ADAM10在胶质瘤中的表达及生物学意义的研究
摘要
前言
胶质瘤是颅内最常见的原发恶性肿瘤,呈浸润性生长,肿瘤与正常脑组织之间无明显界限,手术无法彻底治愈,患者均死于肿瘤的复发。目前认为无法治愈的根本原因在于胶质瘤细胞的无限增殖和向周围正常脑组织的侵袭生长。
研究表明,有多种生物大分子参与胶质瘤细胞的增殖和侵袭过程。这些大分子是锌依赖性的具有蛋白水解酶功能的酶蛋白分子,包括去整合素-金属蛋白酶(adisintegrin and metalloprotease, MMPs)家族、去整合素-金属蛋白酶(a disintegrin and metalloprotease, ADAMs)家族等,这些家族在结构和功能上均有一些相似之处。ADAMs家族近年来成为研究的热点。研究人员已经发现ADAM12在不同级别胶质瘤中存在表达差异,级别越高则表达越多；进一步研究发现ADAM12具有水解细胞外复合分子肝素结合性表皮生长因子(heparinbin-inding epidermal growth factor, HB-EGF)而产生活性分子表皮生长因子(epider mal growth factor, EGF)的作用。正是通过水解产生的活性分子EGF与表皮生长因子受体(epidermal growth factor receptor, EGFR)结合,使细胞外信号传递到细胞内,激活控制胶质瘤细胞增殖的相关基因完成调控作用。
ADAM10作为ADAMs家族中的一员与其他成员有着相似的结构和功能。已经有研究证实ADAM10参与细胞上皮的更新,组织重建,细胞的粘连。国外研究人员研究发现ADAM10在体外胃癌细胞中有过度表达,并证实ADAM10是通过EGFR配子脱落来促进癌细胞增殖。也有人发现其能够水解细胞外Ⅳ型胶原,分析认为可能是通过水解Ⅳ型胶原促进癌细胞向远处侵袭生长。ADAM10在胶质瘤中的表达情况及是否参与癌细胞的增殖目前仍不是很清楚。
本课题拟将临床不同级别胶质瘤依照世界卫生组织(world health organization,WHO)标准分为低级别和高级别两组,以脑膜瘤作为对照组,应用反转录多聚酶链式反应(reverse transcripase polymerase chain reaction, RT-PCR)对三组ADAM10基因表达进行检测,并比较表达差异。利用链霉亲合素-生物素-过氧化物酶免疫组织化学方法(StreptAvidin-BiotinComplex, SABC)检测ADAM10蛋白表达及分布,表达情况及分布进行分析,探索其可能的作用机制。本实验的目的就是为胶质瘤的靶向治疗寻找靶点并提供实验基础。
材料与方法
一、实验标本的获取
取我院2007-2010年共计43例脑胶质瘤患者标本,低级别胶质瘤22例,高级别胶质瘤21例,取脑膜瘤10例作为对照组。所有标本均于肿瘤中心采取,立即置于-70℃保存,并保留病例信息。所有标本均经过病理学核实。
二、实验方法
(一)肿瘤组织RNA的提取
按照TaKaRa公司说明利用RNAiso Plus从组织标本中提取RNA。取100mg-70℃保存的瘤组织剪成匀浆状,立即放入1.5ml去RNA酶的EP管中加入1mlRNAiso Plus,室温静置5分钟,取上清加入0.2ml氯仿,静置后离心,取上清后加入异丙醇静置后再离心可见白色片状物,干燥后加入40ul去RNA酶水溶解用紫外分光光度仪测RNA纯度及含量。
(二)两步法RT-PCR：
引物序列参考文献由TaKaRa公司合成,上下游序列分别为5'-TGGGTCAAAAAGAAAATGGC-3'和5'-CCCAGGTTTCAGTTTGCATT-3'。扩增片段长度为281bp,采用β-actin为内参对照,上游：5'-AAATCGTGCGTGACATTAA-3',下游：5'-CTCG TCATACTCCTGCCTG-3'扩增片段大小为474 bp。RT体系为10ul,取2.5ul模板(cDNA)进行扩增。PCR体系在94℃下变性2分钟,循环条件为94℃30秒,55℃30秒,72℃2分钟,共30个循环,最后延伸10分钟。取产物8ul通过电泳利用琼脂糖凝胶进行分离,并在紫外线灯下照相。最后通过凝胶灰度分析仪进行统计分析。
(三)免疫组织化学染色
按照SABC染色试剂盒说明进行操作,结果判断：在光镜下有棕黄色颗粒反应出现在细胞膜、细胞质均为阳性反应细胞,于5个不同高倍视野相同范围下计数500个细胞及免疫组化染色阳性细胞数,阳性细胞率<5%记为(-),5%-50%为(+),50%-75%为(++),>75%为(+++)。统计学处理。
利用SPSS14.0软件对结果进行数据分析。不同组间参数比较利用One-wayANOVA分析,p<0.05具有统计学意义。
结果
一、ADAM10基因mRNA的表达
对三组共63个条带灰度扫描,平均灰度值提示高级别组ADAM10基因表达最多,对照组略有表达。平均灰度单因素方差分析提示高级别组和低级别组比较具有显著性差异(t=13.31,p<0.05)；低级别组与对照组比较差异明显(t=22.83,p<0.01)。
二、ADAM10蛋白的表达
对照组高倍镜下可见47个阳性细胞(9.4%),低级别组可见269个阳性细胞(53.8%),高级别组可见382个阳性细胞(76.4%)。ADAM10蛋白免疫组化染色显示对照组中可以看到稀少阳性染色细胞；低级别组中可以看到很多瘤细胞结构已经破坏,呈空泡状,背景呈现非特异染色。可以看到散在的瘤细胞胞膜上和胞质部分阳性染色；高级组上可以看到较多阳性染色的瘤细胞,肿瘤内血管壁上有环形阳性染色。
结论
1、ADAM10在脑膜瘤和胶质瘤中均有表达,表达量与胶质瘤级别呈正相关性。胶质瘤中的表达与脑膜瘤中表达的差异有统计学意义。
2、ADAM10在胶质瘤血管壁上有明显的表达,其可能是胶质瘤血管壁通透性增加引起瘤周水肿的机制之一。
Intracranial glioma is the most common primary malignant tumor,which is characterized as invasive growth.Because there are no obvious boundaries between tumor and normal brain tissue so surgery can not be completely cured.And all the patients with giloma died of tumor recurrence finally. The tumor in general bear a grim cure due to diffuse infiltration of tumor cells into the surrounding brain tissue, preventing complete surgical removal of the tumor. Studies have shown that a variety of biological macromolecules involved in proliferation and invasion of glioma cells in the process of growth. These molecules are zinc-dependent protein with proteolytic enzymes function,including MMPs family and ADAMs family.There are some similarities with functions and structures in the two families. ADAMs family have caused widely concern in recent years,and some researchers have found that there were some differents among the ADAM12 expression in different grades of giloma.The higher level of grades,the higher level of expression.Further study have shown that ADAM12 can produce EGF by hydrolysising HB-EGF,which involving the signaling process.Then EGF conbined with EGFR so that the extracellular signal delivered to cell to activate the genes associated with the proliferation of glioma cells. Some studies have proven that AD AM10 involved the epithelial update of cells,the tissue reconstruction,and cell adhesion.Foreign researchers have found that ADAM10 was overexpressed in gastric cells in vitro and confirmed that ADAM10 promotes cancer cells proliferation by shedding gametes. It was also found to be hydrolysis of extracellular collagen typeⅣ, which was thought to promote the growth of cancer cell invasion to the distance.
In our study we divided the sample into two groups of low-level and high-level according to the WHO standards with meningioma as the control group.The three groups gene are detected through RT-PCR and the results were compared with each other. We applied immunohistochemistry to show the protein of ADAM10 in the cell to explore the mechanism.All we done in the experiments are to find the the target for targeted therapy and provide the experimental basis.
Materials and Methods
1. Obtain experimental specimens
43casesof giloma samples are collected in our hospital from 2007-2010,including 22 cases of low-grade and 21 cases of high-grade.10 cases of meningioma are served as control group.The samples were from the core of the tumor and were saved at-70℃immediately.The information of the patients are collected and the pathological results were confirmed.
2. Experimental Methods
(1) Extract RNA
According to the TaKaRa description we extract the RNA from the tumor samples.The 100mg tumor tissue were made into homogenates and was put into 1.5ml free RNA enzymes EP tube and was mingled with 1ml RNAiso Plus. Put it aside for 5 minutes at room temperature. Add 0.2ml chloroform to Supernatant obtained, put it aside, after centrifugation, then the supernatant was added to isopropyl alcohol, white flakes can be seen after centrifugation and then put it aside, adding 40ul water-soluble enzymes to the RNA after dried,then RNA purity and content was measured by UV spectrophotometer.
