MTA1、Tiaml及MMP-9蛋白在皮肤恶性黑色素瘤中的表达
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摘要
背景
皮肤恶性黑色素瘤(cutaneous malignant melanoma, CMM)是一种起源于神经嵴黑色素细胞的皮肤恶性肿瘤。由于诸多因素的影响,近年来我国的CMM发病率有逐年上升的趋势。CMM易发生血行、淋巴转移,预后差、病死率高。大量研究证实CMM的发生发展和诸多恶性肿瘤一样,是一个多因素、多阶段、多步骤相互作用的过程。早期诊断及治疗可有效控制恶性黑色素瘤的发生发展。CMM的治疗方法目前已经趋向多样化,强调个体化治疗、多学科综合治疗。其中针对CMM侵袭转移的基因靶向治疗也已成为今后治疗的一个方向。研究发现肿瘤转移相关基因1(MTAl)和T淋巴瘤侵袭诱导因子1(Tiam1)基因二者和多种恶性肿瘤侵袭转移等生物特征密切相关。MTAl是NuRD (nucleosomeremodeling and histone deacetylase核小体重构及组蛋白脱乙酰基酶)复合物的组成部分,NuRD复合物可以通过影响染色质的状态,进而调整基因的复制；MTAl的功能区含有SH3结合区,该结合区所含的残基序列可以和Src基因的SH3结合域配对,而SH3结合域和信号转导通路中的浸润转移相关基因有关,如Tiam1。研究发现Tiam1是Src基因的下游效应因子,而Tiam1与MAPK通路有相互作用,可以激活P38MAPK通路,而P38活化可以诱导MMP-9的表达。MTA1、Tiam1和MMP-9三者之间是否存在某种联系,目前尚无相关研究；关于MTA1、Tiam1与CMM临床病理特征相关性的研究也鲜有报道。本研究旨在通过对MTAl和Tiam1的研究,以期进一步探索CMM的侵袭转移机制,为CMM的治疗寻找新的治疗靶点。
目的
检测MTA1、Tiam1及基质金属蛋白酶-9(MMP-9)在皮肤恶性黑色素瘤、交界痣和正常皮肤组织中的表达。探讨MTA1、Tiam1及MMP-9蛋白的表达与皮肤恶性黑色素瘤的临床病理学特征的关系,以及三者间的相互关系。
方法
收集2008年1月-2012年12月郑州大学第一附属医院病理科存档的皮肤恶性黑色素瘤蜡块52例,交界痣20例。其中皮肤恶性黑色素瘤患者男性24例,女性28例,年龄在22-76岁之间,平均年龄(56.8±11.2)岁；按有无淋巴结转移分为：有淋巴结转移者24例,无淋巴结转移者28例；按肿瘤细胞浸润深度Clark分级法分为：Ⅰ级(表皮及附属器上皮)14例,Ⅱ-Ⅲ级(真皮乳头层)14例,Ⅳ级(真皮网状层)9例,V级(侵及皮下组织)15例。交界痣20例,男性9例,女性11例,年龄在11-78岁之间,平均年龄(53.5±10.3)岁。选取20例正常皮肤组织作为对照组,20例正常皮肤组织均来自郑州大学第一附属医院整形外科手术切除的多余正常全厚皮肤,男性12例,女性8例,年龄在14-71岁之间,平均年龄(52.8±11.1)岁。所有实验研究对象均具有完整的病史资料,均不合并任何其他疾病,手术前均未行激光治疗、放射治疗和化学药物治疗等其他任何相关治疗。各组患者的性别、年龄以及其病变部位等均无显著性差异,具有可比性(P>0.05)。本实验采用链霉素抗生物素蛋白过氧化物酶(SP)法对52例CMM、20例交界痣和20例正常皮肤组织中MTAl、Tiam1及MMP-9蛋白的表达水平进行检测。本实验采用SPSS17.0软件进行数据处理；采用卡方检验比较MTA1、Tiam1及MMP-9蛋白的阳性表达率及三者与肿瘤细胞浸润转移的关系；采用Spearman等级相关分析方法分析CMM组织中三种蛋白表达的关联性,检验标准α=0.05,以P<0.05为有统计学意义,X2分割检验标准α'=0.05/3=0.0167。
结果
1.MTAl的蛋白产物主要表达于细胞浆和细胞核。MTAl在CMM中呈高表达,阳性表达率为71.2%(37/52);在交界痣和正常皮肤组织中呈低表达,阳性表达率分别为40.0%(8/20)和30.0%(6/20)。随肿瘤浸润深度的增加,MTAl在CMM中的表达水平增高(P<0.05);伴有淋巴结转移者中的表达水平高于不伴有淋巴结转移者中的表达水平(P<0.05)。
2.Tiam1基因的蛋白产物主要表达于细胞浆。Tiam1在CMM中呈高表达,阳性表达率为76.9%(40/52);在交界痣和正常皮肽组织中呈低表达,阳性表达率分别为35.0%(7/20)和25.0%(5/20)。随肿瘤浸润深度的增加,Tiam1在CMM中的表达水平增高(P<0.05);伴有淋巴结转移者中的表达水平高于不伴有淋巴结转移者中的表达水平(P<0.05)。
3.MMP-9蛋白主要表达于细胞浆。MMP-9在CMM中呈高表达；阳性表达率为75.0%(39/52);在皮肤交界痣和正常皮肤组织中呈低表达,阳性表达率分别为40.0%(8/20)和30%(6/20)。随肿瘤浸润深度的增加,MMP-9蛋白在CMM中表达水平增高(P<0.05);伴淋巴结转移者中的表达水平明显高于不伴淋巴结转移者中的表达水平(P<0.05)。
4.MTA1、Tiam1及MMP-9三者相关性的分析结果显示：MTAl与Tiam1表达呈正相关性(rP=0.356,P=0.009,P<0.05),Tiam1与MMP-9表达呈正相关性(rP=0.422,P=0.002,P<0.05),MTAl与MMP-9表达也呈正相关性(rP=0.515,P=0.000,P<0.05)。
结论
1.在CMM组织中,MTA1、Tiam1及MMP-9三者的表达水平都明显高于其各自在交界痣和正常皮肤组织中的表达水平；且三者的表达水平均和CMM组织中肿瘤的浸润深度及淋巴结转移相关(P<0.05)。
2.在CMM组织中,MTA1与Tiam1的表达呈正相关性,Tiam1与MMP-9的表达呈正相关性,MTAl与MMP-9的表达也呈正相关性。推测三者可能在共同促进肿瘤的浸润转移机制中存在某种相互关系或协同作用。
3.MTA1、Tiam1及MMP-9三者在CMM浸润转移中均发挥着重要作用；对三者在CMM中的表达情况进行联合检测,有望为判断CMM患者肿瘤是否发生浸润转移和评估预后提供参考,为CMM的基因治疗提供一个新思路。
Backgroud
Cutaneous malignant melanoma (CMM) is a malignant tumor that is originated from the neural crest melanocytes cells.Due to many factors, the incidence of CMM tends to be increased year by year. CMM is prone to blood and lymph node metastasis, poor prognosis and high mortality.But a large number of experimental studies have confirmed that, like many other malignancies, the occurrence and development of CMM is an interaction process of multi-factor, multi-phase and multi-step. Early diagnosis and treatment can effectively control the occurrence and development of melanoma.The treatment of CMM has been diversifying in recent years,emphasizing on individual therapy and multidisciplinary treatment.Among these treatments,the gene targeted therapy against the invasion and metastasis of CMM has also become a future treatment direction.More and more studies shown that metastasis-associated gene1(MTAl) and T lymphoma invasion and metastasis inducing gene1(Tiaml) are closely related to the invasion and metastasis of many malignant tumors.The study has found that MTA1is a part of the NuRD (nucleosomeremodeling and histone deacetylase)complex.The NuRD composite can affect chromatin state,thereby regulating the replication of the gene. Another study has found that the functional areas of the MTA1contain a SH3-binding area.The residue sequence which is contained in SH3-binding region can pair with the SH3-binding domain of the Src gene.The SH3binding domains are related to the invasion and metastasis-related genes of signal transduction pathway,such as Tiaml. The study has found that Tiaml is a downstream effector factor of the Src gene. There is an interaction between Tiaml and MAPK pathway. Tiaml can activate p38MAPK pathway,and then the activation of p38can induce the expression of MMP-9.There is still no research about whether there is a connection among MTAl,Tiaml and MMP-9.The study about the connection of MTAl,Tiaml and the clinical pathological features of CMM is rarely reported. Now,in order to explore the invasion and metastasis mechanism of CMM and to find a new therapeutic target for the treatment of the CMM, we need some further investigations about MTA1and Tiaml.
Aim
To detect the expression of MTA1, Tiaml and MMP-9protein in cutaneous malignant melanoma,junction nevus and normal skin tissue.To investigate the connection between the expression of MTA1,Tiaml and MMP-9protein and the clinicopathological features of cutaneous malignant melanoma,as well as the interrelation among them.
