSX融合基因的关系
新鲜滑膜肉瘤组织中检测到TGF-β1的mRNA表达量平均为0.154±0.110。在110例(78.6%)滑膜肉瘤石蜡包埋组织中检测到TGF-β1蛋白的表达,其中49例高表达,61例低表达。
TGF-β1在SYT-SSX1型和SYT-SSX2型新鲜滑膜肉瘤组织中的mRNA表达量分别为0.2385±0.1214和0.2385±0.1214,前组明显高于后组(t=2.960,P=0.007)。同样,在140例石蜡包埋组织中TGF-β1蛋白的表达与SYT-SSX亚型有关(t=2.093,P=0.004), SYT-SSX1型滑膜肉瘤(4.3265±2.0350)中TGF-β1蛋白的表达明显高于SYT-SSX2型滑膜肉瘤(3.4187±1.6019)。
2. TGF-β1与临床病理参数及患者生存的关系
TGF-β1的表达与滑膜肉瘤的组织学分型、临床分期、转移有关,在双相型、临床晚期、转移性滑膜肉瘤中的表达明显高于单相型、临床早期和非转移性滑膜肉瘤(均P<0.05)。TGF-β1的表达与患者的性别、年龄、肿瘤的部位、大小、组织学分级无关(均P>0.05)。
单因素生存分析结果显示,患者的年龄、肿瘤大小、病理学分级、临床分期、放疗、转移、TGF-β1是影响患者总体生存的危险因素(均P<0.05),而性别、肿瘤部位、组织学分型、化疗与患者的总体生存无关(均P>0.05)。多因素分析结果显示,TGF-β1的表达(RR=2.451,P=0.000)、肿瘤大小(RR=2.476,P=0.001)和临床分期(RR=2.199,P=0.005)是影响滑膜肉瘤患者总体生存的独立危险因素。
单因素分析影响滑膜肉瘤患者无转移生存的因素,结果表明,患者的年龄、放疗、组织学分级、TGF-β1的表达与滑膜肉瘤的无转移生存有关(均P<0.05),而性别、肿瘤大小、部位、组织学分型、化疗与滑膜肉瘤患者的无转移生存无关(均P>0.05)。多因素分析结果显示TGF-β1(RR=1.695,P=0.031)、患者年龄(RR=1.834,P=0.017)、组织学分级(RR=2.465,P=0.000)是影响滑膜肉瘤患者无转移生存的独立危险因素。
3.基质金属蛋白酶及其抑制剂和微血管密度与滑膜肉瘤转移及TGF-β1表达的关系
MMP-2、MMP-9高表达滑膜肉瘤的转移发生率明显高于低表达组(分别P=0.005,P=0.045),而TIMP-2、TIMP-1与是否发生转移无显著关系(P>0.05)。并且,MMP-2、MMP-9高表达患者的总体生存较差(分别P=0.009,P=0.027),无转移生存较差(分别P=0.000,P=0.018),而TIMP-2、TIMP-1的表达与患者的总体生存和无转移生存无关(P>0.05)。
相关性分析结果显示,TGF-β1与MMP-2(rs=0.238 P=0.005)、MMP-9(rs=0.117 P=0.036)的表达成正相关关系,而TIMP-2、TIMP-1与TGF-β1的表达无关(P>0.05)。
140例滑膜肉瘤的MVD为50.0±18.6个/HPF。MVD与滑膜肉瘤的转移无关,与患者的总体生存和无转移生存无关(P>0.05)。TGF-β1表达与MVD (rs=0.299,P=0.000)成正相关关系。
结论：
1.在大多数滑膜肉瘤中存在TGF-β1的表达。
2.结合前期研究结果,TGF-β1可能是SYT-SSX的一个下游基因,可能在SYT-SSX的调控下影响滑膜肉瘤的发生和进展。
3. TGF-β1可能促进肿瘤的转移,进而影响患者的总体生存和无转移生存。
4. TGF-β1可能通过上调MMP-2、MMP-9的表达,促进滑膜肉瘤的转移。
5.虽然TGF-β1可以促进滑膜肉瘤血管的生成,但是后者与肿瘤的转移没有直接关系。
Object:to test the expression of TGF-β1in synovial sarcoma, to analyze the function of TGF-β1 in synovial sarcoma and to investigate the possible mechanism of TGF-β1 regulating the metastasis of synovial sarcoma.
