Ezrin和CD44v6在胃癌中的表达及临床意义
摘要
背景与目的:
Ezrin属于ERM(Ezrin-Radixin-Moesin)家族成员之一,其编码基因为villin2,定位于染色体6q25-q26,ERM蛋白的C末端与细胞骨架的actin相连,N末端通过与细胞表面的粘附分子Cadherin、CD44等相连接,调节细胞-细胞,细胞-间质粘附性而影响恶性肿瘤细胞侵袭性等生物学行为。Ezrin首先于1981年被发现于鸡的肠上皮细胞的微绒毛,它主要集中于富含肌动蛋白的细胞微绒毛和细胞膜的皱襞中,并参与上皮细胞的膜动力学。Ezrin几乎存在于任何细胞,但在小肠、胃、肺、胰腺和肾组织中有较高的表达水平,在脾脏、胸腺淋巴结和骨髓中的表达水平中等,而在心脏、睾丸和肌肉中的水平较低。在生理状态下,Ezrin参与细胞表面结构如伪足、微绒毛等的形成,并参与细胞间及细胞与基质之间的粘附,信号传导和细胞运动。近年来的研究发现Ezrin在肿瘤发生、浸润和转移中也起到重要作用,Ezrin参与细胞的移动、信号传导以及细胞粘附等与肿瘤进展相关的环节。
CD44分子基因定位于染色体11p13,有至少19-20个高度保守的外显子构成。CD44v6是主要的变体之一。CD44v6是一种细胞表面跨膜糖蛋白,分布极广,在许多上皮细胞和间质细胞长均有分布。作为细胞基质透明质酸受体,参与癌细胞与基质的粘附作用及淋巴细胞归巢,它们可以改变肿瘤细胞表面粘附分子的构成和功能,有利于癌细胞的扩散和转移。近来研究表明,CD44v6过量表达与多种人体恶性肿瘤的发生、发展、侵袭和转移密切相关,肺癌、乳腺癌和大肠癌等肿瘤中均出现CD44v6的高表达。
细胞骨架蛋白Ezrin及细胞粘附分子CD44v6在肿瘤的发生及转移中的作用已为许多研究者探索,但两者在胃癌中的表达及临床分析结果并不统一,两者在胃癌中表达的相关性研究未见报道。而本研究旨在通过检测Ezrin、CD44v6在胃癌中的表达情况,比较分析它们与胃癌转移之间的相关性,以及两者联合检测的可能性,为胃癌转移、预后判断及临床治疗提供新的依据。
方法:
1标本来源
本研究病例资料取自南京军区南京总医院2005年-2006年病理科存档的胃癌手术石蜡包埋标本,共53例,另取正常胃组织20例。
2试剂与方法
采用免疫组化方法进行检测。所有标本均经10%福尔马林固定,常规石蜡包埋,4μm厚连续切片,免疫组化Envision染色。将制好的组织切片,经二甲苯脱蜡,梯度乙醇脱水后性免疫组化染色。采用高压锅高温抗原修复后,余步骤按试剂盒说明书进行操作。DAB显色,苏木精复染,中性树胶封固。Ezrin鼠抗人单克隆抗体(稀释度为1:200)(克隆号3c12)购自NeoMarkers公司,CD44v6鼠抗人单克隆抗体(稀释度为1:200)购于福州迈新生物技术开发公司。
3结果判断
Ezrin在胞质内表达呈棕黄色颗粒,按染色强度和阳性细胞表达细胞数,参考Mathew等分级标准:(-):无表达;(+):＜50%细胞阳性表达或染色较浅;(++):≥50%阳性表达或染色较深。
CD44v6以细胞膜有明确棕黄色为阳性细胞,采用半定量积分法,即根据每张切片的阳性细胞比例及着色深浅计分,着色细胞比例在1/3以下为1分,2/3以上为3分,两者之间为2分;着色程度,无着色0分,浅黄色1分,橘黄色2分,棕褐色3分。根据两者乘积判断等级,0分为(-),1～4分为(+),大于4分为(++)。
4统计学方法
采用SPSS11.0统计软件进行统计分析,采用x~2检验及Spearsman相关分析,P＜0.05认为有显著性统计学意义。
结果:
1.Ezrin在胞质中呈棕色颗粒,在肿瘤组织中呈局部或灶性至弥漫性分布,在正常胃粘膜中也有染色,呈弥漫分布。53例胃癌标本中Ezrin阳性30例,阳性表达率为56.6%,20例正常胃粘膜中Ezrin阳性6例,阳性率30%,经x~2检验两组之间差异有显著性,(P＜0.01)。
CD44v6染色阳性细胞的胞膜和胞质可见深浅不一,染色强度不等的棕黄色颗粒,弥漫或散在分布,在正常胃粘膜中不染色。53例胃癌标本中CD44v6阳性31例,阳性率为58.5%。
2.Ezrin的表达程度与胃癌的分化程度有关(P＜0.05),与临床分期、淋巴结转移及远处转移显著相关(P＜0.01)。CD44v6的表达程度与胃癌的分化程度无关(P＞0.05),与临床分期、淋巴结转移及远处转移显著相关(P＜0.01)。
3.胃癌组织中Ezrin及CD44v6的表达之间呈显著正相关(r_s=0.740,P＜0.01)。
结论:
胃癌组织中Ezrin及CD44v6的高表达与胃癌的临床分期、淋巴结转移及远处转移有关,提示Ezrin和CD44v6与胃癌的进展有关,尤其是在胃癌的转移过程中发挥着重要作用,因此Ezrin和CD44v6的联合检测有望成为胃癌诊断及预后判断的有效指标。
Objective:
The Ezrin protein is a member of the Ezrin,Radixin,Moesin(ERM) proteins family that are proposed to act as linkers between the cytoskeleton and plasma membrane.Ezrin is a cytoplasmic protein enriched in microvilli and other cell surface structures.It resides on chromosome 6q25-q26.Its NH2-terminal domain is associated with the plasma membrane and the COOH-terminal domain with the cytoskeleton.Ezrin regulates cell-cell and cell-matrix interactions playing a role in the regulation of cellular adhesion,movement and morphology in epithelia.Ezrin serves as a tyrosine kinase substrate,and is phosphorylated in epidermal growth factor-stimulated cells.Ezrin is highly expressed in several types of human cancers.