(2) Two-step RT-PCR:
Reference primers synthesized by TaKaRa Company, upstream and downstream sequences:5'-TGGGTCAAAAAGAAAATGGC-3'和5'-CCCAGGTTTCAGTTTGCA TT-3'.Amplified fragment length is 281bp, usingβ-actin as an internal control. upstream and downstream respective is as follw:5'-AAATCGTGCGTGACATTAA-3' ,5'-CTCGTCATACTCCTGCCTG-3', the size of amplify fragment is 474bp,the whole system is 10ul,take 2.5ul template (cDNA)to amplify,RT system denature at 94℃for 2 minutes,cycle condition is at 94℃for 30secend, at 55℃for 30 secend,at 72℃for 2 minute,add up to 30 cycles,extension for 10 minute. The products were separated through electrophoresis using agarose gel,photographs were taken in the UV lamp camera,statistical analysis was made by gray gel analyzer.
(3) Immunohistochemistry
Operation is made according to instructions of SABC staining kit.In the light microscope, there are brown-yellow granules reaction appears on the cell membrane,in the cytoplasm,which was regarded as positive reaction.500 cells were counted in 5 different high power field and the rate of positive cell less than 5% is marked(-),5%-50% marked (+),50%-75% marked (++),>75% marked (+++)
(4) Statistics
The results of data was analysised using SPSS 14.0 software. Different groups parameters were compared using One-way ANOVA analysis, p<0.05 means significant statistically.
Results
1. The expression of AD AM10 gene
63 grayscale strip was scaned and the results showed that the most expression was in high-grade group, little expression was in control group.Single-factor analysis of the average gray showed that the different between high-grade group and low-grade group was statistically significant (f=13.31, p<0.05), Low-grade group and control group differences are significant (t=22.83, p<0.01)
2. The expression of AD AM10 protein
There are 47 positive cells in the control group in the high-powered microscope(9.4%),269 postive cells in the low-grade group(53.8%),382 positive cells in the:high-grade group(76.4%).Many tumor cells had been destroied in the low-grade,tumor cell membrane and cytoplasm was sporadic positive staining. circular positive staining was showed in the blood vessel walls.
Conclusion
1. ADAM 10 is expressed in meningiomas and gliomas and the expression was positively correlated with the level of glioma. Glioma and meningioma was statistically significant differences in the expression.
2. ADAM 10 expression are shown in the vassel of the glioma,which may be one of the mechanisms that increased permeability of glioma blood vessel wall that caused peritumoral edema.
胶质瘤是颅内最常见的原发恶性肿瘤,呈浸润性生长,肿瘤与正常脑组织之间无明显界限,手术无法彻底治愈,患者均死于肿瘤的复发。目前认为无法治愈的根本原因在于胶质瘤细胞的无限增殖和向周围正常脑组织的侵袭生长。
研究表明,有多种生物大分子参与胶质瘤细胞的增殖和侵袭过程。这些大分子是锌依赖性的具有蛋白水解酶功能的酶蛋白分子,包括去整合素-金属蛋白酶(adisintegrin and metalloprotease, MMPs)家族、去整合素-金属蛋白酶(a disintegrin and metalloprotease, ADAMs)家族等,这些家族在结构和功能上均有一些相似之处。ADAMs家族近年来成为研究的热点。研究人员已经发现ADAM12在不同级别胶质瘤中存在表达差异,级别越高则表达越多；进一步研究发现ADAM12具有水解细胞外复合分子肝素结合性表皮生长因子(heparinbin-inding epidermal growth factor, HB-EGF)而产生活性分子表皮生长因子(epider mal growth factor, EGF)的作用。正是通过水解产生的活性分子EGF与表皮生长因子受体(epidermal growth factor receptor, EGFR)结合,使细胞外信号传递到细胞内,激活控制胶质瘤细胞增殖的相关基因完成调控作用。
ADAM10作为ADAMs家族中的一员与其他成员有着相似的结构和功能。已经有研究证实ADAM10参与细胞上皮的更新,组织重建,细胞的粘连。国外研究人员研究发现ADAM10在体外胃癌细胞中有过度表达,并证实ADAM10是通过EGFR配子脱落来促进癌细胞增殖。也有人发现其能够水解细胞外Ⅳ型胶原,分析认为可能是通过水解Ⅳ型胶原促进癌细胞向远处侵袭生长。ADAM10在胶质瘤中的表达情况及是否参与癌细胞的增殖目前仍不是很清楚。
本课题拟将临床不同级别胶质瘤依照世界卫生组织(world health organization,WHO)标准分为低级别和高级别两组,以脑膜瘤作为对照组,应用反转录多聚酶链式反应(reverse transcripase polymerase chain reaction, RT-PCR)对三组ADAM10基因表达进行检测,并比较表达差异。利用链霉亲合素-生物素-过氧化物酶免疫组织化学方法(StreptAvidin-BiotinComplex, SABC)检测ADAM10蛋白表达及分布,表达情况及分布进行分析,探索其可能的作用机制。本实验的目的就是为胶质瘤的靶向治疗寻找靶点并提供实验基础。
材料与方法
一、实验标本的获取
取我院2007-2010年共计43例脑胶质瘤患者标本,低级别胶质瘤22例,高级别胶质瘤21例,取脑膜瘤10例作为对照组。所有标本均于肿瘤中心采取,立即置于-70℃保存,并保留病例信息。所有标本均经过病理学核实。
二、实验方法
(一)肿瘤组织RNA的提取
按照TaKaRa公司说明利用RNAiso Plus从组织标本中提取RNA。取100mg-70℃保存的瘤组织剪成匀浆状,立即放入1.5ml去RNA酶的EP管中加入1mlRNAiso Plus,室温静置5分钟,取上清加入0.2ml氯仿,静置后离心,取上清后加入异丙醇静置后再离心可见白色片状物,干燥后加入40ul去RNA酶水溶解用紫外分光光度仪测RNA纯度及含量。
(二)两步法RT-PCR：
引物序列参考文献由TaKaRa公司合成,上下游序列分别为5'-TGGGTCAAAAAGAAAATGGC-3'和5'-CCCAGGTTTCAGTTTGCATT-3'。扩增片段长度为281bp,采用β-actin为内参对照,上游：5'-AAATCGTGCGTGACATTAA-3',下游：5'-CTCG TCATACTCCTGCCTG-3'扩增片段大小为474 bp。RT体系为10ul,取2.5ul模板(cDNA)进行扩增。PCR体系在94℃下变性2分钟,循环条件为94℃30秒,55℃30秒,72℃2分钟,共30个循环,最后延伸10分钟。取产物8ul通过电泳利用琼脂糖凝胶进行分离,并在紫外线灯下照相。最后通过凝胶灰度分析仪进行统计分析。
(三)免疫组织化学染色
按照SABC染色试剂盒说明进行操作,结果判断：在光镜下有棕黄色颗粒反应出现在细胞膜、细胞质均为阳性反应细胞,于5个不同高倍视野相同范围下计数500个细胞及免疫组化染色阳性细胞数,阳性细胞率<5%记为(-),5%-50%为(+),50%-75%为(++),>75%为(+++)。统计学处理。
利用SPSS14.0软件对结果进行数据分析。不同组间参数比较利用One-wayANOVA分析,p<0.05具有统计学意义。
结果
一、ADAM10基因mRNA的表达
对三组共63个条带灰度扫描,平均灰度值提示高级别组ADAM10基因表达最多,对照组略有表达。平均灰度单因素方差分析提示高级别组和低级别组比较具有显著性差异(t=13.31,p<0.05)；低级别组与对照组比较差异明显(t=22.83,p<0.01)。
二、ADAM10蛋白的表达
对照组高倍镜下可见47个阳性细胞(9.4%),低级别组可见269个阳性细胞(53.8%),高级别组可见382个阳性细胞(76.4%)。ADAM10蛋白免疫组化染色显示对照组中可以看到稀少阳性染色细胞；低级别组中可以看到很多瘤细胞结构已经破坏,呈空泡状,背景呈现非特异染色。可以看到散在的瘤细胞胞膜上和胞质部分阳性染色；高级组上可以看到较多阳性染色的瘤细胞,肿瘤内血管壁上有环形阳性染色。
结论
1、ADAM10在脑膜瘤和胶质瘤中均有表达,表达量与胶质瘤级别呈正相关性。胶质瘤中的表达与脑膜瘤中表达的差异有统计学意义。
2、ADAM10在胶质瘤血管壁上有明显的表达,其可能是胶质瘤血管壁通透性增加引起瘤周水肿的机制之一。
Intracranial glioma is the most common primary malignant tumor,which is characterized as invasive growth.Because there are no obvious boundaries between tumor and normal brain tissue so surgery can not be completely cured.And all the patients with giloma died of tumor recurrence finally. The tumor in general bear a grim cure due to diffuse infiltration of tumor cells into the surrounding brain tissue, preventing complete surgical removal of the tumor. Studies have shown that a variety of biological macromolecules involved in proliferation and invasion of glioma cells in the process of growth. These molecules are zinc-dependent protein with proteolytic enzymes function,including MMPs family and ADAMs family.There are some similarities with functions and structures in the two families. ADAMs family have caused widely concern in recent years,and some researchers have found that there were some differents among the ADAM12 expression in different grades of giloma.The higher level of grades,the higher level of expression.Further study have shown that ADAM12 can produce EGF by hydrolysising HB-EGF,which involving the signaling process.Then EGF conbined with EGFR so that the extracellular signal delivered to cell to activate the genes associated with the proliferation of glioma cells. Some studies have proven that AD AM10 involved the epithelial update of cells,the tissue reconstruction,and cell adhesion.Foreign researchers have found that ADAM10 was overexpressed in gastric cells in vitro and confirmed that ADAM10 promotes cancer cells proliferation by shedding gametes. It was also found to be hydrolysis of extracellular collagen typeⅣ, which was thought to promote the growth of cancer cell invasion to the distance.