Method
52cases of cutaneous malignant melanoma paraffin blocks and20cases of junction nevus paraffin blocks have been collected by the department of pathology in the First Affiliated Hospital of Zhengzhou University during2009～2012.All of these paraffin blocks have complete resection and clear pathological diagnosis. CMM patients include24males and28femals, aged22to76years old,and the average age is (56.8±11.2) years old.According to lymph node metastasis,they can be divided into two groups:18cases with lymph node metastasis,24cases without lymph node metastasis. According to the depth of tumor invasion by Clark classification scheme,they can be divided into five groups:Level I (epidermis and adnexal epithelium)14cases,Level Ⅱ-Ⅲ(papillary dermis)14cases,Level IV(reticular dermis)9cases,Level V (subcutaneous tissue)15cases.20cases of junction nevus:9cases are males and11cases are females, aged11-78years old, the average age is (53.5±10.3) years old.20cases of normal full-thickness skin tissue are chosen as control groups, which come from Plastic Surgery of the First Affiliated Hospital of Zhengzhou University surgery resection.12cases are males,8cases are females. Aged14to71years old.The average age is (52.8±11.1) years old. All of these people have complete medical history information and don't have any other diseases. On the other hand, they don't have any relevant treatments before surgery, such as laser treatment, radiation therapy, chemotherapy and so on. There is no significant difference in patients'gender, age, disease lesion and so on.They are comparable (P＞0.05).We use SP immunohistochemical technique to detect the expression of MTAl, Tiaml and MMP-9in cutaneous malignant melanoma of the52cases, skin junction nevus of the20cases and normal skin tissue in the20cases. The statistics data is processed by SPSS17.0software. We use the Chi-square test to compare the expression of MTAl, Tiaml and MMP-9protein. On the other hand, we analyze the relation between three proteins and tumor cell invasion and metastasis. We analyze the correlation of the expression of three proteins in CMM tissue by the Spearman rank correlation analysis method. The test standard is0.05and the standard of x2division is0.0167.
Results
1. The MTA1protein product are mainly expressed on the cytoplasm of cells, but it also expressed on some cell'nucleus.MTAl is highly expressed in the CMM. The positive expression rate in CMM is71.2%(37/52).The positive expression rate in the junction nevus and normal skin tissue is lower. The positive expression rate is40.0%(8/20) and30.0%(6/20).On the one hand,we have found that, with the depth of tumor infiltration increasing, the expression level of MTA1in CMM has increased (P＜0.05).On the other hand,we have found that the expression level of MTA1in the tissue with lymph node metastasis is significantly higher than that without lymph node metastasis (P<0.05).
2. The Tiaml protein products are mainly expressed on the cytoplasm of cells. Tiaml is highly expressed in the CMM. The positive expression rate in CMM is76.9%(40/52).The positive expression rate in the junction nevus and normal skin tissue is lower. The positive expression rate is35.0%(7/20) and25.0%(5/20).On the one hand,we have found that,with the depth of tumor infiltration increasing, the expression level of Tiaml in CMM has increased (P＜0.05).On the other hand,we have found that the expression level of Tiaml in the tissue with lymph node metastasis is significantly higher than that without lymph node metastasis (P＜0.05).
3. The MMP-9protein is mainly expressed on the cytoplasm of cells. MMP-9is highly expressed in the CMM. The positive expression rate in CMM is75.0%(39/52).The positive expression rate in the junction nevus and normal skin tissue is lower. The positive expression rate is40.0%(8/20) and30%(6/20).On the one hand,we have found that,with the depth of tumor infiltration increasing, the expression level of MMP-9in CMM has increased (P＜0.05).On the other hand,we have found that the expression level of MMP-9in the tissue with lymph node metastasis is significantly higher than that without lymph node metastasis (P＜0.05).
4. The correlation analysis of MTAl,Tiaml and MMP-9has shown that the expression of MTA1and Tiaml in CMM is positively associated (rP=0.356,P=0.009,P＜0.05). The expression of Tiaml and MMP-9in CMM is positively associated (rP=0.422yP=0.002,P＜0.05). The expression of MTAl and MMP-9in CMM is positively associated (rP=0.515, P=0.000, P＜0.05).
Conclusions
1. The expression levels of MTA1,Tiaml and MMP-9in CMM are significantly higher than the expression levels of MTAl,Tiaml and MMP-9in the junction nevus and the normal skin tissue. On the other hand,the expression of MTA1,Tiaml and MMP-9in CMM tissue is related to the invasion depth of tumor and lymph node metastasis (P＜0.05).
2. The expression of MTA1and Tiaml in CMM is positively associated. The expression of Tiaml and MMP-9in CMM is positively associated. The expression of MTA1and MMP-9in CMM is positively associated.In CMM,It's speculated that there may be some existing relationship among MTAl,Tiaml and MMP-9in CMM. They work together to promote tumor invasion and metastasis.
3. MTA1, Tiaml and MMP-9in CMM play an important role in tumor invasion and metastasis. The joint detection of the expression of them in CMM may be expected to provide a reference to the invasion and metastasis of tumor and the assessment of prognosis. On the other hand, it may offer a new idea for the gene therapy of CMM.
皮肤恶性黑色素瘤(cutaneous malignant melanoma, CMM)是一种起源于神经嵴黑色素细胞的皮肤恶性肿瘤。由于诸多因素的影响,近年来我国的CMM发病率有逐年上升的趋势。CMM易发生血行、淋巴转移,预后差、病死率高。大量研究证实CMM的发生发展和诸多恶性肿瘤一样,是一个多因素、多阶段、多步骤相互作用的过程。早期诊断及治疗可有效控制恶性黑色素瘤的发生发展。CMM的治疗方法目前已经趋向多样化,强调个体化治疗、多学科综合治疗。其中针对CMM侵袭转移的基因靶向治疗也已成为今后治疗的一个方向。研究发现肿瘤转移相关基因1(MTAl)和T淋巴瘤侵袭诱导因子1(Tiam1)基因二者和多种恶性肿瘤侵袭转移等生物特征密切相关。MTAl是NuRD (nucleosomeremodeling and histone deacetylase核小体重构及组蛋白脱乙酰基酶)复合物的组成部分,NuRD复合物可以通过影响染色质的状态,进而调整基因的复制；MTAl的功能区含有SH3结合区,该结合区所含的残基序列可以和Src基因的SH3结合域配对,而SH3结合域和信号转导通路中的浸润转移相关基因有关,如Tiam1。研究发现Tiam1是Src基因的下游效应因子,而Tiam1与MAPK通路有相互作用,可以激活P38MAPK通路,而P38活化可以诱导MMP-9的表达。MTA1、Tiam1和MMP-9三者之间是否存在某种联系,目前尚无相关研究；关于MTA1、Tiam1与CMM临床病理特征相关性的研究也鲜有报道。本研究旨在通过对MTAl和Tiam1的研究,以期进一步探索CMM的侵袭转移机制,为CMM的治疗寻找新的治疗靶点。
目的
检测MTA1、Tiam1及基质金属蛋白酶-9(MMP-9)在皮肤恶性黑色素瘤、交界痣和正常皮肤组织中的表达。探讨MTA1、Tiam1及MMP-9蛋白的表达与皮肤恶性黑色素瘤的临床病理学特征的关系,以及三者间的相互关系。
方法
收集2008年1月-2012年12月郑州大学第一附属医院病理科存档的皮肤恶性黑色素瘤蜡块52例,交界痣20例。其中皮肤恶性黑色素瘤患者男性24例,女性28例,年龄在22-76岁之间,平均年龄(56.8±11.2)岁；按有无淋巴结转移分为：有淋巴结转移者24例,无淋巴结转移者28例；按肿瘤细胞浸润深度Clark分级法分为：Ⅰ级(表皮及附属器上皮)14例,Ⅱ-Ⅲ级(真皮乳头层)14例,Ⅳ级(真皮网状层)9例,V级(侵及皮下组织)15例。交界痣20例,男性9例,女性11例,年龄在11-78岁之间,平均年龄(53.5±10.3)岁。选取20例正常皮肤组织作为对照组,20例正常皮肤组织均来自郑州大学第一附属医院整形外科手术切除的多余正常全厚皮肤,男性12例,女性8例,年龄在14-71岁之间,平均年龄(52.8±11.1)岁。所有实验研究对象均具有完整的病史资料,均不合并任何其他疾病,手术前均未行激光治疗、放射治疗和化学药物治疗等其他任何相关治疗。各组患者的性别、年龄以及其病变部位等均无显著性差异,具有可比性(P>0.05)。本实验采用链霉素抗生物素蛋白过氧化物酶(SP)法对52例CMM、20例交界痣和20例正常皮肤组织中MTAl、Tiam1及MMP-9蛋白的表达水平进行检测。本实验采用SPSS17.0软件进行数据处理；采用卡方检验比较MTA1、Tiam1及MMP-9蛋白的阳性表达率及三者与肿瘤细胞浸润转移的关系；采用Spearman等级相关分析方法分析CMM组织中三种蛋白表达的关联性,检验标准α=0.05,以P<0.05为有统计学意义,X2分割检验标准α'=0.05/3=0.0167。
结果
1.MTAl的蛋白产物主要表达于细胞浆和细胞核。MTAl在CMM中呈高表达,阳性表达率为71.2%(37/52);在交界痣和正常皮肤组织中呈低表达,阳性表达率分别为40.0%(8/20)和30.0%(6/20)。随肿瘤浸润深度的增加,MTAl在CMM中的表达水平增高(P<0.05);伴有淋巴结转移者中的表达水平高于不伴有淋巴结转移者中的表达水平(P<0.05)。
2.Tiam1基因的蛋白产物主要表达于细胞浆。Tiam1在CMM中呈高表达,阳性表达率为76.9%(40/52);在交界痣和正常皮肽组织中呈低表达,阳性表达率分别为35.0%(7/20)和25.0%(5/20)。随肿瘤浸润深度的增加,Tiam1在CMM中的表达水平增高(P<0.05);伴有淋巴结转移者中的表达水平高于不伴有淋巴结转移者中的表达水平(P<0.05)。