The CD44 gene resides on chromosome 11p13,and is known to be composed of at least 19-20 exons.As the main variant of CD44,CD44v6 is a kind of cell-surface adhesion molecule,which is important in cell-cell and cell-matrix adhesion.It could increase the metastatic potential of a tumor by facilitating the expansion of malignant cells into the draining lymph nodes.Recent studies have discovered that over expression of CD44v6 plays an important role in the growth,invasion,and metastasis of several kind of tumors such as colon cancer,breast cancer,and lung cancer..
Even though it was shown that Ezrin and CD44v6 are essential for the carcinogenesis,progression and metastasis of several types of cancers,their expressions in gastric carcinoma were not analyzed so far,especially their correlations.This study was initiated to define the relationship between the expression of Ezrin and CD44v6 in gastric carcinoma and clinicopathological parameters.
Methods:
The study population consisted of 53 patients(31 men and 22 women,average 55.4,ranged from 28 to 82 years),diagnosed with gastric carcinoma and 20 with normal gastric mucosa in the Nanjing General Hospital of Nanjing Military Command,between 2005 and 2006.Tissue specimens were taken from operation,and all these specimens were fixed with 10%formalin and embedded in paraffin,and cut into 4μm serial sections.Standard Envision immunohistochemistry was performed using a mouse monoclonal antibody against Ezrin and CD44v6(Maxim IHC World,Fuzhou) at a dilution of 1:200.
The intensity of Ezrin staining was scored as the percentage of positive tumor cells in relation to the total number cells according to Mathew's scale.(-):no staining; (+):＜50%cells staining;(++):≥50%cells staining.
Membrane staining for CD44v6 was calculated as the percentage of positive tumor cells in relation to the total number cells using semiquantitative scale as follows:0=no staining;1=staining of 1-20%of cells;2=staining of 21-50%of cells; and 3=staining of 51-100%of cells.Staining intensity was scored as absent(-);weak/moderate(+);and intense(++).
All statistical analyses were carried out using SPSSv.11.Categorical variables were expressed in percentages and compared using x~2 test.The correlation between Ezrin and CD44v6 was compared using Spearsman's correlation analyse.Statistical significance was accepted at P＜0.05.
Results.
1、The positive expression rates of Ezrin in gastric carcinoma and normal gastric mucosa were 56.6%and 30%.While the positive expression rates of CD44v6 in gastric carcinoma was 58.5%and no expression in normal gastric mucosa.