In our study we divided the sample into two groups of low-level and high-level according to the WHO standards with meningioma as the control group.The three groups gene are detected through RT-PCR and the results were compared with each other. We applied immunohistochemistry to show the protein of ADAM10 in the cell to explore the mechanism.All we done in the experiments are to find the the target for targeted therapy and provide the experimental basis.
Materials and Methods
1. Obtain experimental specimens
43casesof giloma samples are collected in our hospital from 2007-2010,including 22 cases of low-grade and 21 cases of high-grade.10 cases of meningioma are served as control group.The samples were from the core of the tumor and were saved at-70℃immediately.The information of the patients are collected and the pathological results were confirmed.
2. Experimental Methods
(1) Extract RNA
According to the TaKaRa description we extract the RNA from the tumor samples.The 100mg tumor tissue were made into homogenates and was put into 1.5ml free RNA enzymes EP tube and was mingled with 1ml RNAiso Plus. Put it aside for 5 minutes at room temperature. Add 0.2ml chloroform to Supernatant obtained, put it aside, after centrifugation, then the supernatant was added to isopropyl alcohol, white flakes can be seen after centrifugation and then put it aside, adding 40ul water-soluble enzymes to the RNA after dried,then RNA purity and content was measured by UV spectrophotometer.
(2) Two-step RT-PCR:
Reference primers synthesized by TaKaRa Company, upstream and downstream sequences:5'-TGGGTCAAAAAGAAAATGGC-3'和5'-CCCAGGTTTCAGTTTGCA TT-3'.Amplified fragment length is 281bp, usingβ-actin as an internal control. upstream and downstream respective is as follw:5'-AAATCGTGCGTGACATTAA-3' ,5'-CTCGTCATACTCCTGCCTG-3', the size of amplify fragment is 474bp,the whole system is 10ul,take 2.5ul template (cDNA)to amplify,RT system denature at 94℃for 2 minutes,cycle condition is at 94℃for 30secend, at 55℃for 30 secend,at 72℃for 2 minute,add up to 30 cycles,extension for 10 minute. The products were separated through electrophoresis using agarose gel,photographs were taken in the UV lamp camera,statistical analysis was made by gray gel analyzer.
(3) Immunohistochemistry
Operation is made according to instructions of SABC staining kit.In the light microscope, there are brown-yellow granules reaction appears on the cell membrane,in the cytoplasm,which was regarded as positive reaction.500 cells were counted in 5 different high power field and the rate of positive cell less than 5% is marked(-),5%-50% marked (+),50%-75% marked (++),>75% marked (+++)
(4) Statistics
The results of data was analysised using SPSS 14.0 software. Different groups parameters were compared using One-way ANOVA analysis, p<0.05 means significant statistically.
Results
1. The expression of AD AM10 gene
63 grayscale strip was scaned and the results showed that the most expression was in high-grade group, little expression was in control group.Single-factor analysis of the average gray showed that the different between high-grade group and low-grade group was statistically significant (f=13.31, p<0.05), Low-grade group and control group differences are significant (t=22.83, p<0.01)
2. The expression of AD AM10 protein
There are 47 positive cells in the control group in the high-powered microscope(9.4%),269 postive cells in the low-grade group(53.8%),382 positive cells in the:high-grade group(76.4%).Many tumor cells had been destroied in the low-grade,tumor cell membrane and cytoplasm was sporadic positive staining. circular positive staining was showed in the blood vessel walls.
Conclusion
1. ADAM 10 is expressed in meningiomas and gliomas and the expression was positively correlated with the level of glioma. Glioma and meningioma was statistically significant differences in the expression.
2. ADAM 10 expression are shown in the vassel of the glioma,which may be one of the mechanisms that increased permeability of glioma blood vessel wall that caused peritumoral edema.
引文
1 WolfsbergTG,White JM. ADAMs in fertilization and development (J).DevelopmentalBiology, 1996,180(2):389-91.
2 Wolfsberg TG, Primakoff P, Myles DG. ADAM, a novel family of membrane proteins containing A Disintegrin And Metalloprotease domain:multipotential functions in cell-cell and cell-matrix interactions. J Cell Biol.1995 Oct;131(2):275-8
3 Huovila AP, Almeida EA, White JM. ADAMs and cell fusion. Curr Opin Cell Biol.1996 Oct;8(5):692-9.
4 Mochizuki S,Okada Y.ADAMs in cancer cell proliferation and pro-gressio (J).CancerSc,i 2007, 98(5):621-6.
5 Weskamp G, Kratzschmar J, Reid MS, MDC9, a widely expressed cellular disintegrin containing cytoplasmic SH3 ligand domains. J Cell Biol.1996 Feb;132(4):717-26.
6 Evans JP, Schultz RM, Kopf GS. Roles of the disintegrin domains of mouse fertilins alpha and beta in fertilization. Biol Reprod.1998 Jul;59(l):145-52.
7 Yuan R, Primakoff P, Myles DG. A role for the disintegrin domain of cyritestin, a sperm surface protein belonging to the ADAM family, in mouse sperm-egg plasma membrane adhesion and fusion. J Cell Biol.1997 Apr 7; 137(1):105-12.
8 Millichip MI, Dallas DJ, Wu E, The metallo-disintegrin ADAM10 (MADM) from bovine kidney has type IV collagenase activity in vitro. Biochem Biophys Res Commun.1998 Apr 17;245(2):594-8.
9 Merlos-Suarez A, Fernandez-Larrea J, Reddy P,Pro-tumor necrosis factor-alpha processing activity is tightly controlled by a component that does not affect notch processing. J Biol Chem. 1998 Sep 18;273(38):24955-62.
10 Qi H, Rand MD, Wu X, Processing of the notch ligand delta by the metalloprotease Kuzbanian. Science.1999 Jan 1;283(5398):91-4.
11 Wen C, Metzstein MM, Greenwald I SUP-17, a Caenorhabditis elegans ADAM protein related to Drosophila KUZBANIAN, and its role in LIN-12/NOTCH signalling.. Development.1997 Dec;124(23):4759-67.
12 Peschon JJ, Slack JL, Reddy PAn essential role for ectodomain shedding in mammalian development.Science.1998 Nov 13;282(5392):1281-4.
13 Buxbaum JD, Liu KN, Luo Y, Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. J Biol Chem.1998 Oct 23;273(43):27765-7.
14 Takahide Kodama, Eiji Ikeda, Aiko Okada. ADAM12 Is Selectively Overexpressed in Human Glioblastomas and Is Associated with Glioblastoma Cell Proliferation and Shedding of Heparin-Binding Epidermal Growth Factor. (American Journal of Pathology.
2004;165:1743-1753.)
15 Schulz B, Pruessmeyer J, Maretzky T, ADAM10 regulates endothelial permeability and T-Cell transmigration by proteolysis of vascular endothelial cadherin.2008 May 23; 102(10): 1192-201.
16 Reiss K, Ludwig A, ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and betacatenin translocation. Proc Natl Acad Sci U S A.2005 Jun 28; 102(26):9182-7.
17 Fridman JS, Caulder E, Hansbury M,Selective inhibition of ADAM metalloproteases as a novel approach for modulating ErbB pathways in cancer. Clin Cancer Res.2007 Mar 15;13(6):1892-902.
18 Kanazawa R, Yoshida D, Takahashi H. Drug-induced apoptosis by a matrix metalloproteinase inhibitor, SI-27 on human malignant glioma cell lines; in vitro study. J Neurooncol. 2004;66(1-2):91-9.