3.MMP-9蛋白主要表达于细胞浆。MMP-9在CMM中呈高表达；阳性表达率为75.0%(39/52);在皮肤交界痣和正常皮肤组织中呈低表达,阳性表达率分别为40.0%(8/20)和30%(6/20)。随肿瘤浸润深度的增加,MMP-9蛋白在CMM中表达水平增高(P<0.05);伴淋巴结转移者中的表达水平明显高于不伴淋巴结转移者中的表达水平(P<0.05)。
4.MTA1、Tiam1及MMP-9三者相关性的分析结果显示：MTAl与Tiam1表达呈正相关性(rP=0.356,P=0.009,P<0.05),Tiam1与MMP-9表达呈正相关性(rP=0.422,P=0.002,P<0.05),MTAl与MMP-9表达也呈正相关性(rP=0.515,P=0.000,P<0.05)。
结论
1.在CMM组织中,MTA1、Tiam1及MMP-9三者的表达水平都明显高于其各自在交界痣和正常皮肤组织中的表达水平；且三者的表达水平均和CMM组织中肿瘤的浸润深度及淋巴结转移相关(P<0.05)。
2.在CMM组织中,MTA1与Tiam1的表达呈正相关性,Tiam1与MMP-9的表达呈正相关性,MTAl与MMP-9的表达也呈正相关性。推测三者可能在共同促进肿瘤的浸润转移机制中存在某种相互关系或协同作用。
3.MTA1、Tiam1及MMP-9三者在CMM浸润转移中均发挥着重要作用；对三者在CMM中的表达情况进行联合检测,有望为判断CMM患者肿瘤是否发生浸润转移和评估预后提供参考,为CMM的基因治疗提供一个新思路。
Backgroud
Cutaneous malignant melanoma (CMM) is a malignant tumor that is originated from the neural crest melanocytes cells.Due to many factors, the incidence of CMM tends to be increased year by year. CMM is prone to blood and lymph node metastasis, poor prognosis and high mortality.But a large number of experimental studies have confirmed that, like many other malignancies, the occurrence and development of CMM is an interaction process of multi-factor, multi-phase and multi-step. Early diagnosis and treatment can effectively control the occurrence and development of melanoma.The treatment of CMM has been diversifying in recent years,emphasizing on individual therapy and multidisciplinary treatment.Among these treatments,the gene targeted therapy against the invasion and metastasis of CMM has also become a future treatment direction.More and more studies shown that metastasis-associated gene1(MTAl) and T lymphoma invasion and metastasis inducing gene1(Tiaml) are closely related to the invasion and metastasis of many malignant tumors.The study has found that MTA1is a part of the NuRD (nucleosomeremodeling and histone deacetylase)complex.The NuRD composite can affect chromatin state,thereby regulating the replication of the gene. Another study has found that the functional areas of the MTA1contain a SH3-binding area.The residue sequence which is contained in SH3-binding region can pair with the SH3-binding domain of the Src gene.The SH3binding domains are related to the invasion and metastasis-related genes of signal transduction pathway,such as Tiaml. The study has found that Tiaml is a downstream effector factor of the Src gene. There is an interaction between Tiaml and MAPK pathway. Tiaml can activate p38MAPK pathway,and then the activation of p38can induce the expression of MMP-9.There is still no research about whether there is a connection among MTAl,Tiaml and MMP-9.The study about the connection of MTAl,Tiaml and the clinical pathological features of CMM is rarely reported. Now,in order to explore the invasion and metastasis mechanism of CMM and to find a new therapeutic target for the treatment of the CMM, we need some further investigations about MTA1and Tiaml.
Aim
To detect the expression of MTA1, Tiaml and MMP-9protein in cutaneous malignant melanoma,junction nevus and normal skin tissue.To investigate the connection between the expression of MTA1,Tiaml and MMP-9protein and the clinicopathological features of cutaneous malignant melanoma,as well as the interrelation among them.
Method
52cases of cutaneous malignant melanoma paraffin blocks and20cases of junction nevus paraffin blocks have been collected by the department of pathology in the First Affiliated Hospital of Zhengzhou University during2009～2012.All of these paraffin blocks have complete resection and clear pathological diagnosis. CMM patients include24males and28femals, aged22to76years old,and the average age is (56.8±11.2) years old.According to lymph node metastasis,they can be divided into two groups:18cases with lymph node metastasis,24cases without lymph node metastasis. According to the depth of tumor invasion by Clark classification scheme,they can be divided into five groups:Level I (epidermis and adnexal epithelium)14cases,Level Ⅱ-Ⅲ(papillary dermis)14cases,Level IV(reticular dermis)9cases,Level V (subcutaneous tissue)15cases.20cases of junction nevus:9cases are males and11cases are females, aged11-78years old, the average age is (53.5±10.3) years old.20cases of normal full-thickness skin tissue are chosen as control groups, which come from Plastic Surgery of the First Affiliated Hospital of Zhengzhou University surgery resection.12cases are males,8cases are females. Aged14to71years old.The average age is (52.8±11.1) years old. All of these people have complete medical history information and don't have any other diseases. On the other hand, they don't have any relevant treatments before surgery, such as laser treatment, radiation therapy, chemotherapy and so on. There is no significant difference in patients'gender, age, disease lesion and so on.They are comparable (P＞0.05).We use SP immunohistochemical technique to detect the expression of MTAl, Tiaml and MMP-9in cutaneous malignant melanoma of the52cases, skin junction nevus of the20cases and normal skin tissue in the20cases. The statistics data is processed by SPSS17.0software. We use the Chi-square test to compare the expression of MTAl, Tiaml and MMP-9protein. On the other hand, we analyze the relation between three proteins and tumor cell invasion and metastasis. We analyze the correlation of the expression of three proteins in CMM tissue by the Spearman rank correlation analysis method. The test standard is0.05and the standard of x2division is0.0167.
Results
1. The MTA1protein product are mainly expressed on the cytoplasm of cells, but it also expressed on some cell'nucleus.MTAl is highly expressed in the CMM. The positive expression rate in CMM is71.2%(37/52).The positive expression rate in the junction nevus and normal skin tissue is lower. The positive expression rate is40.0%(8/20) and30.0%(6/20).On the one hand,we have found that, with the depth of tumor infiltration increasing, the expression level of MTA1in CMM has increased (P＜0.05).On the other hand,we have found that the expression level of MTA1in the tissue with lymph node metastasis is significantly higher than that without lymph node metastasis (P<0.05).
2. The Tiaml protein products are mainly expressed on the cytoplasm of cells. Tiaml is highly expressed in the CMM. The positive expression rate in CMM is76.9%(40/52).The positive expression rate in the junction nevus and normal skin tissue is lower. The positive expression rate is35.0%(7/20) and25.0%(5/20).On the one hand,we have found that,with the depth of tumor infiltration increasing, the expression level of Tiaml in CMM has increased (P＜0.05).On the other hand,we have found that the expression level of Tiaml in the tissue with lymph node metastasis is significantly higher than that without lymph node metastasis (P＜0.05).
3. The MMP-9protein is mainly expressed on the cytoplasm of cells. MMP-9is highly expressed in the CMM. The positive expression rate in CMM is75.0%(39/52).The positive expression rate in the junction nevus and normal skin tissue is lower. The positive expression rate is40.0%(8/20) and30%(6/20).On the one hand,we have found that,with the depth of tumor infiltration increasing, the expression level of MMP-9in CMM has increased (P＜0.05).On the other hand,we have found that the expression level of MMP-9in the tissue with lymph node metastasis is significantly higher than that without lymph node metastasis (P＜0.05).