2、The expression of Ezrin was correlated to differentiation(P＜0.05),and clinical stage,lymph node metastasis and metastasis in the distance(P＜0.01).The expression of CD44v6 was correlated to clinical stage,lymph node metastasis and metastasis in the distance(P＜0.01),but not to differentiation(P＞0.05).
3、The expression of Ezrin was positively correlated with that of CD44v6 in gastric carcinoma(r_s=0.740,P＜0.01).
Conclusion:
The high expression of Ezrin and CD44v6 were correlated to the clinical stage,lymph node metastasis and metastasis in the distance.They might be served as an important parameter for determining tumor biological behavior.It is useful to forecast metastasis and prognosis of gastric carcinoma by combined examine.
Ezrin属于ERM(Ezrin-Radixin-Moesin)家族成员之一,其编码基因为villin2,定位于染色体6q25-q26,ERM蛋白的C末端与细胞骨架的actin相连,N末端通过与细胞表面的粘附分子Cadherin、CD44等相连接,调节细胞-细胞,细胞-间质粘附性而影响恶性肿瘤细胞侵袭性等生物学行为。Ezrin首先于1981年被发现于鸡的肠上皮细胞的微绒毛,它主要集中于富含肌动蛋白的细胞微绒毛和细胞膜的皱襞中,并参与上皮细胞的膜动力学。Ezrin几乎存在于任何细胞,但在小肠、胃、肺、胰腺和肾组织中有较高的表达水平,在脾脏、胸腺淋巴结和骨髓中的表达水平中等,而在心脏、睾丸和肌肉中的水平较低。在生理状态下,Ezrin参与细胞表面结构如伪足、微绒毛等的形成,并参与细胞间及细胞与基质之间的粘附,信号传导和细胞运动。近年来的研究发现Ezrin在肿瘤发生、浸润和转移中也起到重要作用,Ezrin参与细胞的移动、信号传导以及细胞粘附等与肿瘤进展相关的环节。
CD44分子基因定位于染色体11p13,有至少19-20个高度保守的外显子构成。CD44v6是主要的变体之一。CD44v6是一种细胞表面跨膜糖蛋白,分布极广,在许多上皮细胞和间质细胞长均有分布。作为细胞基质透明质酸受体,参与癌细胞与基质的粘附作用及淋巴细胞归巢,它们可以改变肿瘤细胞表面粘附分子的构成和功能,有利于癌细胞的扩散和转移。近来研究表明,CD44v6过量表达与多种人体恶性肿瘤的发生、发展、侵袭和转移密切相关,肺癌、乳腺癌和大肠癌等肿瘤中均出现CD44v6的高表达。
细胞骨架蛋白Ezrin及细胞粘附分子CD44v6在肿瘤的发生及转移中的作用已为许多研究者探索,但两者在胃癌中的表达及临床分析结果并不统一,两者在胃癌中表达的相关性研究未见报道。而本研究旨在通过检测Ezrin、CD44v6在胃癌中的表达情况,比较分析它们与胃癌转移之间的相关性,以及两者联合检测的可能性,为胃癌转移、预后判断及临床治疗提供新的依据。
方法:
1标本来源
本研究病例资料取自南京军区南京总医院2005年-2006年病理科存档的胃癌手术石蜡包埋标本,共53例,另取正常胃组织20例。
2试剂与方法
采用免疫组化方法进行检测。所有标本均经10%福尔马林固定,常规石蜡包埋,4μm厚连续切片,免疫组化Envision染色。将制好的组织切片,经二甲苯脱蜡,梯度乙醇脱水后性免疫组化染色。采用高压锅高温抗原修复后,余步骤按试剂盒说明书进行操作。DAB显色,苏木精复染,中性树胶封固。Ezrin鼠抗人单克隆抗体(稀释度为1:200)(克隆号3c12)购自NeoMarkers公司,CD44v6鼠抗人单克隆抗体(稀释度为1:200)购于福州迈新生物技术开发公司。
3结果判断
Ezrin在胞质内表达呈棕黄色颗粒,按染色强度和阳性细胞表达细胞数,参考Mathew等分级标准:(-):无表达;(+):＜50%细胞阳性表达或染色较浅;(++):≥50%阳性表达或染色较深。
CD44v6以细胞膜有明确棕黄色为阳性细胞,采用半定量积分法,即根据每张切片的阳性细胞比例及着色深浅计分,着色细胞比例在1/3以下为1分,2/3以上为3分,两者之间为2分;着色程度,无着色0分,浅黄色1分,橘黄色2分,棕褐色3分。根据两者乘积判断等级,0分为(-),1～4分为(+),大于4分为(++)。
4统计学方法
采用SPSS11.0统计软件进行统计分析,采用x~2检验及Spearsman相关分析,P＜0.05认为有显著性统计学意义。
结果:
1.Ezrin在胞质中呈棕色颗粒,在肿瘤组织中呈局部或灶性至弥漫性分布,在正常胃粘膜中也有染色,呈弥漫分布。53例胃癌标本中Ezrin阳性30例,阳性表达率为56.6%,20例正常胃粘膜中Ezrin阳性6例,阳性率30%,经x~2检验两组之间差异有显著性,(P＜0.01)。
CD44v6染色阳性细胞的胞膜和胞质可见深浅不一,染色强度不等的棕黄色颗粒,弥漫或散在分布,在正常胃粘膜中不染色。53例胃癌标本中CD44v6阳性31例,阳性率为58.5%。
2.Ezrin的表达程度与胃癌的分化程度有关(P＜0.05),与临床分期、淋巴结转移及远处转移显著相关(P＜0.01)。CD44v6的表达程度与胃癌的分化程度无关(P＞0.05),与临床分期、淋巴结转移及远处转移显著相关(P＜0.01)。
3.胃癌组织中Ezrin及CD44v6的表达之间呈显著正相关(r_s=0.740,P＜0.01)。