19 WolfsbergTG,White JM. ADAMs in fertilization and development (J).DevelopmentalBiology, 1996,180(2):389-94.
20 Mochizuki S,Okada Y.ADAMs in cancer cell proliferation and pro-gressio (J).CancerSc,i 2007, 98(5):621-5.
21 Darren F.etc.The ADAMs family of metalloproteases:multidomain proteins with multiple functions [J]. Genes Dev.2003 17:7-30
22 Wolfsberg TG, White JM. ADAMs in fertilization and development[J].DevelopmentalBiology, 1996,180(2):389-401.
23 施文 李俊生.ADAM 家族与肿瘤关系的研究概况[J].实用癌症杂志,2008 06-0671-03
24 Wildeboer D, Naus S, Amy Sang QX. Metalloproteinase disintegrins ADAM8 and ADAM 19 are highly regulated in human primary brain tumors and their expression levels and activities are associated with invasiveness.[J]. Neuropathol Exp Neurol.2006 May;65(5):516-27.
25 Takahide Kodama, Eiji Ikeda, Aiko Okada. ADAM12 Is Selectively Overexpressed in Human Glioblastomas and Is Associated with Glioblastoma Cell Proliferation and Shedding of Heparin-Binding Epidermal Growth Factor.[J].American Journal of Pathology. 2004;165:1743-53.
26 D'Abaco GM, Ng K, Paradiso L. ADAM22, expressed in normal brain but not in high-grade gliomas, inhibits cellular proliferation via the disintegrin domain. [J].Neurosurgery. 2006,58(1):179-86
27 Xuguang Zheng, Feng Jiang, Mark Katakowski. Inhibition of ADAM 17 reduces hypoxia-induced brain tumor cell invasiveness[J]. Cancer Sci 2007; 98:674-84
28 Kodama T, Ikeda E, Okada A, et al. ADAM12 is selectively overexpressed in human glioblastomas and is associated with glioblastoma cell proliferation and shedding of heparin-binding epidermal growth factor.[J].Am J Pathol 2004;165:1743-53
29 Yoshimura T, Tomita T, Dixon MF,et al ADAMs (a disintegrin and metalloproteinase) messenger RNA expression in Helicobacter pylori-infected, normal, and neoplastic gastric mucosa. [J]. J Infect Dis,2002,185(3):332-40
30 Millichip MI, Dallas DJ, Wu E, The Metallo-Disintegrin ADAM10 (MADM) from Bovine Kidney Has Type IV Collagenase Activity inVitro[J].Biochem Biophys Res Commun,1998;245(2):594-8.
31 Louis DN, Gusella JF:A tiger behind many doors:multiple genetic pathways to malignant glioma. [J]Trends Genet 1995,11:412-415
32 Wong AJ, Ruppert JM, Bigner SH et al.Structural alterations of the epidermal growth factor receptor gene in human gliomas. [J] Proc Natl Acad Sci USA 1992,89:2965-2969
33 Humphrey PA, Wong AJ, Vogelstein B, et al. Anti-synthetic peptide antibody reacting at the fusion junction of deletionmutant epidermal growth factor receptors in human glioblastoma. [J].Proc Natl Acad Sci USA 1990,87:4207-4211
34 Sugawa N, Ekstrand AJ, James CD, et al. Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged genes in human glioblastomas. [J].Proc Natl Acad Sci USA 1990,87:8602-6
35 Nishikawa R, Ji XD, Harmon RC, et al. A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. [J].Proc Natl Acad Sci USA 1994,91:7727-31
36 Ekstrand AJ,James CD,Cavenee WK,et al.Genes for epidermal growth factor receptor, transforming growth factor and epidermal growth factor and their expression in human gliomas in vivo. [J].Cancer Res 1991,51:2164-72
37 Asakura M, Kitakaze M, Takashima S, et al.Cardiac hypertrophy is inhibited by antagonism of AD AMI2 processing of HB-EGF:metalloproteinase inhibitors as a new therapy. [J].Nat Med 2002,8:35-40
38 Kurisaki T, Masuda A, Sudo K, etal.Phenotypic analysis of meltrin(ADAM12)-deficierit mice: involvement of meltrin in adipogenesis and myogenesis. [J].Mol Cell Biol 2003,23:55-61
39 Schulz B, Pruessmeyer J,MaretzkyT, ADAM10 regulates endothelial permeability and T-Cell transmigration by proteolysis of vascular endothelial cadherin. [J].2008;102(10):1192-201.
1 J Folkman J, Ryeem S. Is oncogene addiction angiogenesis-dependent? [J]. Cold Sp Harb Symp Quant BiOl,2005,70:389-397.
2 J Chan AS, LeungSY, WongMP, et al. Expression of vascular endotheli.algowthfact or andits receptorsintheanaplastic progression of astrocytoma, oH8Dde IIdrOgbOm, endymorna[J]. Am J Surg Pathol,1998,22(7):816-826.
3 J Egscrt A, lkegaki N, Kwiatkowski J,et al. Hish-level expression of an-giogenlcfactorsis associated withadvanced tulnor stag-in human neu roblastomas[JJ. Clin Cancer Res,2000, 6(5):1900-1908.
4 Dunn IF, HeeseO, BlackPM,et al. Growthfactorsin siogenesis FGFs, PDGF, EGF, and TGFs[J]. J Neumoncol,2000,50(1-2):121-137.
5 BambaH, Ota S, KatoA, et al. prost,landins up-regulate vascular endothdiM growthfactor production throughdistinct pathwaysin differenfiated U937 cells[J].Biochem Biephys Res Commun,2000,273(2):485-491.
6 Sufan RI, Jewett MA, Ohh M, et al.Re role of yon Hippel-Lindan tunlor suppressor protein and hypoxiain renal clear cell carcinoma[J]. Am J Phvsiol Renal Physiol,2004,287(2):F1-F6
7 Jones MK, SzaboIL, KawanakaH,et al. VonHippelLindantunlor sup-pressor and H]F-la1Dh8: new targets of NSAIDs inhibition of hypoxia-induced angiogenesis[J]FASEB J,2002,16(2): 264-266
8 Mabjeesh NJ, Escuin D, LaVallee TM, et al.2ME2 inhibits tulnor growth and angiogenesis by disrupting micmtulxfles and dysregulating HIF[J]. Cancer Cell,2003,3(4):363-375.
9 Sonnni NE, Devy L, Hajitou A, et al. MT1-MMP expression promotes tulnor growth andongiogenesisthroughan up-regulation of vascular endothelial gowth factor expression[J]. FASEB J,2002,16(6):555-564.
10 Their M, Reeb E, Breuer B, et al. Expression of matrix metallepmteinase-2 in glial and netlronal tulnor cell lines:inverse correlation with proliferation rate[J]. Cancer Lett,2000, 149(1-2):163-170.
11 CuferT, Borstnar S, Vrhovec J. Prognostic and predictive value of the urokinase-type plasminogen activator(UPA)and its inhibitors PAI-1 and PAJ-2 in operable breast e-qileel"[J]. Markers,2003,18(2):106-115.
12 Jaworski DM, Kelly GM, Piepmeier JM, et al. BEHAB(brain enriched hyali. iuonan binding)is expressed in surgical samples of glioma and in intracranial grafts ofinvasive ollla cell lines[J]. Cancer Res,1996,56(3):2293-2298.
13 Khatib AM, Nip J, Fauavoilita L, et al. Regulation of urokinase plas-mino-n activator/plasmin-mediated invasion of melanonm cells by the integrin vitronactin receptor alphaVbeta3[J]. Int Cancer,2001,91(3):300-308.
14 Savani RC, CaoG, PoolerPM, et al. Differential involvementofthe hy. Aluronan (HA)receptorsC and receptor. mediatedmotilityin endothelialcellfunction and angiogenesis[J]. J Biol Chem,2001,276(39):36770-36778.
15 FritzG, Brachetti C, Bahlmann F, etal. Rho GTPasesin human breast tulnors:expression and mutation analyses and ceFiTelation with clinical parameters[J]. Br J Cancer,2002,87(6): 635-644.
16 Forget MA, Desrosiers RR, Del M, et al. The expression of rho protdns decreaseswith human brain tumor progression:potential tulnor marker [J]. Clin Exp Matastasis,2002,19(1):9-15.
17 Tsatas D, Kanagasundaram V, Kaye A, et al. EGF receptor roodifies cellular responses to hyaluronan in glioblastoma cell lines[J]. J Clin Neurosurgical2002,9(3):282-288.
18 Choe G, Park JK, JoubenSteele L, et al. Active matrix metaUoproteinabe 9 expression is associated with primary glioblastoma subtype[J]. Clin Cancer Res,2002,8(9):2894-2901.