4. The correlation analysis of MTAl,Tiaml and MMP-9has shown that the expression of MTA1and Tiaml in CMM is positively associated (rP=0.356,P=0.009,P＜0.05). The expression of Tiaml and MMP-9in CMM is positively associated (rP=0.422yP=0.002,P＜0.05). The expression of MTAl and MMP-9in CMM is positively associated (rP=0.515, P=0.000, P＜0.05).
Conclusions
1. The expression levels of MTA1,Tiaml and MMP-9in CMM are significantly higher than the expression levels of MTAl,Tiaml and MMP-9in the junction nevus and the normal skin tissue. On the other hand,the expression of MTA1,Tiaml and MMP-9in CMM tissue is related to the invasion depth of tumor and lymph node metastasis (P＜0.05).
2. The expression of MTA1and Tiaml in CMM is positively associated. The expression of Tiaml and MMP-9in CMM is positively associated. The expression of MTA1and MMP-9in CMM is positively associated.In CMM,It's speculated that there may be some existing relationship among MTAl,Tiaml and MMP-9in CMM. They work together to promote tumor invasion and metastasis.
3. MTA1, Tiaml and MMP-9in CMM play an important role in tumor invasion and metastasis. The joint detection of the expression of them in CMM may be expected to provide a reference to the invasion and metastasis of tumor and the assessment of prognosis. On the other hand, it may offer a new idea for the gene therapy of CMM.
引文
[1]张晓实,陈映波,黄文林主编.黑色素瘤基础与临床[M].北京：人民卫生出版社,2010,第一版.
[2]Toh Y,Pencil SD,Nicolson GL.A Novel candidate metastasis-associated gene, mtal, differentially expressed in high metastatic adenocarcinoma cell lines [J].JBiolChem,1994,269(37):22958-22963.
[3]Pencil SD, Toh Y, Nicolson GL. Candidate metastasis-associated gene of the rat 13762NF mammary adenocarcinoma[J].Breast Cancer Res Treat,1993,25(2):165-174.
[4]Toh Y, Pencil SD, Nicolson GL. Analysis of the complete sequence of the novel cetastatic metastasis-associated gene,mtal,differentlially expressed in highly metastatic mammary adenocarcinoma and breast cancer cell lines[J],Gene,1995,759(1):97-104.
[5]Nawa A, Nishimori K, Lin P, et al.Tumor metastasis-associated human MTA1 gene:its reduced protein sequence, localization and association with breast cancer proliferation using antisense phosphorothioate oligonuleotides[J].J Cell Biochem,2000,79(2):201-212.
[6]Bowen NJ et al. Biochim Biophys Acta,2004,1677:52-57.
[7]Mertens AE, Roovers RC, Collard JG Regulation of Tiaml-Rac signaling[J]. FEBS Lett,2003,546(1):11-16.
[8]Buchsbaum RJ, Connolly BA, Feig LA, et al. Regulation of p70 S6 kinase by complex formation between the rac guanine nucleotide exchange factor (Rac-GEF) TIAM1 and the scaffold spinophilin J Biol Chem,2003,278(21):18833-18841.
[9]Mark A, Baumeister, Lenka Martinu,et,al. Loss of phosphatidy-linositol 3-Phosohate binding by the c-terminal Tiam-1 pleckstrin homology domain prevents in vivo racl activation without affecting membrane targeting. J Biol Chem,2003,278(13):11457-11464.
[10]Eva E, Sander, Same van Delft, et al.Matrix-dependent Tiaml/Rac signaling in epithelial cells promotes either cell-cell Adhesion or cell migration and is regulated by phosphatidylinositol 3-Kinase.J Cell Biol,1998,143(5):1385-1398.
[11]Servitja JM, Marinissen MJ, Sodhi A, et al. Racl function is required for tiaml and vav2 in rac activation by src.J Biol Chem,2003,278(36):34449-34346.
[12]Makinen PI, Koponen JK, Karkkainen AM,et al. Stable RNA interference:comparison of U6 and H1 promoters in endothelial cells and in mouse brain[J].J Gene Med,2006,8(4):433-441.
[13]Verville GJ, Sanderson GA.Early atokan fusulinids from the lower Antler overlap sequence, Lander and Humboldt counties, Nevada [J]. Journal of Paleontology,2000,62(4):520-530.
[14]Jian R, Peng T, Deng S, et al. A simple strategy for generation of gene knockdown constructs with convergent H1 and U6 promoters[J].Eur J Cell Biol,2006,85(5):433-440.
[15]Fish RJ,Kruithof EK. Short-term cytotoxic effects and long-term instability of RNAi delivered using lentiviral vectors[J]. BMC Mol Biol,2004,8(4):2005-2011.
[16]Wang H, Tan SS, Wang XY, et al. Silencing livin gene by siRNA leads to apoptosis induction,cell cycle arrest, and proliferation inhibition in malignant melanoma LiBr cells[J].Acta pharmacol Sin,2007,28(6):1968-1974.
[17]陈华江,基质金属蛋白酶及其抑制物与肿瘤侵袭和转移的关系[J],国外医学,肿瘤学分册,2001,28(1)：23-26.
[18]Sato F, Shimada Y, Watanable G, et al. Expression of vascular endothelial growth factor,matrix metalloproteinase-9 and E-cadherin in the process of lymph node metastasis in esophageal cancer[J]Br J Cancer,1999,80(9):1366-1372.
[19]Kan V. Lu,Jeffrey P. Chang,Christine A. Parachoniak,Melissa M. Pandika,Manish K. Aghi,David Meyronet,Nadezda Isachenko,Shaun D. Fouse,Joanna J. Phillips,David A. Cheresh,Morag Park,Gabriele Bergers. VEGF Inhibits Tumor Cell Invasion and Mesenchymal Transition through a MET/VEGFR2 Complex[J]. Cancer Cell,2012,22(1):.
[20]Ichiyama T, Kajimoto M, Hasegawa M, Hashimoto K, Matsubara T, Furukawa S.Cysteinyl leukotrienes enhance tumour necrosis factor-alpha-induced matrix metalloproteinase-9 in human monocytes/macrophages. [J]. Clin Exp Allergy.2007 Apr;37(4):608-14.
[21]Lee LY, Wu CM, Wang CC, et al. Expression of matrix metalloproteinases MMP-2 and MMP-9 in gastric cancer and their relation to claudin-4 expression[J]. Histol Histopathol, 2008,23(5):515-521.
[22]杨定忠,王作仁,何晶等.基质金属蛋白酶-9在胆管癌中的表达与侵袭转移的关系[J]中华肝胆外科杂志,2004,18(2)：95-97.
[23]刘彤华,编著.诊断病理学[M].北京：人民卫生出版社,2006,第二版.
[24]Bagheri-Yarmand R, Balasenthil S, Gururaj AE, et al.Metastasis-associated protein 1 transgenic mice:a new model of spontaneous B-cell lympjomas[J]. Cancer Res,2007,67(15):7062-7067.
[25]Nicolson G L, Moustafa AS.Metastasis-Associated genes and metastatic tumor progression[J].InVivo,1998,12(6):579-88.
[26]Toh Y, Oki E, Oda S, et al. Overexpression of the MTA1 gene in gastrointestinal carcinomas: correlation with invasion and metastasis[J]. Int J Cancer,1997,74(4):459-63.
[27]Simpson A,Uitto J, Rodeck U, et al. Differential expression and subcellular distribution of the mouse metastasiss-associated proteins Mtal and Mta3[J]. Gene,2001,273(1):29-39.
[28]Kidd M, Modlin IM, Mane SM, et al. The role of genetic markers-NAP1L1, MAGE-D2, and MTAl--in defining small-intestinal carcinoid neop lasia. Oncogene.2006; 13(2): 253-62.
[29]TOH Y,OHGA T,ENDO K, et al.Expression of the metastasis-associated MTAlprotein and its relationship to deacetylation of the histone H4 in esophageal squamous cellcarcinomas[J].Int J Cancer,2004,110:363-367.
[30]NICOLSON G L,NAWA A,TOH Y,et al. Tumor metastasis-associated human MTA1 gene and its MTA1 protein product:role in epithelial cancer cell invasion,proliferation and nuclear regulation[J],Clin Exp Metastasis,2003,20:29-24.
[31]]邱前辉,刘鹏,陈少华,蒙翠原,朱振宇,李添应.MTAl基因在鼻咽癌中表达与肿瘤转移和EB病毒感染的关系[J].中山大学学报(医学科学版),2004,(S2)：105-107.
[32]Christopher Hassett. Effects of Chemical Inducers on Human Microsomal Epoxide Hydrolase in Primary Hepatocyte Cultures. [J].Biochemical Pharmacology,1998,55(7)
[33]Buchsbaum RJ,Connolly BA, eig LA, et al.Regulation of p70 S6 kinase by complex formation between the rac guanine nucleotide exchange factor (Rac-GEF) TIAM1 and the scaffold spinophilin. J Biol Chem,2003,278(21):18833-18841.