结论:
胃癌组织中Ezrin及CD44v6的高表达与胃癌的临床分期、淋巴结转移及远处转移有关,提示Ezrin和CD44v6与胃癌的进展有关,尤其是在胃癌的转移过程中发挥着重要作用,因此Ezrin和CD44v6的联合检测有望成为胃癌诊断及预后判断的有效指标。
Objective:
The Ezrin protein is a member of the Ezrin,Radixin,Moesin(ERM) proteins family that are proposed to act as linkers between the cytoskeleton and plasma membrane.Ezrin is a cytoplasmic protein enriched in microvilli and other cell surface structures.It resides on chromosome 6q25-q26.Its NH2-terminal domain is associated with the plasma membrane and the COOH-terminal domain with the cytoskeleton.Ezrin regulates cell-cell and cell-matrix interactions playing a role in the regulation of cellular adhesion,movement and morphology in epithelia.Ezrin serves as a tyrosine kinase substrate,and is phosphorylated in epidermal growth factor-stimulated cells.Ezrin is highly expressed in several types of human cancers.
The CD44 gene resides on chromosome 11p13,and is known to be composed of at least 19-20 exons.As the main variant of CD44,CD44v6 is a kind of cell-surface adhesion molecule,which is important in cell-cell and cell-matrix adhesion.It could increase the metastatic potential of a tumor by facilitating the expansion of malignant cells into the draining lymph nodes.Recent studies have discovered that over expression of CD44v6 plays an important role in the growth,invasion,and metastasis of several kind of tumors such as colon cancer,breast cancer,and lung cancer..
Even though it was shown that Ezrin and CD44v6 are essential for the carcinogenesis,progression and metastasis of several types of cancers,their expressions in gastric carcinoma were not analyzed so far,especially their correlations.This study was initiated to define the relationship between the expression of Ezrin and CD44v6 in gastric carcinoma and clinicopathological parameters.
Methods:
The study population consisted of 53 patients(31 men and 22 women,average 55.4,ranged from 28 to 82 years),diagnosed with gastric carcinoma and 20 with normal gastric mucosa in the Nanjing General Hospital of Nanjing Military Command,between 2005 and 2006.Tissue specimens were taken from operation,and all these specimens were fixed with 10%formalin and embedded in paraffin,and cut into 4μm serial sections.Standard Envision immunohistochemistry was performed using a mouse monoclonal antibody against Ezrin and CD44v6(Maxim IHC World,Fuzhou) at a dilution of 1:200.
The intensity of Ezrin staining was scored as the percentage of positive tumor cells in relation to the total number cells according to Mathew's scale.(-):no staining; (+):＜50%cells staining;(++):≥50%cells staining.