19 ManningTJ Jr, Parker JC, SontheimerH. Roleoflysophosphatidieacid and rho in onla cell motilityl[J]. cell Motil Cytoskdeton,2000,45(3):185-199
1 WolfsbergTG,White JM. ADAMs in fertilization and development (J).DevelopmentalBiology, 1996,180(2):389.
2 Wolfsberg TG, Primakoff P, Myles DG. ADAM, a novel family of membrane proteins containing A Disintegrin And Metalloprotease domain:multipotential functions in cell-cell and cell-matrix interactions. J Cell Biol.1995,131(2):275-8
3 Huovila AP, Almeida EA, White JM. ADAMs and cell fusion. Curr Opin Cell Biol. 1996,8(5):692-9.
4 Mochizuki S,Okada Y.ADAMs in cancer cell proliferation and pro-gressio (J).CancerSc,i 2007, 98(5):621.
5 Kheradmand F, Werb Z. Shedding light on sheddases:role in growth and development. Bioessays,2002,24:8-12.
6 Inoue D, Reid M, Lum L. Cloning and initial characterization of mouse meltrin and analysis of the expression of four metalloprotease-disintegrins in bone cells. J. Biol. Chem.1998,273: 4180-4187.
7 Pan D, Rubin G. M. Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis. Cell,1997,90:271-280.
8 Rosendahl M, Ko S, Long D.Identification and characterization of a protumor necrosis factor-processing enzyme from the ADAM family of zinc metalloproteases. J. Biol. Chem. 1997,272:24588-24593.
9 Skovronsky D, Moore D. Protein kinase C-dependent-secretase competes with secretase for cleavage of amyloid-precursor protein in the trans Golgi network. J. Biol. Chem.2000,275: 2568-2575.
10 Maskos K,Fernandez-Catalan C, Huber R.Crystal structure of the catalytic domain of human tumor necrosis factor-converting enzyme. Proc. Natl. Acad. Sci. USA,1998,95:3408-3412.
11 Weskamp G, Kratzschmar J, Reid MS. A widely expressed cellular disintegrin containing cytoplasmic SH3 ligand domains. J Cell Biol.1996,132(4):717-26.
12 Evans JP, Schultz RM, Kopf GS. Roles of the disintegrin domains of mouse fertilins alpha and beta in fertilization. Biol Reprod.1998,59(1):145-52.
13 Yuan R, Primakoff P, Myles DG. A role for the disintegrin domain of cyritestin, a sperm surface protein belonging to the ADAM family, in mouse sperm-egg plasma membrane adhesion and fusion. J Cell Biol.1997,137(1):105-12.
14 Millichip MI, Dallas DJ, Wu E. The metallo-disintegrin ADAM10 (MADM) from bovine kidney has type IV collagenase activity in vitro. Biochem Biophys Res Commun. 1998,17;245(2):594-8.
15 Dundore P,Marsh W,Schultz D. S. Architectural patterns of high-grade prostatic intraepithe lial neoplasia. Hum. Pathol.1993,24:298-310.
16 Xuguang Zheng,Feng Jiang,Mark Katakowski.Inhibition of ADAM 17 reduces hypoxia-induced brain tumor cell invasiveness. Cancer Sci 2007,98:674-684
17 Moss M, White M, Lambert M. TACE and other ADAM proteases as targets for drug discovery. Drug.Discov. Today,2001,6:417-426.
18 Yan B,Shirakabe K,Werb Z.The metalloprotease Kuzbanian (ADAM 10) mediates the transactivation of EGF receptor by G protein-coupled receptors. J. Cell Biol.2002,158: 221-226.
19 Qi H, Rand M, Wu X. Processing of the notch ligand Delta by the metalloprotease Kuzbanian. Science (Wash. DC),1999,283:91-94.
20 Lammich S,Kojro E, Postina R. Constitutive and regulated secretase cleavage of Alzheimer's amyloid precursor protein by adisintegrin metalloprotease.Proc.Natl.Acad.Sci. USA,1999,96: 3922-3927.
21 Hattori M, Osterfield M, Flanagan J.Regulated cleavage of a contact-mediated axon repellent. Science (Wash. DC),2000,289:1360-1365.
22 White J, Bigler D, Chen M.ADAMs. In:M. C. Beckerle (ed.) Cell Adhesion, pp. New York: Oxford University Press,2001.189-216.
23 Mechtersheimer S,Gutwein P,Agmon-Levin N. Ectodomain shedding of L1 adhesion molecule promotes cell migration by autocrine binding to integrins. J. Cell Biol.2001,155:661-673.
24 Merlos-Suarez A, Fernandez-Larrea J, Reddy P,Pro-tumor necrosis factor-alpha processing activity is tightly controlled by a component that does not affect notch processing. J Biol Chem. 1998,18;273(38):24955-62.
25 Qi H, Rand MD, Wu X, Processing of the notch ligand delta by the metalloprotease Kuzbanian. Science.1999,1;283(5398):91-4.
26 Wen C,Metzstein MM.Greenwald I SUP-17, a Caenorhabditis elegans ADAM protein related to Drosophila KUZBANIAN, and its role in LIN-12/NOTCH signalling.Development. 1997,124(23):4759-67.
27 Peschon JJ, Slack JL, Reddy PAn essential role for ectodomain shedding inmammalian development.Science.1998,282(5392):1281-4.
28 Buxbaum JD, Liu KN, Luo Y. Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. J Biol Chem.1998,273(43):27765-7.
29 Wildeboer D, Naus S, Amy Sang QX. Metalloproteinase disintegrins ADAM8 and ADAM19 are highly regulated in human primary brain tumors and their expression levels and activities are associated with invasiveness.[J] Neuropathol Exp Neurol.2006,65(5):516-27.
30 Takahide Kodama, Eiji Ikeda, Aiko Okada. ADAM12 Is Selectively Overexpressed in Human Glioblastomas and Is Associated with Glioblastoma Cell Proliferation and Shedding of Heparin-Binding Epidermal Growth Factor. (American Journal of Pathology. 2004,165:1743-1753.)
31 Schulz B, Pruessmeyer J, Maretzky T, ADAM 10 regulates endothelial permeability and T-Cell transmigration by proteolysis of vascular endothelial cadherin.2008,102(10):1192-201.
32 Bergers G,CoussensL.Extrinsic regulators of epithelial tumor progression:metalloproteinases. Curr. Opin. Genet. Dev,2000,10:120-127.
33 Russell P, Bennett S,Stricker P. Growth factor involvement in progression of prostate cancer. Clin. Chem.1998,44:705-723.
34 Long L, Navab R,Brodt P. Regulation of the Mr72,000 typeⅣ collagenase by the type Ⅰ insulin-like growth factor receptor. Cancer Res.1998,58:3243-3247.
35 Maretzky T, Reiss K, Ludwig A. ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and beta-catenin translocation. Proc Natl Acad Sci U S A.2005,102(26):9182-7.
36 Sundareshan P, Nagle R, Bowden G. EGF induces the expression of matrilysin in the human prostate adenocarcinoma cell line,LNCaP. Prostate,1999,40:159-166.
37 McCulloch R, Harvey M, Herington A.The expression of the ADAMs proteases in prostate cancer cell lines and their regulation by dihydrotestosterone. Mol. Cell. Endocrinol. 2000,167:11-21.
38 Bostwick G,Amin B, Dundore P. Architectural patterns of high-grade prostatic intraepithe lial neoplasia. Hum. Pathol.1993,24:298-310.
39 Iwamura M, SlussM, CasamentoB.Insulin-like growth factor I:action and receptor characterization in human prostate cancer cell lines. Prostate,1993,22:243-252.
40 Siu W, Lau W, TamC. Melatonin and prostate cancer cell proliferation:interplay with castration, epidermal growth factor, and androgen sensitivity. Prostate,2002,52:106-122.
41 Montgomery T,Young Y,Bilhartz L.Hormonal regulation of prostate-specific antigen (PSA) glycoprotein in the human prostatic adenocarcinoma cell line, LNCaP. Prostate,1992,21: 63-73.
42 Gutwein P,Mechtersheimer S, Riedle S. ADAM10-mediated cleavage of Ll adhesion molecule at the cell surface and in released membrane vesicles. FASEB J,2003,17:292-294.
43 Franzke W, Tasanen K, Schacke H. Transmembrane collagen XVII, an epithelial adhesion protein, is shed from the cell surface by ADAMs. EMBOJ.2002,21:5026-5035.
44 Nagle B, Hao J, Knox D. Expression of hemidesmosomal and extracellular matrix proteins by normal and malignant human prostate tissue. Am. J. Pathol.1995,146:1498-1507.
45 Amour A, Knight G, Webster A. The in vitro activity of ADAM-10 is inhibited by TIMP-1 and TIMP-3. FEBS Lett.2000,473:275-279.