[34]Mark A, Baumeister, Lenka Martinu, et al. Loss of phosphatidy-linositol 3-Phosphate binding by the c-terminal Tiam-1 pleckstrin homology domain prevents in vivo racl activation without affecting membrane targeting.J Biol Chen,2003,278(13):11457-11464.
[35]Hamelers IH,Olivo C,Mertens AE, et al.Interation between Tiaml is required for (alpha)3(beta)1-mediated laminin-5 deposition,cell spreading,and cell migration[J].J Cell Biol,2005,171(5):871-881.
[36]Related Articles, Links Patel V,Rosenfeldt HM,et al.Persistent activation of RAC1 in squamous carcinomas of the head and neck:evidence for an EGFR/Vav2 signaling axis involved in cell invasion [J].Carcinogenesis,2007,28(6):1145-1152.
[37]Ten Klooster JP,Evers EE,Janssen L,et al. Interaction between Tiaml and the Arp2/3 complex links activation of Rac to action polymerization[J]. Biochem J,2006,397(1):39-45.
[38]Otsuki Y, Tanaka M,Yoshii S,et al. Tumor metastasis qupperssor nm23H1 regulates Rac1GTPase by interaction with Tiaml[J].Proc Natl Acad Sci USA,2001,98(8):4386-4390.
[39]Engers R,Springer E,Kehren V, et al. Rac upregulates tissue inhibitor of metalloproteinase-1 expression by redox-dependent activation of extacellular signal-regulated kinase signaling[J].FEBS J,2006,273(20):475-4769.
[40]Stanley Zucker.Paul Mancuso.Betty DiMassimo,Rita M. Lysik,Cathleen Conner,Chien-Liang Wu. Comparison of techniques for measurement of gelatinases/type IV collagenases:enzyme-linked immunoassays versus substrate degradation assays[J]. Clinical & Experimental Metastasis,1994,12(1):.
[41]M. Jeziorska,N. Y. Haboubi,P. F. Schofield,Y. Ogata,H. Nagase,D. E. Woolley. Distribution of gelatinase B (MMP-9) and type IV collagen in colorectal carcinoma[J]. International Journal of Colorectal Disease,1994,9(3):.
[42]L. C. Tetlow.M. Lees,Y. Ogata.H. Nagase.D. E. Woolley. Differential expression of gelatinase B (MMP-9) and stromelysin-1 (MMP-3) by rheumatoid synovial cells in vitro and in vivo[J]. Rheumatology International,1993,13(2):.
[1]张晓实,陈映波,黄文林主编.黑色素瘤基础与临床[M].北京：人民卫生出版社,2010,第一版.
[2]孙东杰.中国西部两大医院皮肤恶性肿瘤20年回顾[D].中国人民解放军第四军医大学,2003.
[3]高天文,孙东杰,李春英,何弘,李青,刘友生,刁庆春,黄高升,郝飞,钟白玉,马福成,柳凤轩,闫小初,刘东梅,刘玉峰,刘荣卿.中国西部两医院1905例皮肤恶性肿瘤回顾分析[J].北京大学学报(医学版),2004,(05)：469-472.
[4]夏莉,冯悦,张晓鸣,黄继辉,王乐,杨晶,张宁妹.老年人面部皮肤癌130例临床分析[J].宁夏医学杂志,2009,(01)：74-75.
[5]Pencil SD, Toh Y, Nicolson GL. Candidate metastasis-associated gene of the rat 13762NF mammary adenocarcinoma[J].Breast Cancer Res Treat,1993,25(2):165-174.
[6]Toh Y,Pencil SD,Nicolson GL.A Novel candidate metastasis-associated gene,mtal, differentially expressed in high metastatic adenocarcinoma cell lines [J]. JBiolChem, 1994,269(37):22958-22963.
[7]Toh Y, Pencil SD, Nicolson GL. Analysis of the complete sequence of the novel cetastatic metastasis-associated gene,mtal,differentlially expressed in highly metastatic mammary adenocarcinoma and breast cancer cell lines[J],Gene,1995,759(1):97-104.
[8]Nawa A, Nishimori K, Lin P, et al.Tumor metastasis-associated human MTA1 gene:its reduced protein sequence, localization and association with breast cancer proliferation using antisense phosphorothioate oligonuleotides[J].J Cell Biochem,2000,79(2):201-212.
[9]Manavathi B, Singh K, Kumar R, et al. MTA family of coregulators in nuclear receptor biology and pathology [J].Nucl Recept Signal,2007,30(5):e010.
[10]Toh Y,Oki E,Oda S, et al. Overexpression of the MTA1 gene in gastrointestinal carcinomas: correlation with invasion and metastasis[J].Int J Cancer,1997,74(4):459-63.
[11]Nicolson G L,Moustafa A S.Merastasis-Associated genes and metastatic tumor progression[J].In Vivo,1998,12(6):579-88.
[12]Bagher-Yarmand R,Balasenthil S,Gururaj AE,et al.Metastasis-associated protein 1 transgenic mice:a new model of spontaneous B-cell lymphomas[J].Cancer Res,2007,67(15):7062-7067.
[13]Zhang Y, leRoy QSeelig HP,et al.Molecular analysis of a candidate metastasis-associated gene,MTAl:possible interaction with histone deacetylasel[J].I Exp Clin Cancer Res,2000,19(1):105-111.
[14]Zhang Y,Ng HH,Erdjument Bromage H,et al.Analysis of the NuRD submits reveals a histone deacetylase core complex and a correction with DNA methylation[J].Genes Dev,1999, 13(15):1924-1935.
[15]Solari F,Bateman A,Ahringer J. The caenorhabditis elegans genes eg127 and her-1 are similar to MTA1,a member of a chromation regulatory complex,and are redundantly required for embryonic patterning[J].Development,1999,126(11):2483-2494.
[16]Manacathi B,Singh K,Kumar R,et al. MTA family of coregulators innuclear receptor biology and pathology[J].Nucl Recept Signal,2007,30(5):e010.
[17]Bowen NJ et al. Biochim Biophys Acta,2004,1677:52-57.
[18]De Craene B et al.Cancer Res,2005,65(14):6237-6244.
[19]Simpson A,Uitto J, Rodeck U, et al. Differential expression and subcellular distribution of the mouse metastasiss-associated proteins Mtal and Mta3[J]. Gene,2001,273(1):29-39.
[20]TOH Y.OHGA T,ENDO K, et al.Expression of the metastasis-associated MTA1 protein and its relationship to deacetylation of the histone H4 in esophageal squamous cellcarcinomas [J].Int J Cancer,2004,110:363-367.
[21]NICOLSON G L,NAWA A,TOH Y,et al. Tumor metastasis-associated human MTA1 gene and its MTA1 protein product:role in epithelial cancer cell invasion,proliferation and nuclear regulation[J],Clin Exp Metastasis,2003,20:29-24.
[22]Simpson A,Uitto J, Rodeck U, et al. Differential expression and subcellular distribution of the mouse metastasiss-associated proteins Mtal and Mta3[J]. Gene,2001,273(1):29-39.
[23]Mahoneu M G, Simpson A,Jost M,et al.Metastasis-associated protein(MTA)1 enhances migration,invasion,and anchorage-independent survival of immortalized human keratinocytes[J].Oncogene,2002,21(41):2161-70.
[24]邱前辉,刘鹏,陈少华,蒙翠原,朱振宇,李添应.MTAl基因在鼻咽癌中表达与肿瘤转移和EB病毒感染的关系[J].中山大学学报(医学科学版),2004,(S2)：105-107.
[25]Talukder AH,Mishra SK,Mandal M,et al. MTA1 interacts with MTA1,a cyclin-dependent kinase-activating kinase comples ring finger factor,and regulatesestrogen receptor transactivation fuctions[J].J Biol Chem.2003,278(13):11676-11685.
[26]Martin M D,Hilsenbeck S G,Mohsin S K, et al.Breast tumors that overexpression nuclear metastasis-associated 1(MTAl)protein have high recurrence risks but enhanced responses to systemic therapies[J].Breast Cancer Res Treat.2006,95(1):7-12.
[27]Bagheri-Yarmand R,Talukder AH,Wang RA,et al.Metastasis-associated protein lderegulation cause inappropriate mammary gland development and umorigenesis [J]. Development,2004,131(141):3469-3479.
[28]Sasaki H,Moriyama S,Nakashima Y, et al.Expression of the MTA1 Mrna in advanced lung cancer[J].Lung Cancer,2002,35(2):149-154.
[29]钱锦贤,李定彪,洪志鹏.肿瘤转移相关基因MTAl在肿瘤中的研究进展[J].云南医药,2008,(05)：515-518.