Membrane staining for CD44v6 was calculated as the percentage of positive tumor cells in relation to the total number cells using semiquantitative scale as follows:0=no staining;1=staining of 1-20%of cells;2=staining of 21-50%of cells; and 3=staining of 51-100%of cells.Staining intensity was scored as absent(-);weak/moderate(+);and intense(++).
All statistical analyses were carried out using SPSSv.11.Categorical variables were expressed in percentages and compared using x~2 test.The correlation between Ezrin and CD44v6 was compared using Spearsman's correlation analyse.Statistical significance was accepted at P＜0.05.
Results.
1、The positive expression rates of Ezrin in gastric carcinoma and normal gastric mucosa were 56.6%and 30%.While the positive expression rates of CD44v6 in gastric carcinoma was 58.5%and no expression in normal gastric mucosa.
2、The expression of Ezrin was correlated to differentiation(P＜0.05),and clinical stage,lymph node metastasis and metastasis in the distance(P＜0.01).The expression of CD44v6 was correlated to clinical stage,lymph node metastasis and metastasis in the distance(P＜0.01),but not to differentiation(P＞0.05).
3、The expression of Ezrin was positively correlated with that of CD44v6 in gastric carcinoma(r_s=0.740,P＜0.01).
Conclusion:
The high expression of Ezrin and CD44v6 were correlated to the clinical stage,lymph node metastasis and metastasis in the distance.They might be served as an important parameter for determining tumor biological behavior.It is useful to forecast metastasis and prognosis of gastric carcinoma by combined examine.
引文
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[19]史荣亮,李建芳,瞿颖,等.肿瘤转移相关基因Ezrin在胃癌中的表达及意义[J].中华肿瘤外科杂志,2006,9(9):433-5.
[20]Pang ST,Fang XL,Valdman A,et al.Expression of ezrin in prostatic intraepithelial neoplasia.Urology,2004,63(3):609-12.
[21]Ohtani K,Sakamoto H,Rutherford T,et al.Ezrin,a membrane-cytoskeletal linking protein,is highly expressed in atypical endometrial hyperplasia and uterine endometrioid adenocarcinoma.Cancer Lett,2002,179(1):79-86.
[22]Weber GF,Bronson RT,Lagan J,et al.Absence of the CD44geneprevents sarcoma metastasis[J].Cancer Res,2002,62(8):2281-6.
[23]Yoshida R,KimuraN,Harada Y,et al.The loss of E2cadherin,alpha2 and beta2catenin expression is associated with metastasis and poor prognosis in invasive breast cancer[J].Int J Oncol,2001,18(3):513-20.
[24]杨树成,胥传海.CD44v6在胃癌中的表达及临床意义探讨.江苏大学学报(医学版),2005,15(3):232-234.
[25]徐胜军,胡炳奎,凌志强,等.CD44v6在胃癌中的表达及其临床意义.中国普外基础与临床杂志,2006,13(1):42-44.
[26]Jun-Qiang Chen,Wen-Hua Zhan,et al.Expression of heparanase gene,CD44v6,MMP-7 and nm23 protein and their relationship with the invasion and metastasis of gastric carcinomas[J].World J Gastroenterol,2004,10(6):776-82.
[27]Montgomery E,Abraham SC.CD44 loss in gastric stromal tumors as a prognostic marker[J].Am J Suyg Pathal,2004,28(2):168-77.
[28]Vizoso FJ,Femandez JC,Corte MD,er al.Expression and clinical significance CD44v5 and CD44v6 in respectable colorectal cancer[J].J Cancer Clin Oncol,2004,130(11):679-84.
[29]Mangeat P,Roy C,Martin M.ERM proteins in cell adhesion and membrane dynamics[J].Trends Cell Biol,1999,9(5):187-92.
[1] Martin TA, Harrison G,, Mansel RE, et al. The role of the CD44/ezrin complex in cancer metastasis. Crit Rev Oncol Hematol[J], 2003, 46(2): 165-86.
[2] Yonemura S, Tsukita S, Tsukita S. Direct involvement of ezrin/radixin/moesin (ERM) -binding membrane proteins in the organization of microvilli in collaboration with activated ERM proteins[J]. J Cell Biol, 1999, 145 (7):1497-509.
[3] Tasken K, Aandahl E. MLocalized Effects of cAMP Mediated by Distinct Routes of Protein Kinase A [J] . Physiol Rev, 2004, 84 (1): 137-67.