Methods:
1. Thirty five synovial sarcoma cases in Tianjin cancer hospital from 2005-2009 were collected in this study. RT-PCR detected the fusion gene subtype of synovial sarcoma. Real-time PCR detected the mRNA of TGF-β1. RT-PCR detected the fusion gene subtype of synovial sarcoma. Analyze the correlation between the expression of TGF-β1 and the subtype SYT-SSX.
140 synovial sarcoma tissues undergoing surgery and being Paraffin-embedded in Tianjin cancer hospital from 1974-2005 were selected in this study, the expression of TGF-β1 protein in synovial sarcoma were detected by immunohistochemistry. RT-PCR detected the subtype of fusion gene. Analyze the correlation between the protein expression of TGF-β1 and SYT-SSX.
2. The clinicopathological and follow-up data of 140 synovial sarcoma patients were reviewed. Analyze the correlation between TGF-β1 and clinicopathological parameters and the effect of TGF-β1 on the survival of synovial sarcoma patients. To study the contribution of TGF-β1 in synovial sarcoma
3. CD31, MMP-2, TIMP-2, MMP-9, TIMP-1 were detected by immunohistochemisry. Analyze the role of these factors in the metastasis and survival in synovial sarcoma. To study the correlation MVD, MMP-2, TIMP-2, MMP-9, TIMP-1 and TGF-β1, To study the mechanism of TGF-β1 regulating the metastasis of synovial sarcoma,
Results:
1. The expression of TGF-β1 in synovial sarcoma and the correlation between TGF-β1 and SYT-SSX fusion gene
The mRNA expression of TGF-β1 in fresh synovial sarcoma was 0.154±0.110.The protein expression of TGF-β1 was tested in 110 (78.6%) cases Paraffin-embedded tissues of synovial sarcoma. higher expression of TGF-β1 in 49 cases, lower expression of TGF-β1 in 61 cases.
The amount of TGF-β1 mRNA in SYT-SSX1 an SYT-SSX2 fresh synovial sarcoma tissues was 0.2385±0.1214 and 0.2385±0.1214, the SYT-SSX1 group was higher than SYT-SSX2 group (t=2.960,P=0.007). The expression of TGF-β1 protein correlated with subtype of SYT-SSX(t=2.093, P=0.004), The expression of TGF-β1 protein in SYT-SSX1 synovial sarcoma(4.3265±2.0350) was higher than SYT-SSX2 synovial sarcoma(3.4187±1.6019).
2. The correlation of TGF-β1 with clinicopathologic parameters and the survival of patients
The expression of TGF-β1 protein correlated with the type of histology, clinical stage, metastasis of synovial sarcomas. the expression of TGF-β1 protein in biphasic synovial sarcoma, later stage and metastatic synovial sarcomas were higher than monophasic synovial sarcomas, early stage and non-metastatic synovial sarcomas(P<0.05), the expression of TGF-β1 protein had no correlation with the sex, age, location, size, grade of synovial sarcomas (P>0.05).
Unvariable analyzed the factors that affecting the overall survival of synovial sarcoma patients. The results revealed that age, tumor size, histological grade, clinical stage, radiotherapy, metastasis, TGF-β1 affected the patients overall survival.(P<0.05). while sex, location, the subtype of histology, chemotherapy had no correlation with patients overall survival (P>0.05), multivariable analysis revealed that TGF-β1(RR=2.451 P=0.000), tumor size(RR=2.476 P=0.001), clinical stage(RR=2.199 P=0.005)were independent risk factors affecting the overall survival of synovial sarcoma patients.
Unvariable analyzed the factors that affecting the metastasis-free-survival of synovial sarcoma, which results revealed that age, radiotherapy, histological grade, TGF-β1 correlated with the metastasis-free-survival of synovial sarcoma(P<0.05). while sex, tumor size, location, subtype of histology therapy, chemotherapy had no correlation with the metastasis-free-survival of synovial sarcoma (P>0.05). Multivariable analysis revealed that TGF-β1(RR=1.695, P=0.031), patients age(RR=1.834, P=0.017), histological grade(RR=2.465,P=0.000) were independent risk factors affecting metastasis-free-survival of synovial sarcoma patients.
3. The correlation matrix metalloproteinases, Inhibitor of matrix metalloproteinases and microvessel density with the expression of TGF-β1
The synovial sarcomas with higher expression of MMP-2, MMP-9 were easily metastasis than that with lower expression of MMP-2, MMP-9(P=0.005,P=0.045),while TIMP-2、TIMP-1 had no correlation with the metastasis of synovial sarcoma(P<0.05). The synovial sarcomas patients with higher expression of MMP-2, MMP-9 had poor overall survival(P=0.009, P=0.027) and poor metastasis-free-survival of synovial sarcoma, (P=0.000,P=0.018). While TIMP-2、TIMP-1 had no correlation with the overall survival of synovial sarcoma and metastasis-free-survival of synovial sarcoma patients(P>0.05). Correlation analysis revealed that TGF-β1 correlated with MMP-2(rs=0.228 P=0.005), MMP-9 (rs=0.117 P=0.036), While TIMP-2、TIMP-1 had no correlated with TGF-β1(P>0.05).