46 Bauvois B.Transmembrane proteases in focus:diversity and redundancy? J. Leukocyte Biol. 2001,70:11-17.
47 Chang C, Werb Z. The many faces of metalloproteases:cell growth, invasion, angiogenesis and metastasis. Trends Cell Biol.2001,11:S37-S43.
48 Lobie E, Garcia-Aragon J, Wang S.Cellular localization of the growth hormone binding protein in the rat. Endocrinology,1992,130:3057-3065.
49 Henderson E,Amizuka N, Warshawsky H.Nucleolar localization of parathyroid hormone-related peptide enhances survival of chondrocytes under conditions that promote apoptotic cell death. Mol. Cell.Biol.1995,15:4064-4075.
50 Schedlich J, Le Page L, Firth M.Nuclear import of insulin-like growth factor binding protein-3 and-5 is mediated by the importin subunit. J. Biol.Chem.2000,275:23462-23470.
51 Lin Y, Makino K, Xia W. Nuclear localization of EGF receptor and its potential new role as a transcription factor. Nat. Cell. Biol.2001,3:802-808.
52 Adam M,Danciu T,McLellan L.A nuclear form of the heparin-binding epidermal growth factor-like growth factor precursor is a feature of aggressive transitional cell carcinoma. Cancer Res.2003,63:484-490.
53 Jans A, Xiao Y, Lam H. Nuclear targeting signal recognition:a key control point in nuclear transport? Bioessays,2000,22:532-544.
54 Jans A, Hubner S. Regulation of protein transport to the nucleus:central role of phosphorylation. Physiol. Rev.1996,76:651-685.
55 Quimby B, Corbett H. Nuclear transport mechanisms.Cell. Mol. Life Sci.2001,58:1766-1773.
56 Yarwood J,Woodgett R. Extracellular matrix composition determines the transcriptional response to epidermal growth factor receptor activation. Proc. Natl. Acad. Sci. USA,2001,98: 4472-4477.
57 Fridman JS, Caulder E, Hansbury M.Selective inhibition of ADAM metalloproteases as a novel approach for modulating ErbB pathways in cancer. Clin Cancer Res.2007,13(6):1892-902.
58 DallasJ, Genever G, Patton J.Localization of ADAM10 and notch receptors in bone. Bone, 1999,25:9-15.
59 Endres K, Anders A, Kojro E.Tumor necrosis factor-converting enzyme is processed by proprotein-convertases to its mature form which is degraded upon phorbol ester stimulation. Eur. J. Biochem.2003,270:2386-2393.
60 Culig Z, Hobisch A, Cronauer V. Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-Ⅰ, keratinocyte growth factor, and epidermal growth factor. Cancer Res.1994,54:5474-5478.
2 Wolfsberg TG, Primakoff P, Myles DG. ADAM, a novel family of membrane proteins containing A Disintegrin And Metalloprotease domain:multipotential functions in cell-cell and cell-matrix interactions. J Cell Biol.1995 Oct;131(2):275-8
3 Huovila AP, Almeida EA, White JM. ADAMs and cell fusion. Curr Opin Cell Biol.1996 Oct;8(5):692-9.
4 Mochizuki S,Okada Y.ADAMs in cancer cell proliferation and pro-gressio (J).CancerSc,i 2007, 98(5):621-6.
5 Weskamp G, Kratzschmar J, Reid MS, MDC9, a widely expressed cellular disintegrin containing cytoplasmic SH3 ligand domains. J Cell Biol.1996 Feb;132(4):717-26.
6 Evans JP, Schultz RM, Kopf GS. Roles of the disintegrin domains of mouse fertilins alpha and beta in fertilization. Biol Reprod.1998 Jul;59(l):145-52.
7 Yuan R, Primakoff P, Myles DG. A role for the disintegrin domain of cyritestin, a sperm surface protein belonging to the ADAM family, in mouse sperm-egg plasma membrane adhesion and fusion. J Cell Biol.1997 Apr 7; 137(1):105-12.
8 Millichip MI, Dallas DJ, Wu E, The metallo-disintegrin ADAM10 (MADM) from bovine kidney has type IV collagenase activity in vitro. Biochem Biophys Res Commun.1998 Apr 17;245(2):594-8.
9 Merlos-Suarez A, Fernandez-Larrea J, Reddy P,Pro-tumor necrosis factor-alpha processing activity is tightly controlled by a component that does not affect notch processing. J Biol Chem. 1998 Sep 18;273(38):24955-62.
10 Qi H, Rand MD, Wu X, Processing of the notch ligand delta by the metalloprotease Kuzbanian. Science.1999 Jan 1;283(5398):91-4.
11 Wen C, Metzstein MM, Greenwald I SUP-17, a Caenorhabditis elegans ADAM protein related to Drosophila KUZBANIAN, and its role in LIN-12/NOTCH signalling.. Development.1997 Dec;124(23):4759-67.
12 Peschon JJ, Slack JL, Reddy PAn essential role for ectodomain shedding in mammalian development.Science.1998 Nov 13;282(5392):1281-4.
13 Buxbaum JD, Liu KN, Luo Y, Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. J Biol Chem.1998 Oct 23;273(43):27765-7.
14 Takahide Kodama, Eiji Ikeda, Aiko Okada. ADAM12 Is Selectively Overexpressed in Human Glioblastomas and Is Associated with Glioblastoma Cell Proliferation and Shedding of Heparin-Binding Epidermal Growth Factor. (American Journal of Pathology.
2004;165:1743-1753.)
15 Schulz B, Pruessmeyer J, Maretzky T, ADAM10 regulates endothelial permeability and T-Cell transmigration by proteolysis of vascular endothelial cadherin.2008 May 23; 102(10): 1192-201.
16 Reiss K, Ludwig A, ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and betacatenin translocation. Proc Natl Acad Sci U S A.2005 Jun 28; 102(26):9182-7.
17 Fridman JS, Caulder E, Hansbury M,Selective inhibition of ADAM metalloproteases as a novel approach for modulating ErbB pathways in cancer. Clin Cancer Res.2007 Mar 15;13(6):1892-902.
18 Kanazawa R, Yoshida D, Takahashi H. Drug-induced apoptosis by a matrix metalloproteinase inhibitor, SI-27 on human malignant glioma cell lines; in vitro study. J Neurooncol. 2004;66(1-2):91-9.
19 WolfsbergTG,White JM. ADAMs in fertilization and development (J).DevelopmentalBiology, 1996,180(2):389-94.
20 Mochizuki S,Okada Y.ADAMs in cancer cell proliferation and pro-gressio (J).CancerSc,i 2007, 98(5):621-5.
21 Darren F.etc.The ADAMs family of metalloproteases:multidomain proteins with multiple functions [J]. Genes Dev.2003 17:7-30
22 Wolfsberg TG, White JM. ADAMs in fertilization and development[J].DevelopmentalBiology, 1996,180(2):389-401.
23 施文 李俊生.ADAM 家族与肿瘤关系的研究概况[J].实用癌症杂志,2008 06-0671-03
24 Wildeboer D, Naus S, Amy Sang QX. Metalloproteinase disintegrins ADAM8 and ADAM 19 are highly regulated in human primary brain tumors and their expression levels and activities are associated with invasiveness.[J]. Neuropathol Exp Neurol.2006 May;65(5):516-27.
25 Takahide Kodama, Eiji Ikeda, Aiko Okada. ADAM12 Is Selectively Overexpressed in Human Glioblastomas and Is Associated with Glioblastoma Cell Proliferation and Shedding of Heparin-Binding Epidermal Growth Factor.[J].American Journal of Pathology. 2004;165:1743-53.
26 D'Abaco GM, Ng K, Paradiso L. ADAM22, expressed in normal brain but not in high-grade gliomas, inhibits cellular proliferation via the disintegrin domain. [J].Neurosurgery. 2006,58(1):179-86
27 Xuguang Zheng, Feng Jiang, Mark Katakowski. Inhibition of ADAM 17 reduces hypoxia-induced brain tumor cell invasiveness[J]. Cancer Sci 2007; 98:674-84
28 Kodama T, Ikeda E, Okada A, et al. ADAM12 is selectively overexpressed in human glioblastomas and is associated with glioblastoma cell proliferation and shedding of heparin-binding epidermal growth factor.[J].Am J Pathol 2004;165:1743-53
29 Yoshimura T, Tomita T, Dixon MF,et al ADAMs (a disintegrin and metalloproteinase) messenger RNA expression in Helicobacter pylori-infected, normal, and neoplastic gastric mucosa. [J]. J Infect Dis,2002,185(3):332-40
30 Millichip MI, Dallas DJ, Wu E, The Metallo-Disintegrin ADAM10 (MADM) from Bovine Kidney Has Type IV Collagenase Activity inVitro[J].Biochem Biophys Res Commun,1998;245(2):594-8.