[30]刘晨旭,周斌.MTA1蛋白在非小细胞肺癌中的表达及临床意义[J].医学信息,2010,(04)：923-924.
[31]张华,张明月,王洲,刘相燕,陈钢,刘凡英.肿瘤转移相关基因表达与Ⅰ期非小细胞肺癌预后的相关性[J].肿瘤,2010,(10)：881-885.
[32]刘运贤,胡亚翎,刘菊梅,张弦,蔡贽,杨倩.肺癌PTEN、MTAl、p73表达与预后相关性[J].蚌埠医学院学报,2005,(06)：52-54.
[33]Yi S, Guangqi H. Guoli H. The association of the expression of MTAl, rim23HI with theinvasion. metastasis of ovarian carcinoma[JJ. Chin MedSci J,2003,18(2):87—92.
[34]王艳伟,宋文歧.MTA1蛋白在卵巢癌中的表达及意义[J].中外医疗,2009,(06)：71.
[35]Luo J,Su F,Chen D, et al. Deacetylation of p53 modulates its effect on cell growth and apoptosis[J].Nature,2000,408(6810):377-381.
[36]Kumar DS,Pakala SB,Nair VS,er al.Mechanism of MTA1 over expression-linked invasion:MTAl regulation of HMMR expression and function[J].Biol Chem,2011,287 (8):5483-5491.
[37]李焱,张涛,高辉,等.MTAl和VEGF-C在结肠癌组织中的表达及其与淋巴管转移的关系[J]现代医学,2009,37(6)：401-404.
[38]高冬玲,陈奎生,赵志华,等.食管鳞状细胞癌组织中MTAl和E-cadherin蛋白的表达[J].郑州大学学报(医学版).2007,42(6)：1028-1030.
[39]李江,杨竹林,黄江生,杨乐平,苗雄鹰,兰思根.胆囊腺癌雌激素受体、转移相关基因1表达和微血管计数及其相关性研究[J].中国医学工程,2007,(11)：871-875.
[40]李江,黄江生,杨竹林,杨乐平,付汐.胆囊良恶性病变转移相关基因1表达和淋巴管计数及相关性研究[J].中国现代医学杂志,2008,(02)：202-205+208.
[41]Hamatsu T, Rikimaru T, Yamashita Y, et al. The role of MTA1 gene expression in human hepatocellular carcinoma[J]. Oncol Rep.2003,10(3):599-604.
[42]林川,陈汉,吴盂超,等.肿瘤转移基因MTAl的分子克隆及其在肝癌组织中表达的初步研究[J].中华普通外科杂志,2000,15(10)：634.
[43]Moon W S, Chang K, Tarnawski A S. Overexpression of metastatic tumor, antigen 1 in hepatocellular carcinoma:Relationship to vascular invasion and estrogen receptor-alpha[J]. Hum Pathol.2004,35(4):424-429.
[44]Iguchi H, Imura G, Toh Y, et al. Expression of MTA1, a metastasis-associated gene with histone deacetylase activity in pancreatic cancer[J]. Int J Oncol.2000,16(6):1211-1214.
[45]王会河,黄光武,莫立根,赵惠柳,邝国乾.MTA1表达与鼻咽癌浸润转移的关系[J].广西医科大学学报,2006,(04)：546-548.
[46]莫立根,王会河,赵惠柳,邝国乾,黄光武.MTAl在鼻咽癌中的表达及意义[J].现代肿瘤医学,2005,(06)：18-20.
[47]王会河,莫立根,黄光武,邝国乾.mtal基因和癌肿转移[J].中国医学文摘(肿瘤学),2004,(02)：147-149.
[48]王会河.基因Mtal. Tiaml mRNA表达与鼻咽癌浸润转移的关系[D].广西医科大学,2005.
[49]周冬妮,邓燕飞,曾亮,胡骏,张其清.MTAl基因在鼻咽癌中的表达及临床意义[J].临床耳鼻咽喉头颈外科杂志,2009,(04)：178-180.
[50]邓燕飞,周冬妮,曾亮.MTAl和RECK基因在鼻咽癌中的表达及意义[J].临床耳鼻咽喉头颈外科杂志,2011,(12)：534-538.
[51]许小涛,泽璋.肿瘤转移相关基因MTA1与鼻咽癌细胞浸润和转移的关系[J].中国美容医学,2010,(10)：7-8.
[52]唐桥筵,季文樾,潘子民,等.转移相关基因表达与喉鳞状细胞癌淋巴结转移的天系[J].中华耳鼻咽喉科杂志,2003,38(3)：213-216.
[53]王会河,黄光武,韦福依,莫立根,邝国乾.基因MTA1在喉癌中的表达和意义[J].临床耳鼻咽喉科杂志,2006,(03)：113-115.
[54]Hofer MD, Kuefer R, Varambally S, et al. The role of metastasis——associated protein 1 in prostate cancer progression[J]. Cancer Res,2004,64(3):825-829.
[55]YI Chengla, LI Xinzhi, XU Weiguo, et al. Relationship between the expression of MTA1 gene and the metastasis and invasion in human osteosareomal[J].J Huazhong Univ Sci Technolog Med Sci,2005,25(4):445—447.
[56]钱海利.MTA1基因在肿瘤侵袭转移中的作用及机制研究[D].中国协和医科大学,2005.
[2]Toh Y,Pencil SD,Nicolson GL.A Novel candidate metastasis-associated gene, mtal, differentially expressed in high metastatic adenocarcinoma cell lines [J].JBiolChem,1994,269(37):22958-22963.
[3]Pencil SD, Toh Y, Nicolson GL. Candidate metastasis-associated gene of the rat 13762NF mammary adenocarcinoma[J].Breast Cancer Res Treat,1993,25(2):165-174.
[4]Toh Y, Pencil SD, Nicolson GL. Analysis of the complete sequence of the novel cetastatic metastasis-associated gene,mtal,differentlially expressed in highly metastatic mammary adenocarcinoma and breast cancer cell lines[J],Gene,1995,759(1):97-104.
[5]Nawa A, Nishimori K, Lin P, et al.Tumor metastasis-associated human MTA1 gene:its reduced protein sequence, localization and association with breast cancer proliferation using antisense phosphorothioate oligonuleotides[J].J Cell Biochem,2000,79(2):201-212.
[6]Bowen NJ et al. Biochim Biophys Acta,2004,1677:52-57.
[7]Mertens AE, Roovers RC, Collard JG Regulation of Tiaml-Rac signaling[J]. FEBS Lett,2003,546(1):11-16.
[8]Buchsbaum RJ, Connolly BA, Feig LA, et al. Regulation of p70 S6 kinase by complex formation between the rac guanine nucleotide exchange factor (Rac-GEF) TIAM1 and the scaffold spinophilin J Biol Chem,2003,278(21):18833-18841.
[9]Mark A, Baumeister, Lenka Martinu,et,al. Loss of phosphatidy-linositol 3-Phosohate binding by the c-terminal Tiam-1 pleckstrin homology domain prevents in vivo racl activation without affecting membrane targeting. J Biol Chem,2003,278(13):11457-11464.
[10]Eva E, Sander, Same van Delft, et al.Matrix-dependent Tiaml/Rac signaling in epithelial cells promotes either cell-cell Adhesion or cell migration and is regulated by phosphatidylinositol 3-Kinase.J Cell Biol,1998,143(5):1385-1398.
[11]Servitja JM, Marinissen MJ, Sodhi A, et al. Racl function is required for tiaml and vav2 in rac activation by src.J Biol Chem,2003,278(36):34449-34346.
[12]Makinen PI, Koponen JK, Karkkainen AM,et al. Stable RNA interference:comparison of U6 and H1 promoters in endothelial cells and in mouse brain[J].J Gene Med,2006,8(4):433-441.
[13]Verville GJ, Sanderson GA.Early atokan fusulinids from the lower Antler overlap sequence, Lander and Humboldt counties, Nevada [J]. Journal of Paleontology,2000,62(4):520-530.
[14]Jian R, Peng T, Deng S, et al. A simple strategy for generation of gene knockdown constructs with convergent H1 and U6 promoters[J].Eur J Cell Biol,2006,85(5):433-440.
[15]Fish RJ,Kruithof EK. Short-term cytotoxic effects and long-term instability of RNAi delivered using lentiviral vectors[J]. BMC Mol Biol,2004,8(4):2005-2011.
[16]Wang H, Tan SS, Wang XY, et al. Silencing livin gene by siRNA leads to apoptosis induction,cell cycle arrest, and proliferation inhibition in malignant melanoma LiBr cells[J].Acta pharmacol Sin,2007,28(6):1968-1974.
[17]陈华江,基质金属蛋白酶及其抑制物与肿瘤侵袭和转移的关系[J],国外医学,肿瘤学分册,2001,28(1)：23-26.