The average density of microvessel in 140 synovial sarcomas were 50.0±18.6. MVD had no correlation with metastasis of synovial sarcomas, MVD had no correlation with the overall survival of synovial sarcoma and metastasis-free-survival of synovial sarcoma patients(P>0.05). While MVD had positive correlated with the expression of TGF-β1(rs=0.299,P=0.000). Conclusions:
1. The expression of TGF-β1 exists in most synovial sarcoma.
2. TGF-β1 might be a down-stream gene of SYT-SSX, SYT-SSX might regulate the genetic and development of synovial sarcoma by TGF-β1.
3. TGF-β1 possible promotes the metastasis of synovial sarcoma, which affectes patients survival.
4. TGF-β1 might control the metastasis of synovial sarcoma by up-regulating MMP-2, MMP-9.
5. Although TGF-β1 promotes the angiogenesis of synovial sarcoma, the microvessel has no direct correlation with the metastasis of synovial sarcoma.
检测TGF-β1在滑膜肉瘤中的表达,分析它在滑膜肉瘤发生发展中的作用,并探讨其促进滑膜肉瘤转移的可能机制。
方法：
1.分析滑膜肉瘤中TGF-β1的表达及其与SYT-SSX融合基因的关系。
收集天津医科大学附属肿瘤医院2005-2009年冻存的新鲜滑膜肉瘤组织标本35例,利用RT-PCR技术检测滑膜肉瘤的SYT-SSX亚型,应用Real-time PCR技术检测TGF-β1 mRNA的表达,分析TGF-β1 mRNA表达与SYT-SSX亚型的关系。
筛选1974-2005年经手术切除石蜡包埋的滑膜肉瘤组织标本140例,使用免疫组化技术检测TGF-β1蛋白的表达,RT-PCR检测SYT-SSX亚型,分析TGF-β1蛋白表达与SYT-SSX亚型的关系。
2.收集140例滑膜肉瘤的临床病理资料和随访资料,回顾性分析TGF-β1表达与患者临床病理参数及总体生存、无转移生存之间的关系,探讨TGF-β1在滑膜肉瘤发生发展中的作用。
3.在滑膜肉瘤石蜡包埋组织中,使用免疫组化方法检测CD31、MMP-2、TIMP-2、MMP-9、TIMP-1的表达,分析微血管密度(MVD)、基质金属蛋白酶及其抑制剂与肿瘤转移及患者总体生存、无转移生存的关系,进而分析它们与TGF-β1的关系,探讨TGF-β1促进滑膜肉瘤转移的作用机制。
结果：
1.TGF-β1在滑膜肉瘤中的表达及其与SYT-SSX融合基因的关系
新鲜滑膜肉瘤组织中检测到TGF-β1的mRNA表达量平均为0.154±0.110。在110例(78.6%)滑膜肉瘤石蜡包埋组织中检测到TGF-β1蛋白的表达,其中49例高表达,61例低表达。
TGF-β1在SYT-SSX1型和SYT-SSX2型新鲜滑膜肉瘤组织中的mRNA表达量分别为0.2385±0.1214和0.2385±0.1214,前组明显高于后组(t=2.960,P=0.007)。同样,在140例石蜡包埋组织中TGF-β1蛋白的表达与SYT-SSX亚型有关(t=2.093,P=0.004), SYT-SSX1型滑膜肉瘤(4.3265±2.0350)中TGF-β1蛋白的表达明显高于SYT-SSX2型滑膜肉瘤(3.4187±1.6019)。
2. TGF-β1与临床病理参数及患者生存的关系
TGF-β1的表达与滑膜肉瘤的组织学分型、临床分期、转移有关,在双相型、临床晚期、转移性滑膜肉瘤中的表达明显高于单相型、临床早期和非转移性滑膜肉瘤(均P<0.05)。TGF-β1的表达与患者的性别、年龄、肿瘤的部位、大小、组织学分级无关(均P>0.05)。
单因素生存分析结果显示,患者的年龄、肿瘤大小、病理学分级、临床分期、放疗、转移、TGF-β1是影响患者总体生存的危险因素(均P<0.05),而性别、肿瘤部位、组织学分型、化疗与患者的总体生存无关(均P>0.05)。多因素分析结果显示,TGF-β1的表达(RR=2.451,P=0.000)、肿瘤大小(RR=2.476,P=0.001)和临床分期(RR=2.199,P=0.005)是影响滑膜肉瘤患者总体生存的独立危险因素。
单因素分析影响滑膜肉瘤患者无转移生存的因素,结果表明,患者的年龄、放疗、组织学分级、TGF-β1的表达与滑膜肉瘤的无转移生存有关(均P<0.05),而性别、肿瘤大小、部位、组织学分型、化疗与滑膜肉瘤患者的无转移生存无关(均P>0.05)。多因素分析结果显示TGF-β1(RR=1.695,P=0.031)、患者年龄(RR=1.834,P=0.017)、组织学分级(RR=2.465,P=0.000)是影响滑膜肉瘤患者无转移生存的独立危险因素。
3.基质金属蛋白酶及其抑制剂和微血管密度与滑膜肉瘤转移及TGF-β1表达的关系