31 Louis DN, Gusella JF:A tiger behind many doors:multiple genetic pathways to malignant glioma. [J]Trends Genet 1995,11:412-415
32 Wong AJ, Ruppert JM, Bigner SH et al.Structural alterations of the epidermal growth factor receptor gene in human gliomas. [J] Proc Natl Acad Sci USA 1992,89:2965-2969
33 Humphrey PA, Wong AJ, Vogelstein B, et al. Anti-synthetic peptide antibody reacting at the fusion junction of deletionmutant epidermal growth factor receptors in human glioblastoma. [J].Proc Natl Acad Sci USA 1990,87:4207-4211
34 Sugawa N, Ekstrand AJ, James CD, et al. Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged genes in human glioblastomas. [J].Proc Natl Acad Sci USA 1990,87:8602-6
35 Nishikawa R, Ji XD, Harmon RC, et al. A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. [J].Proc Natl Acad Sci USA 1994,91:7727-31
36 Ekstrand AJ,James CD,Cavenee WK,et al.Genes for epidermal growth factor receptor, transforming growth factor and epidermal growth factor and their expression in human gliomas in vivo. [J].Cancer Res 1991,51:2164-72
37 Asakura M, Kitakaze M, Takashima S, et al.Cardiac hypertrophy is inhibited by antagonism of AD AMI2 processing of HB-EGF:metalloproteinase inhibitors as a new therapy. [J].Nat Med 2002,8:35-40
38 Kurisaki T, Masuda A, Sudo K, etal.Phenotypic analysis of meltrin(ADAM12)-deficierit mice: involvement of meltrin in adipogenesis and myogenesis. [J].Mol Cell Biol 2003,23:55-61
39 Schulz B, Pruessmeyer J,MaretzkyT, ADAM10 regulates endothelial permeability and T-Cell transmigration by proteolysis of vascular endothelial cadherin. [J].2008;102(10):1192-201.
1 J Folkman J, Ryeem S. Is oncogene addiction angiogenesis-dependent? [J]. Cold Sp Harb Symp Quant BiOl,2005,70:389-397.
2 J Chan AS, LeungSY, WongMP, et al. Expression of vascular endotheli.algowthfact or andits receptorsintheanaplastic progression of astrocytoma, oH8Dde IIdrOgbOm, endymorna[J]. Am J Surg Pathol,1998,22(7):816-826.
3 J Egscrt A, lkegaki N, Kwiatkowski J,et al. Hish-level expression of an-giogenlcfactorsis associated withadvanced tulnor stag-in human neu roblastomas[JJ. Clin Cancer Res,2000, 6(5):1900-1908.
4 Dunn IF, HeeseO, BlackPM,et al. Growthfactorsin siogenesis FGFs, PDGF, EGF, and TGFs[J]. J Neumoncol,2000,50(1-2):121-137.
5 BambaH, Ota S, KatoA, et al. prost,landins up-regulate vascular endothdiM growthfactor production throughdistinct pathwaysin differenfiated U937 cells[J].Biochem Biephys Res Commun,2000,273(2):485-491.
6 Sufan RI, Jewett MA, Ohh M, et al.Re role of yon Hippel-Lindan tunlor suppressor protein and hypoxiain renal clear cell carcinoma[J]. Am J Phvsiol Renal Physiol,2004,287(2):F1-F6
7 Jones MK, SzaboIL, KawanakaH,et al. VonHippelLindantunlor sup-pressor and H]F-la1Dh8: new targets of NSAIDs inhibition of hypoxia-induced angiogenesis[J]FASEB J,2002,16(2): 264-266
8 Mabjeesh NJ, Escuin D, LaVallee TM, et al.2ME2 inhibits tulnor growth and angiogenesis by disrupting micmtulxfles and dysregulating HIF[J]. Cancer Cell,2003,3(4):363-375.
9 Sonnni NE, Devy L, Hajitou A, et al. MT1-MMP expression promotes tulnor growth andongiogenesisthroughan up-regulation of vascular endothelial gowth factor expression[J]. FASEB J,2002,16(6):555-564.
10 Their M, Reeb E, Breuer B, et al. Expression of matrix metallepmteinase-2 in glial and netlronal tulnor cell lines:inverse correlation with proliferation rate[J]. Cancer Lett,2000, 149(1-2):163-170.
11 CuferT, Borstnar S, Vrhovec J. Prognostic and predictive value of the urokinase-type plasminogen activator(UPA)and its inhibitors PAI-1 and PAJ-2 in operable breast e-qileel"[J]. Markers,2003,18(2):106-115.
12 Jaworski DM, Kelly GM, Piepmeier JM, et al. BEHAB(brain enriched hyali. iuonan binding)is expressed in surgical samples of glioma and in intracranial grafts ofinvasive ollla cell lines[J]. Cancer Res,1996,56(3):2293-2298.
13 Khatib AM, Nip J, Fauavoilita L, et al. Regulation of urokinase plas-mino-n activator/plasmin-mediated invasion of melanonm cells by the integrin vitronactin receptor alphaVbeta3[J]. Int Cancer,2001,91(3):300-308.
14 Savani RC, CaoG, PoolerPM, et al. Differential involvementofthe hy. Aluronan (HA)receptorsC and receptor. mediatedmotilityin endothelialcellfunction and angiogenesis[J]. J Biol Chem,2001,276(39):36770-36778.
15 FritzG, Brachetti C, Bahlmann F, etal. Rho GTPasesin human breast tulnors:expression and mutation analyses and ceFiTelation with clinical parameters[J]. Br J Cancer,2002,87(6): 635-644.
16 Forget MA, Desrosiers RR, Del M, et al. The expression of rho protdns decreaseswith human brain tumor progression:potential tulnor marker [J]. Clin Exp Matastasis,2002,19(1):9-15.
17 Tsatas D, Kanagasundaram V, Kaye A, et al. EGF receptor roodifies cellular responses to hyaluronan in glioblastoma cell lines[J]. J Clin Neurosurgical2002,9(3):282-288.
18 Choe G, Park JK, JoubenSteele L, et al. Active matrix metaUoproteinabe 9 expression is associated with primary glioblastoma subtype[J]. Clin Cancer Res,2002,8(9):2894-2901.
19 ManningTJ Jr, Parker JC, SontheimerH. Roleoflysophosphatidieacid and rho in onla cell motilityl[J]. cell Motil Cytoskdeton,2000,45(3):185-199
1 WolfsbergTG,White JM. ADAMs in fertilization and development (J).DevelopmentalBiology, 1996,180(2):389.
2 Wolfsberg TG, Primakoff P, Myles DG. ADAM, a novel family of membrane proteins containing A Disintegrin And Metalloprotease domain:multipotential functions in cell-cell and cell-matrix interactions. J Cell Biol.1995,131(2):275-8
3 Huovila AP, Almeida EA, White JM. ADAMs and cell fusion. Curr Opin Cell Biol. 1996,8(5):692-9.
4 Mochizuki S,Okada Y.ADAMs in cancer cell proliferation and pro-gressio (J).CancerSc,i 2007, 98(5):621.
5 Kheradmand F, Werb Z. Shedding light on sheddases:role in growth and development. Bioessays,2002,24:8-12.
6 Inoue D, Reid M, Lum L. Cloning and initial characterization of mouse meltrin and analysis of the expression of four metalloprotease-disintegrins in bone cells. J. Biol. Chem.1998,273: 4180-4187.
7 Pan D, Rubin G. M. Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis. Cell,1997,90:271-280.
8 Rosendahl M, Ko S, Long D.Identification and characterization of a protumor necrosis factor-processing enzyme from the ADAM family of zinc metalloproteases. J. Biol. Chem. 1997,272:24588-24593.
9 Skovronsky D, Moore D. Protein kinase C-dependent-secretase competes with secretase for cleavage of amyloid-precursor protein in the trans Golgi network. J. Biol. Chem.2000,275: 2568-2575.
10 Maskos K,Fernandez-Catalan C, Huber R.Crystal structure of the catalytic domain of human tumor necrosis factor-converting enzyme. Proc. Natl. Acad. Sci. USA,1998,95:3408-3412.
11 Weskamp G, Kratzschmar J, Reid MS. A widely expressed cellular disintegrin containing cytoplasmic SH3 ligand domains. J Cell Biol.1996,132(4):717-26.
12 Evans JP, Schultz RM, Kopf GS. Roles of the disintegrin domains of mouse fertilins alpha and beta in fertilization. Biol Reprod.1998,59(1):145-52.
13 Yuan R, Primakoff P, Myles DG. A role for the disintegrin domain of cyritestin, a sperm surface protein belonging to the ADAM family, in mouse sperm-egg plasma membrane adhesion and fusion. J Cell Biol.1997,137(1):105-12.
14 Millichip MI, Dallas DJ, Wu E. The metallo-disintegrin ADAM10 (MADM) from bovine kidney has type IV collagenase activity in vitro. Biochem Biophys Res Commun. 1998,17;245(2):594-8.