[18]Sato F, Shimada Y, Watanable G, et al. Expression of vascular endothelial growth factor,matrix metalloproteinase-9 and E-cadherin in the process of lymph node metastasis in esophageal cancer[J]Br J Cancer,1999,80(9):1366-1372.
[19]Kan V. Lu,Jeffrey P. Chang,Christine A. Parachoniak,Melissa M. Pandika,Manish K. Aghi,David Meyronet,Nadezda Isachenko,Shaun D. Fouse,Joanna J. Phillips,David A. Cheresh,Morag Park,Gabriele Bergers. VEGF Inhibits Tumor Cell Invasion and Mesenchymal Transition through a MET/VEGFR2 Complex[J]. Cancer Cell,2012,22(1):.
[20]Ichiyama T, Kajimoto M, Hasegawa M, Hashimoto K, Matsubara T, Furukawa S.Cysteinyl leukotrienes enhance tumour necrosis factor-alpha-induced matrix metalloproteinase-9 in human monocytes/macrophages. [J]. Clin Exp Allergy.2007 Apr;37(4):608-14.
[21]Lee LY, Wu CM, Wang CC, et al. Expression of matrix metalloproteinases MMP-2 and MMP-9 in gastric cancer and their relation to claudin-4 expression[J]. Histol Histopathol, 2008,23(5):515-521.
[22]杨定忠,王作仁,何晶等.基质金属蛋白酶-9在胆管癌中的表达与侵袭转移的关系[J]中华肝胆外科杂志,2004,18(2)：95-97.
[23]刘彤华,编著.诊断病理学[M].北京：人民卫生出版社,2006,第二版.
[24]Bagheri-Yarmand R, Balasenthil S, Gururaj AE, et al.Metastasis-associated protein 1 transgenic mice:a new model of spontaneous B-cell lympjomas[J]. Cancer Res,2007,67(15):7062-7067.
[25]Nicolson G L, Moustafa AS.Metastasis-Associated genes and metastatic tumor progression[J].InVivo,1998,12(6):579-88.
[26]Toh Y, Oki E, Oda S, et al. Overexpression of the MTA1 gene in gastrointestinal carcinomas: correlation with invasion and metastasis[J]. Int J Cancer,1997,74(4):459-63.
[27]Simpson A,Uitto J, Rodeck U, et al. Differential expression and subcellular distribution of the mouse metastasiss-associated proteins Mtal and Mta3[J]. Gene,2001,273(1):29-39.
[28]Kidd M, Modlin IM, Mane SM, et al. The role of genetic markers-NAP1L1, MAGE-D2, and MTAl--in defining small-intestinal carcinoid neop lasia. Oncogene.2006; 13(2): 253-62.
[29]TOH Y,OHGA T,ENDO K, et al.Expression of the metastasis-associated MTAlprotein and its relationship to deacetylation of the histone H4 in esophageal squamous cellcarcinomas[J].Int J Cancer,2004,110:363-367.
[30]NICOLSON G L,NAWA A,TOH Y,et al. Tumor metastasis-associated human MTA1 gene and its MTA1 protein product:role in epithelial cancer cell invasion,proliferation and nuclear regulation[J],Clin Exp Metastasis,2003,20:29-24.
[31]]邱前辉,刘鹏,陈少华,蒙翠原,朱振宇,李添应.MTAl基因在鼻咽癌中表达与肿瘤转移和EB病毒感染的关系[J].中山大学学报(医学科学版),2004,(S2)：105-107.
[32]Christopher Hassett. Effects of Chemical Inducers on Human Microsomal Epoxide Hydrolase in Primary Hepatocyte Cultures. [J].Biochemical Pharmacology,1998,55(7)
[33]Buchsbaum RJ,Connolly BA, eig LA, et al.Regulation of p70 S6 kinase by complex formation between the rac guanine nucleotide exchange factor (Rac-GEF) TIAM1 and the scaffold spinophilin. J Biol Chem,2003,278(21):18833-18841.
[34]Mark A, Baumeister, Lenka Martinu, et al. Loss of phosphatidy-linositol 3-Phosphate binding by the c-terminal Tiam-1 pleckstrin homology domain prevents in vivo racl activation without affecting membrane targeting.J Biol Chen,2003,278(13):11457-11464.
[35]Hamelers IH,Olivo C,Mertens AE, et al.Interation between Tiaml is required for (alpha)3(beta)1-mediated laminin-5 deposition,cell spreading,and cell migration[J].J Cell Biol,2005,171(5):871-881.
[36]Related Articles, Links Patel V,Rosenfeldt HM,et al.Persistent activation of RAC1 in squamous carcinomas of the head and neck:evidence for an EGFR/Vav2 signaling axis involved in cell invasion [J].Carcinogenesis,2007,28(6):1145-1152.
[37]Ten Klooster JP,Evers EE,Janssen L,et al. Interaction between Tiaml and the Arp2/3 complex links activation of Rac to action polymerization[J]. Biochem J,2006,397(1):39-45.
[38]Otsuki Y, Tanaka M,Yoshii S,et al. Tumor metastasis qupperssor nm23H1 regulates Rac1GTPase by interaction with Tiaml[J].Proc Natl Acad Sci USA,2001,98(8):4386-4390.
[39]Engers R,Springer E,Kehren V, et al. Rac upregulates tissue inhibitor of metalloproteinase-1 expression by redox-dependent activation of extacellular signal-regulated kinase signaling[J].FEBS J,2006,273(20):475-4769.
[40]Stanley Zucker.Paul Mancuso.Betty DiMassimo,Rita M. Lysik,Cathleen Conner,Chien-Liang Wu. Comparison of techniques for measurement of gelatinases/type IV collagenases:enzyme-linked immunoassays versus substrate degradation assays[J]. Clinical & Experimental Metastasis,1994,12(1):.
[41]M. Jeziorska,N. Y. Haboubi,P. F. Schofield,Y. Ogata,H. Nagase,D. E. Woolley. Distribution of gelatinase B (MMP-9) and type IV collagen in colorectal carcinoma[J]. International Journal of Colorectal Disease,1994,9(3):.
[42]L. C. Tetlow.M. Lees,Y. Ogata.H. Nagase.D. E. Woolley. Differential expression of gelatinase B (MMP-9) and stromelysin-1 (MMP-3) by rheumatoid synovial cells in vitro and in vivo[J]. Rheumatology International,1993,13(2):.
[1]张晓实,陈映波,黄文林主编.黑色素瘤基础与临床[M].北京：人民卫生出版社,2010,第一版.
[2]孙东杰.中国西部两大医院皮肤恶性肿瘤20年回顾[D].中国人民解放军第四军医大学,2003.
[3]高天文,孙东杰,李春英,何弘,李青,刘友生,刁庆春,黄高升,郝飞,钟白玉,马福成,柳凤轩,闫小初,刘东梅,刘玉峰,刘荣卿.中国西部两医院1905例皮肤恶性肿瘤回顾分析[J].北京大学学报(医学版),2004,(05)：469-472.
[4]夏莉,冯悦,张晓鸣,黄继辉,王乐,杨晶,张宁妹.老年人面部皮肤癌130例临床分析[J].宁夏医学杂志,2009,(01)：74-75.
[5]Pencil SD, Toh Y, Nicolson GL. Candidate metastasis-associated gene of the rat 13762NF mammary adenocarcinoma[J].Breast Cancer Res Treat,1993,25(2):165-174.
[6]Toh Y,Pencil SD,Nicolson GL.A Novel candidate metastasis-associated gene,mtal, differentially expressed in high metastatic adenocarcinoma cell lines [J]. JBiolChem, 1994,269(37):22958-22963.
[7]Toh Y, Pencil SD, Nicolson GL. Analysis of the complete sequence of the novel cetastatic metastasis-associated gene,mtal,differentlially expressed in highly metastatic mammary adenocarcinoma and breast cancer cell lines[J],Gene,1995,759(1):97-104.
[8]Nawa A, Nishimori K, Lin P, et al.Tumor metastasis-associated human MTA1 gene:its reduced protein sequence, localization and association with breast cancer proliferation using antisense phosphorothioate oligonuleotides[J].J Cell Biochem,2000,79(2):201-212.
[9]Manavathi B, Singh K, Kumar R, et al. MTA family of coregulators in nuclear receptor biology and pathology [J].Nucl Recept Signal,2007,30(5):e010.
[10]Toh Y,Oki E,Oda S, et al. Overexpression of the MTA1 gene in gastrointestinal carcinomas: correlation with invasion and metastasis[J].Int J Cancer,1997,74(4):459-63.
[11]Nicolson G L,Moustafa A S.Merastasis-Associated genes and metastatic tumor progression[J].In Vivo,1998,12(6):579-88.
[12]Bagher-Yarmand R,Balasenthil S,Gururaj AE,et al.Metastasis-associated protein 1 transgenic mice:a new model of spontaneous B-cell lymphomas[J].Cancer Res,2007,67(15):7062-7067.