MMP-2、MMP-9高表达滑膜肉瘤的转移发生率明显高于低表达组(分别P=0.005,P=0.045),而TIMP-2、TIMP-1与是否发生转移无显著关系(P>0.05)。并且,MMP-2、MMP-9高表达患者的总体生存较差(分别P=0.009,P=0.027),无转移生存较差(分别P=0.000,P=0.018),而TIMP-2、TIMP-1的表达与患者的总体生存和无转移生存无关(P>0.05)。
相关性分析结果显示,TGF-β1与MMP-2(rs=0.238 P=0.005)、MMP-9(rs=0.117 P=0.036)的表达成正相关关系,而TIMP-2、TIMP-1与TGF-β1的表达无关(P>0.05)。
140例滑膜肉瘤的MVD为50.0±18.6个/HPF。MVD与滑膜肉瘤的转移无关,与患者的总体生存和无转移生存无关(P>0.05)。TGF-β1表达与MVD (rs=0.299,P=0.000)成正相关关系。
结论：
1.在大多数滑膜肉瘤中存在TGF-β1的表达。
2.结合前期研究结果,TGF-β1可能是SYT-SSX的一个下游基因,可能在SYT-SSX的调控下影响滑膜肉瘤的发生和进展。
3. TGF-β1可能促进肿瘤的转移,进而影响患者的总体生存和无转移生存。
4. TGF-β1可能通过上调MMP-2、MMP-9的表达,促进滑膜肉瘤的转移。
5.虽然TGF-β1可以促进滑膜肉瘤血管的生成,但是后者与肿瘤的转移没有直接关系。
Object:to test the expression of TGF-β1in synovial sarcoma, to analyze the function of TGF-β1 in synovial sarcoma and to investigate the possible mechanism of TGF-β1 regulating the metastasis of synovial sarcoma.
Methods:
1. Thirty five synovial sarcoma cases in Tianjin cancer hospital from 2005-2009 were collected in this study. RT-PCR detected the fusion gene subtype of synovial sarcoma. Real-time PCR detected the mRNA of TGF-β1. RT-PCR detected the fusion gene subtype of synovial sarcoma. Analyze the correlation between the expression of TGF-β1 and the subtype SYT-SSX.
140 synovial sarcoma tissues undergoing surgery and being Paraffin-embedded in Tianjin cancer hospital from 1974-2005 were selected in this study, the expression of TGF-β1 protein in synovial sarcoma were detected by immunohistochemistry. RT-PCR detected the subtype of fusion gene. Analyze the correlation between the protein expression of TGF-β1 and SYT-SSX.
2. The clinicopathological and follow-up data of 140 synovial sarcoma patients were reviewed. Analyze the correlation between TGF-β1 and clinicopathological parameters and the effect of TGF-β1 on the survival of synovial sarcoma patients. To study the contribution of TGF-β1 in synovial sarcoma
3. CD31, MMP-2, TIMP-2, MMP-9, TIMP-1 were detected by immunohistochemisry. Analyze the role of these factors in the metastasis and survival in synovial sarcoma. To study the correlation MVD, MMP-2, TIMP-2, MMP-9, TIMP-1 and TGF-β1, To study the mechanism of TGF-β1 regulating the metastasis of synovial sarcoma,
Results:
1. The expression of TGF-β1 in synovial sarcoma and the correlation between TGF-β1 and SYT-SSX fusion gene
The mRNA expression of TGF-β1 in fresh synovial sarcoma was 0.154±0.110.The protein expression of TGF-β1 was tested in 110 (78.6%) cases Paraffin-embedded tissues of synovial sarcoma. higher expression of TGF-β1 in 49 cases, lower expression of TGF-β1 in 61 cases.