15 Dundore P,Marsh W,Schultz D. S. Architectural patterns of high-grade prostatic intraepithe lial neoplasia. Hum. Pathol.1993,24:298-310.
16 Xuguang Zheng,Feng Jiang,Mark Katakowski.Inhibition of ADAM 17 reduces hypoxia-induced brain tumor cell invasiveness. Cancer Sci 2007,98:674-684
17 Moss M, White M, Lambert M. TACE and other ADAM proteases as targets for drug discovery. Drug.Discov. Today,2001,6:417-426.
18 Yan B,Shirakabe K,Werb Z.The metalloprotease Kuzbanian (ADAM 10) mediates the transactivation of EGF receptor by G protein-coupled receptors. J. Cell Biol.2002,158: 221-226.
19 Qi H, Rand M, Wu X. Processing of the notch ligand Delta by the metalloprotease Kuzbanian. Science (Wash. DC),1999,283:91-94.
20 Lammich S,Kojro E, Postina R. Constitutive and regulated secretase cleavage of Alzheimer's amyloid precursor protein by adisintegrin metalloprotease.Proc.Natl.Acad.Sci. USA,1999,96: 3922-3927.
21 Hattori M, Osterfield M, Flanagan J.Regulated cleavage of a contact-mediated axon repellent. Science (Wash. DC),2000,289:1360-1365.
22 White J, Bigler D, Chen M.ADAMs. In:M. C. Beckerle (ed.) Cell Adhesion, pp. New York: Oxford University Press,2001.189-216.
23 Mechtersheimer S,Gutwein P,Agmon-Levin N. Ectodomain shedding of L1 adhesion molecule promotes cell migration by autocrine binding to integrins. J. Cell Biol.2001,155:661-673.
24 Merlos-Suarez A, Fernandez-Larrea J, Reddy P,Pro-tumor necrosis factor-alpha processing activity is tightly controlled by a component that does not affect notch processing. J Biol Chem. 1998,18;273(38):24955-62.
25 Qi H, Rand MD, Wu X, Processing of the notch ligand delta by the metalloprotease Kuzbanian. Science.1999,1;283(5398):91-4.
26 Wen C,Metzstein MM.Greenwald I SUP-17, a Caenorhabditis elegans ADAM protein related to Drosophila KUZBANIAN, and its role in LIN-12/NOTCH signalling.Development. 1997,124(23):4759-67.
27 Peschon JJ, Slack JL, Reddy PAn essential role for ectodomain shedding inmammalian development.Science.1998,282(5392):1281-4.
28 Buxbaum JD, Liu KN, Luo Y. Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. J Biol Chem.1998,273(43):27765-7.
29 Wildeboer D, Naus S, Amy Sang QX. Metalloproteinase disintegrins ADAM8 and ADAM19 are highly regulated in human primary brain tumors and their expression levels and activities are associated with invasiveness.[J] Neuropathol Exp Neurol.2006,65(5):516-27.
30 Takahide Kodama, Eiji Ikeda, Aiko Okada. ADAM12 Is Selectively Overexpressed in Human Glioblastomas and Is Associated with Glioblastoma Cell Proliferation and Shedding of Heparin-Binding Epidermal Growth Factor. (American Journal of Pathology. 2004,165:1743-1753.)
31 Schulz B, Pruessmeyer J, Maretzky T, ADAM 10 regulates endothelial permeability and T-Cell transmigration by proteolysis of vascular endothelial cadherin.2008,102(10):1192-201.
32 Bergers G,CoussensL.Extrinsic regulators of epithelial tumor progression:metalloproteinases. Curr. Opin. Genet. Dev,2000,10:120-127.
33 Russell P, Bennett S,Stricker P. Growth factor involvement in progression of prostate cancer. Clin. Chem.1998,44:705-723.
34 Long L, Navab R,Brodt P. Regulation of the Mr72,000 typeⅣ collagenase by the type Ⅰ insulin-like growth factor receptor. Cancer Res.1998,58:3243-3247.
35 Maretzky T, Reiss K, Ludwig A. ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and beta-catenin translocation. Proc Natl Acad Sci U S A.2005,102(26):9182-7.
36 Sundareshan P, Nagle R, Bowden G. EGF induces the expression of matrilysin in the human prostate adenocarcinoma cell line,LNCaP. Prostate,1999,40:159-166.
37 McCulloch R, Harvey M, Herington A.The expression of the ADAMs proteases in prostate cancer cell lines and their regulation by dihydrotestosterone. Mol. Cell. Endocrinol. 2000,167:11-21.
38 Bostwick G,Amin B, Dundore P. Architectural patterns of high-grade prostatic intraepithe lial neoplasia. Hum. Pathol.1993,24:298-310.
39 Iwamura M, SlussM, CasamentoB.Insulin-like growth factor I:action and receptor characterization in human prostate cancer cell lines. Prostate,1993,22:243-252.
40 Siu W, Lau W, TamC. Melatonin and prostate cancer cell proliferation:interplay with castration, epidermal growth factor, and androgen sensitivity. Prostate,2002,52:106-122.
41 Montgomery T,Young Y,Bilhartz L.Hormonal regulation of prostate-specific antigen (PSA) glycoprotein in the human prostatic adenocarcinoma cell line, LNCaP. Prostate,1992,21: 63-73.
42 Gutwein P,Mechtersheimer S, Riedle S. ADAM10-mediated cleavage of Ll adhesion molecule at the cell surface and in released membrane vesicles. FASEB J,2003,17:292-294.
43 Franzke W, Tasanen K, Schacke H. Transmembrane collagen XVII, an epithelial adhesion protein, is shed from the cell surface by ADAMs. EMBOJ.2002,21:5026-5035.
44 Nagle B, Hao J, Knox D. Expression of hemidesmosomal and extracellular matrix proteins by normal and malignant human prostate tissue. Am. J. Pathol.1995,146:1498-1507.
45 Amour A, Knight G, Webster A. The in vitro activity of ADAM-10 is inhibited by TIMP-1 and TIMP-3. FEBS Lett.2000,473:275-279.
46 Bauvois B.Transmembrane proteases in focus:diversity and redundancy? J. Leukocyte Biol. 2001,70:11-17.
47 Chang C, Werb Z. The many faces of metalloproteases:cell growth, invasion, angiogenesis and metastasis. Trends Cell Biol.2001,11:S37-S43.
48 Lobie E, Garcia-Aragon J, Wang S.Cellular localization of the growth hormone binding protein in the rat. Endocrinology,1992,130:3057-3065.
49 Henderson E,Amizuka N, Warshawsky H.Nucleolar localization of parathyroid hormone-related peptide enhances survival of chondrocytes under conditions that promote apoptotic cell death. Mol. Cell.Biol.1995,15:4064-4075.
50 Schedlich J, Le Page L, Firth M.Nuclear import of insulin-like growth factor binding protein-3 and-5 is mediated by the importin subunit. J. Biol.Chem.2000,275:23462-23470.
51 Lin Y, Makino K, Xia W. Nuclear localization of EGF receptor and its potential new role as a transcription factor. Nat. Cell. Biol.2001,3:802-808.
52 Adam M,Danciu T,McLellan L.A nuclear form of the heparin-binding epidermal growth factor-like growth factor precursor is a feature of aggressive transitional cell carcinoma. Cancer Res.2003,63:484-490.
53 Jans A, Xiao Y, Lam H. Nuclear targeting signal recognition:a key control point in nuclear transport? Bioessays,2000,22:532-544.
54 Jans A, Hubner S. Regulation of protein transport to the nucleus:central role of phosphorylation. Physiol. Rev.1996,76:651-685.
55 Quimby B, Corbett H. Nuclear transport mechanisms.Cell. Mol. Life Sci.2001,58:1766-1773.
56 Yarwood J,Woodgett R. Extracellular matrix composition determines the transcriptional response to epidermal growth factor receptor activation. Proc. Natl. Acad. Sci. USA,2001,98: 4472-4477.
57 Fridman JS, Caulder E, Hansbury M.Selective inhibition of ADAM metalloproteases as a novel approach for modulating ErbB pathways in cancer. Clin Cancer Res.2007,13(6):1892-902.
58 DallasJ, Genever G, Patton J.Localization of ADAM10 and notch receptors in bone. Bone, 1999,25:9-15.
59 Endres K, Anders A, Kojro E.Tumor necrosis factor-converting enzyme is processed by proprotein-convertases to its mature form which is degraded upon phorbol ester stimulation. Eur. J. Biochem.2003,270:2386-2393.
60 Culig Z, Hobisch A, Cronauer V. Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-Ⅰ, keratinocyte growth factor, and epidermal growth factor. Cancer Res.1994,54:5474-5478.