[4] Ng T, Parsons M, Hughes W E, et al. Ezrin is a downstream effector of trafficking PKC-integrin complexes involved in the control of cell motility [J]. J EMBO, 2001, 20 (11): 2723-41.
[5] Stapleton G, Malliri A, Ozanne B W. Downregulated AP-1 activity is associated with inhibition of Protein-Kinase-C-dependent CD44 and ezrin localization and upregulation of PKC theta in A431 cells [J]. J Cell Sci, 2002, 115 (pt13):2713-24.
[6] Yu Y, Khanna C, et al. Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators[J]. NatMed, 2004, 10 (2): 175-81.
[7] Khanna C, Wan X, Bose S, et al. The membrane - cytoskeleton linker ezrin is necessary for osteosarcoma metastasis [J]. NatMed, 2004, 10 (2): 182-86.
[8] Pujuguet P, Del Maestro L, Gautreau A, et al. Ezrin regulates E-cadherin dependent adherens junction assembly through Racl activation [J]. Mol Biol Cell, 2003, 14 (5): 2181-91.
[9]管小琴,王朝杰,李圆圆.Ezrin对肝细胞癌分化及粘附作用的影响.癌症2002,2l(3):281-84.
[10]史荣亮,李建芳,瞿颖,等.肿瘤转移相关基因Ezrin在胃癌中的表达及意义.中华肿瘤外科杂志,2006,9(9):433-435.
[11]Akisawa N,Nishimori I,Iwamura T,et al.High levels of ezrin expressed by human pancreatic adenocarcinoma cell lines with high metastatic potential [J].Biochem Biophys Res Commun,1999,258(2):395-400.
[12]Valdman A,Fang X,Pang S T,et al.Ezrin expression in prostatecancer and benign prostatic tissue[J].Eur Urol,2005,48(5):852-57.
[13]Weng W H,Ahlen J,Astrom K,et al.Prognostic impact of immunohistochemical expression of ezrin in highly malignant soft tissue sarcomas[J].Clin Cancer Res,2005,11(17):6198-204.
[14]Moilanen J,Lassus H,Leminen A,et al.Ezrin immunoreactivity in relation to survival in serous ovarian carainoma patients[J].Gynecol Oncol,2003,90(8):273-81.
[15]Weber GF,Bronson RT,Lagan J,et al.Absence of the CD44geneprevents sarcoma metastasis[J].Cancer Res,2002,62(8):2281-86.
[16]荆雪宁.CD44与肿瘤的免疫逃逸.国外医学肿瘤学分册,2004,31(3):186-189.
[17]Dustin M.A supercede for inflammation[J].Immunity,2004,20:361-62.
[18]谷化平,尚培中,周翠玲.甲状腺肿瘤中CD44v6表达及其意义.中国普通外科杂志,2002,11(5):303-04.
[19]张连斌,孙玉鹗.人肺癌CD44蛋白和基金的异常表达与淋巴结转移的相关性.癌症,2001,20(6):595-98.
[20]周烨,朱慰祺,师英强.CD44s和CD44v6的mRNA在胃癌中的表达及其临床意义.肿瘤,2002,22(6):509-11.
[21]Yoshida R,Kimura N,Harada Y,et al.The loss of E2cadherin,alpha2 and beta2catenin expression is associated with metastasis and poor prognosis in invasive breast cancer[J].Int J Oncol,2001,18(3):513-20.
[22]孙喜文,申宝忠,石美森,等.CD44v6基因表达与胃癌危险因素的关系[J].世界华人消化杂志,2002,10(10):1129-32.
[23]Jun-Qiang Chen,Wen-Hua Zhan,et al.Expression of heparanase gene,CD44v6,MMP-7 and nm23 protein and their relationship with the invasion and metastasis of gastric carcinomas[J].World J Gastroenterol,2004,10(6):776-82.
[24]杨树成,胥传海.CD44v6在胃癌中的表达及临床意义探讨.江苏大学学报(医学版),2005,15(3):232-234.
[25]徐胜军,胡炳奎,凌志强,等.CD44v6在胃癌中的表达及其临床意义.中国普外基础与临床杂志,2006,13(1):42-44.
[26]Montgomery E,Abraham SC.CD44 loss in gastric stromal tumors as a prognostic marker[J].Am J Suyg Pathal,2004,28(2):168-77.