[13]Zhang Y, leRoy QSeelig HP,et al.Molecular analysis of a candidate metastasis-associated gene,MTAl:possible interaction with histone deacetylasel[J].I Exp Clin Cancer Res,2000,19(1):105-111.
[14]Zhang Y,Ng HH,Erdjument Bromage H,et al.Analysis of the NuRD submits reveals a histone deacetylase core complex and a correction with DNA methylation[J].Genes Dev,1999, 13(15):1924-1935.
[15]Solari F,Bateman A,Ahringer J. The caenorhabditis elegans genes eg127 and her-1 are similar to MTA1,a member of a chromation regulatory complex,and are redundantly required for embryonic patterning[J].Development,1999,126(11):2483-2494.
[16]Manacathi B,Singh K,Kumar R,et al. MTA family of coregulators innuclear receptor biology and pathology[J].Nucl Recept Signal,2007,30(5):e010.
[17]Bowen NJ et al. Biochim Biophys Acta,2004,1677:52-57.
[18]De Craene B et al.Cancer Res,2005,65(14):6237-6244.
[19]Simpson A,Uitto J, Rodeck U, et al. Differential expression and subcellular distribution of the mouse metastasiss-associated proteins Mtal and Mta3[J]. Gene,2001,273(1):29-39.
[20]TOH Y.OHGA T,ENDO K, et al.Expression of the metastasis-associated MTA1 protein and its relationship to deacetylation of the histone H4 in esophageal squamous cellcarcinomas [J].Int J Cancer,2004,110:363-367.
[21]NICOLSON G L,NAWA A,TOH Y,et al. Tumor metastasis-associated human MTA1 gene and its MTA1 protein product:role in epithelial cancer cell invasion,proliferation and nuclear regulation[J],Clin Exp Metastasis,2003,20:29-24.
[22]Simpson A,Uitto J, Rodeck U, et al. Differential expression and subcellular distribution of the mouse metastasiss-associated proteins Mtal and Mta3[J]. Gene,2001,273(1):29-39.
[23]Mahoneu M G, Simpson A,Jost M,et al.Metastasis-associated protein(MTA)1 enhances migration,invasion,and anchorage-independent survival of immortalized human keratinocytes[J].Oncogene,2002,21(41):2161-70.
[24]邱前辉,刘鹏,陈少华,蒙翠原,朱振宇,李添应.MTAl基因在鼻咽癌中表达与肿瘤转移和EB病毒感染的关系[J].中山大学学报(医学科学版),2004,(S2)：105-107.
[25]Talukder AH,Mishra SK,Mandal M,et al. MTA1 interacts with MTA1,a cyclin-dependent kinase-activating kinase comples ring finger factor,and regulatesestrogen receptor transactivation fuctions[J].J Biol Chem.2003,278(13):11676-11685.
[26]Martin M D,Hilsenbeck S G,Mohsin S K, et al.Breast tumors that overexpression nuclear metastasis-associated 1(MTAl)protein have high recurrence risks but enhanced responses to systemic therapies[J].Breast Cancer Res Treat.2006,95(1):7-12.
[27]Bagheri-Yarmand R,Talukder AH,Wang RA,et al.Metastasis-associated protein lderegulation cause inappropriate mammary gland development and umorigenesis [J]. Development,2004,131(141):3469-3479.
[28]Sasaki H,Moriyama S,Nakashima Y, et al.Expression of the MTA1 Mrna in advanced lung cancer[J].Lung Cancer,2002,35(2):149-154.
[29]钱锦贤,李定彪,洪志鹏.肿瘤转移相关基因MTAl在肿瘤中的研究进展[J].云南医药,2008,(05)：515-518.
[30]刘晨旭,周斌.MTA1蛋白在非小细胞肺癌中的表达及临床意义[J].医学信息,2010,(04)：923-924.
[31]张华,张明月,王洲,刘相燕,陈钢,刘凡英.肿瘤转移相关基因表达与Ⅰ期非小细胞肺癌预后的相关性[J].肿瘤,2010,(10)：881-885.
[32]刘运贤,胡亚翎,刘菊梅,张弦,蔡贽,杨倩.肺癌PTEN、MTAl、p73表达与预后相关性[J].蚌埠医学院学报,2005,(06)：52-54.
[33]Yi S, Guangqi H. Guoli H. The association of the expression of MTAl, rim23HI with theinvasion. metastasis of ovarian carcinoma[JJ. Chin MedSci J,2003,18(2):87—92.
[34]王艳伟,宋文歧.MTA1蛋白在卵巢癌中的表达及意义[J].中外医疗,2009,(06)：71.
[35]Luo J,Su F,Chen D, et al. Deacetylation of p53 modulates its effect on cell growth and apoptosis[J].Nature,2000,408(6810):377-381.
[36]Kumar DS,Pakala SB,Nair VS,er al.Mechanism of MTA1 over expression-linked invasion:MTAl regulation of HMMR expression and function[J].Biol Chem,2011,287 (8):5483-5491.
[37]李焱,张涛,高辉,等.MTAl和VEGF-C在结肠癌组织中的表达及其与淋巴管转移的关系[J]现代医学,2009,37(6)：401-404.
[38]高冬玲,陈奎生,赵志华,等.食管鳞状细胞癌组织中MTAl和E-cadherin蛋白的表达[J].郑州大学学报(医学版).2007,42(6)：1028-1030.
[39]李江,杨竹林,黄江生,杨乐平,苗雄鹰,兰思根.胆囊腺癌雌激素受体、转移相关基因1表达和微血管计数及其相关性研究[J].中国医学工程,2007,(11)：871-875.
[40]李江,黄江生,杨竹林,杨乐平,付汐.胆囊良恶性病变转移相关基因1表达和淋巴管计数及相关性研究[J].中国现代医学杂志,2008,(02)：202-205+208.
[41]Hamatsu T, Rikimaru T, Yamashita Y, et al. The role of MTA1 gene expression in human hepatocellular carcinoma[J]. Oncol Rep.2003,10(3):599-604.
[42]林川,陈汉,吴盂超,等.肿瘤转移基因MTAl的分子克隆及其在肝癌组织中表达的初步研究[J].中华普通外科杂志,2000,15(10)：634.
[43]Moon W S, Chang K, Tarnawski A S. Overexpression of metastatic tumor, antigen 1 in hepatocellular carcinoma:Relationship to vascular invasion and estrogen receptor-alpha[J]. Hum Pathol.2004,35(4):424-429.
[44]Iguchi H, Imura G, Toh Y, et al. Expression of MTA1, a metastasis-associated gene with histone deacetylase activity in pancreatic cancer[J]. Int J Oncol.2000,16(6):1211-1214.
[45]王会河,黄光武,莫立根,赵惠柳,邝国乾.MTA1表达与鼻咽癌浸润转移的关系[J].广西医科大学学报,2006,(04)：546-548.
[46]莫立根,王会河,赵惠柳,邝国乾,黄光武.MTAl在鼻咽癌中的表达及意义[J].现代肿瘤医学,2005,(06)：18-20.
[47]王会河,莫立根,黄光武,邝国乾.mtal基因和癌肿转移[J].中国医学文摘(肿瘤学),2004,(02)：147-149.
[48]王会河.基因Mtal. Tiaml mRNA表达与鼻咽癌浸润转移的关系[D].广西医科大学,2005.
[49]周冬妮,邓燕飞,曾亮,胡骏,张其清.MTAl基因在鼻咽癌中的表达及临床意义[J].临床耳鼻咽喉头颈外科杂志,2009,(04)：178-180.
[50]邓燕飞,周冬妮,曾亮.MTAl和RECK基因在鼻咽癌中的表达及意义[J].临床耳鼻咽喉头颈外科杂志,2011,(12)：534-538.
[51]许小涛,泽璋.肿瘤转移相关基因MTA1与鼻咽癌细胞浸润和转移的关系[J].中国美容医学,2010,(10)：7-8.
[52]唐桥筵,季文樾,潘子民,等.转移相关基因表达与喉鳞状细胞癌淋巴结转移的天系[J].中华耳鼻咽喉科杂志,2003,38(3)：213-216.
[53]王会河,黄光武,韦福依,莫立根,邝国乾.基因MTA1在喉癌中的表达和意义[J].临床耳鼻咽喉科杂志,2006,(03)：113-115.
[54]Hofer MD, Kuefer R, Varambally S, et al. The role of metastasis——associated protein 1 in prostate cancer progression[J]. Cancer Res,2004,64(3):825-829.
[55]YI Chengla, LI Xinzhi, XU Weiguo, et al. Relationship between the expression of MTA1 gene and the metastasis and invasion in human osteosareomal[J].J Huazhong Univ Sci Technolog Med Sci,2005,25(4):445—447.
[56]钱海利.MTA1基因在肿瘤侵袭转移中的作用及机制研究[D].中国协和医科大学,2005.