The amount of TGF-β1 mRNA in SYT-SSX1 an SYT-SSX2 fresh synovial sarcoma tissues was 0.2385±0.1214 and 0.2385±0.1214, the SYT-SSX1 group was higher than SYT-SSX2 group (t=2.960,P=0.007). The expression of TGF-β1 protein correlated with subtype of SYT-SSX(t=2.093, P=0.004), The expression of TGF-β1 protein in SYT-SSX1 synovial sarcoma(4.3265±2.0350) was higher than SYT-SSX2 synovial sarcoma(3.4187±1.6019).
2. The correlation of TGF-β1 with clinicopathologic parameters and the survival of patients
The expression of TGF-β1 protein correlated with the type of histology, clinical stage, metastasis of synovial sarcomas. the expression of TGF-β1 protein in biphasic synovial sarcoma, later stage and metastatic synovial sarcomas were higher than monophasic synovial sarcomas, early stage and non-metastatic synovial sarcomas(P<0.05), the expression of TGF-β1 protein had no correlation with the sex, age, location, size, grade of synovial sarcomas (P>0.05).
Unvariable analyzed the factors that affecting the overall survival of synovial sarcoma patients. The results revealed that age, tumor size, histological grade, clinical stage, radiotherapy, metastasis, TGF-β1 affected the patients overall survival.(P<0.05). while sex, location, the subtype of histology, chemotherapy had no correlation with patients overall survival (P>0.05), multivariable analysis revealed that TGF-β1(RR=2.451 P=0.000), tumor size(RR=2.476 P=0.001), clinical stage(RR=2.199 P=0.005)were independent risk factors affecting the overall survival of synovial sarcoma patients.
Unvariable analyzed the factors that affecting the metastasis-free-survival of synovial sarcoma, which results revealed that age, radiotherapy, histological grade, TGF-β1 correlated with the metastasis-free-survival of synovial sarcoma(P<0.05). while sex, tumor size, location, subtype of histology therapy, chemotherapy had no correlation with the metastasis-free-survival of synovial sarcoma (P>0.05). Multivariable analysis revealed that TGF-β1(RR=1.695, P=0.031), patients age(RR=1.834, P=0.017), histological grade(RR=2.465,P=0.000) were independent risk factors affecting metastasis-free-survival of synovial sarcoma patients.
3. The correlation matrix metalloproteinases, Inhibitor of matrix metalloproteinases and microvessel density with the expression of TGF-β1
The synovial sarcomas with higher expression of MMP-2, MMP-9 were easily metastasis than that with lower expression of MMP-2, MMP-9(P=0.005,P=0.045),while TIMP-2、TIMP-1 had no correlation with the metastasis of synovial sarcoma(P<0.05). The synovial sarcomas patients with higher expression of MMP-2, MMP-9 had poor overall survival(P=0.009, P=0.027) and poor metastasis-free-survival of synovial sarcoma, (P=0.000,P=0.018). While TIMP-2、TIMP-1 had no correlation with the overall survival of synovial sarcoma and metastasis-free-survival of synovial sarcoma patients(P>0.05). Correlation analysis revealed that TGF-β1 correlated with MMP-2(rs=0.228 P=0.005), MMP-9 (rs=0.117 P=0.036), While TIMP-2、TIMP-1 had no correlated with TGF-β1(P>0.05).
The average density of microvessel in 140 synovial sarcomas were 50.0±18.6. MVD had no correlation with metastasis of synovial sarcomas, MVD had no correlation with the overall survival of synovial sarcoma and metastasis-free-survival of synovial sarcoma patients(P>0.05). While MVD had positive correlated with the expression of TGF-β1(rs=0.299,P=0.000). Conclusions:
1. The expression of TGF-β1 exists in most synovial sarcoma.
2. TGF-β1 might be a down-stream gene of SYT-SSX, SYT-SSX might regulate the genetic and development of synovial sarcoma by TGF-β1.
3. TGF-β1 possible promotes the metastasis of synovial sarcoma, which affectes patients survival.
4. TGF-β1 might control the metastasis of synovial sarcoma by up-regulating MMP-2, MMP-9.
5. Although TGF-β1 promotes the angiogenesis of synovial sarcoma, the microvessel has no direct correlation with the metastasis of synovial sarcoma.
引文
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