[27]Vizoso FJ,Femandez JC,Corte MD,er al.Expression and clinical significance CD44v5 and CD44v6 in respectable colorectal cancer[J].J Cancer Clin Oncol,2004,130(11):679-84.
[28]Yamamichi K,Uehara Y,Kitamura N,et al.Increased expression of CD44v6mRNA significantly correlates with distant metastasis and poor prognosis in gastric cancer[J].Int J Cancer,1998,79(3):256.
[29]Saito H,Tsujitara S,Katano K,et al.Serum concentration of CD44 variant 6 and its relation to prognosis in patients with gastric carcinoma[J].Cancer,1998,83(6):1094-101.
[2]Tasken K,Aandahl E.MLocalized Effects of cAMP Mediated by Distinct Routes of Protein Kinase A[J].Physiol Rev,2004,84(1):137-67.
[3]Ng T,Parsons M,Hughes W E,et al.Ezrin is a downstream effector of trafficking PKC-integrin complexes involved in the control of cell motility[J].J EMBO,2001,20(11):2723-41.
[4]Stapleton G,Malliri A,Ozanne B W.Downregulated AP-1 activity is associated with inhibition of Protein-Kinase-C-dependent CD44 and ezrin localization and upregulation of PKC theta in A431 cells[J].J Cell Sci,2002,115(pt13):2713-24.
[5]Martin TA,Harrison G,,Mansel RE,et al.The role of the CD44/ezrin complex in cancer metastasis.Crit Rev Oncol Hematol[J],2003,46(2):165-86.
[6]Moclatchey AI.Merlin and ERM proteins:unappreciated roles in cancer development[J].Cancer,2003,3(11):877-84.
[7]荆雪宁.CD44与肿瘤的免疫逃逸[J].国外医学肿瘤学分册,2004,31(3):186-9.
[8]Dustin M.A supercede for inflammation[J].Immunity,2004,20:361-2.
[9]谷化平,尚培中,周翠玲.甲状腺肿瘤中CD44v6表达及其意义[J].中国普通外科杂志,2002,11(5):303-4.
[10]张连斌,孙玉鹗.人肺癌CD44蛋白和基金的异常表达与淋巴结转移的相关性[J].癌症,2001,20(6):595-8.
[11]周烨,朱慰祺,师英强.CD44s和CD44v6的mRNA在胃癌中的表达及其临床意义[J].肿瘤,2002,22(6):509-11.
[12]Mathew J,Hines JE,Obafunwa JO,et al.CD44 is exPressed in heaPtocellular carcinomas showing vascular invasion[J].J Pathol,1996,179(10):74-9.
[13]陈江,张振玉,祝金泉,等.CD44v6蛋白在胃癌中表达及其临床意义[J].临床与实验病理学杂志,1998,14(5):440-1.
[14]Yu Y,Khanna C,et al.Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators[J].NatMed,2004,10(2):175-81.
[15]Khanna C,Wan X,Bose S,et al.The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis[J].NatMed,2004,10(2):182-6.
[16]Moilanen J,Lassus H,Leminen A,et al.Ezrin immunoreactivity in relation to survival in serious ovarian carcinoma patients[J].Gynecol Oncol,2003,90(2):273-81.
[17]Akisawa N,Nishimori I,Iwamura T,et al High levels of ezrin expressed by human pancreatic adenocarcinoma cell lines with high metastatic potential [J].Biochem Biophys Res Commun,1999,258(2):395-400.
[18]管小琴,王朝杰,李圆圆.Ezrin对肝细胞癌分化及粘附作用的影响[J].癌症2002,21(3):281-4.
[19]史荣亮,李建芳,瞿颖,等.肿瘤转移相关基因Ezrin在胃癌中的表达及意义[J].中华肿瘤外科杂志,2006,9(9):433-5.
[20]Pang ST,Fang XL,Valdman A,et al.Expression of ezrin in prostatic intraepithelial neoplasia.Urology,2004,63(3):609-12.
[21]Ohtani K,Sakamoto H,Rutherford T,et al.Ezrin,a membrane-cytoskeletal linking protein,is highly expressed in atypical endometrial hyperplasia and uterine endometrioid adenocarcinoma.Cancer Lett,2002,179(1):79-86.
[22]Weber GF,Bronson RT,Lagan J,et al.Absence of the CD44geneprevents sarcoma metastasis[J].Cancer Res,2002,62(8):2281-6.
[23]Yoshida R,KimuraN,Harada Y,et al.The loss of E2cadherin,alpha2 and beta2catenin expression is associated with metastasis and poor prognosis in invasive breast cancer[J].Int J Oncol,2001,18(3):513-20.
[24]杨树成,胥传海.CD44v6在胃癌中的表达及临床意义探讨.江苏大学学报(医学版),2005,15(3):232-234.
[25]徐胜军,胡炳奎,凌志强,等.CD44v6在胃癌中的表达及其临床意义.中国普外基础与临床杂志,2006,13(1):42-44.
[26]Jun-Qiang Chen,Wen-Hua Zhan,et al.Expression of heparanase gene,CD44v6,MMP-7 and nm23 protein and their relationship with the invasion and metastasis of gastric carcinomas[J].World J Gastroenterol,2004,10(6):776-82.
[27]Montgomery E,Abraham SC.CD44 loss in gastric stromal tumors as a prognostic marker[J].Am J Suyg Pathal,2004,28(2):168-77.
[28]Vizoso FJ,Femandez JC,Corte MD,er al.Expression and clinical significance CD44v5 and CD44v6 in respectable colorectal cancer[J].J Cancer Clin Oncol,2004,130(11):679-84.
[29]Mangeat P,Roy C,Martin M.ERM proteins in cell adhesion and membrane dynamics[J].Trends Cell Biol,1999,9(5):187-92.
[1] Martin TA, Harrison G,, Mansel RE, et al. The role of the CD44/ezrin complex in cancer metastasis. Crit Rev Oncol Hematol[J], 2003, 46(2): 165-86.
[2] Yonemura S, Tsukita S, Tsukita S. Direct involvement of ezrin/radixin/moesin (ERM) -binding membrane proteins in the organization of microvilli in collaboration with activated ERM proteins[J]. J Cell Biol, 1999, 145 (7):1497-509.
[3] Tasken K, Aandahl E. MLocalized Effects of cAMP Mediated by Distinct Routes of Protein Kinase A [J] . Physiol Rev, 2004, 84 (1): 137-67.
[4] Ng T, Parsons M, Hughes W E, et al. Ezrin is a downstream effector of trafficking PKC-integrin complexes involved in the control of cell motility [J]. J EMBO, 2001, 20 (11): 2723-41.
[5] Stapleton G, Malliri A, Ozanne B W. Downregulated AP-1 activity is associated with inhibition of Protein-Kinase-C-dependent CD44 and ezrin localization and upregulation of PKC theta in A431 cells [J]. J Cell Sci, 2002, 115 (pt13):2713-24.
[6] Yu Y, Khanna C, et al. Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators[J]. NatMed, 2004, 10 (2): 175-81.
[7] Khanna C, Wan X, Bose S, et al. The membrane - cytoskeleton linker ezrin is necessary for osteosarcoma metastasis [J]. NatMed, 2004, 10 (2): 182-86.
[8] Pujuguet P, Del Maestro L, Gautreau A, et al. Ezrin regulates E-cadherin dependent adherens junction assembly through Racl activation [J]. Mol Biol Cell, 2003, 14 (5): 2181-91.
[9]管小琴,王朝杰,李圆圆.Ezrin对肝细胞癌分化及粘附作用的影响.癌症2002,2l(3):281-84.
[10]史荣亮,李建芳,瞿颖,等.肿瘤转移相关基因Ezrin在胃癌中的表达及意义.中华肿瘤外科杂志,2006,9(9):433-435.
[11]Akisawa N,Nishimori I,Iwamura T,et al.High levels of ezrin expressed by human pancreatic adenocarcinoma cell lines with high metastatic potential [J].Biochem Biophys Res Commun,1999,258(2):395-400.
[12]Valdman A,Fang X,Pang S T,et al.Ezrin expression in prostatecancer and benign prostatic tissue[J].Eur Urol,2005,48(5):852-57.
[13]Weng W H,Ahlen J,Astrom K,et al.Prognostic impact of immunohistochemical expression of ezrin in highly malignant soft tissue sarcomas[J].Clin Cancer Res,2005,11(17):6198-204.
[14]Moilanen J,Lassus H,Leminen A,et al.Ezrin immunoreactivity in relation to survival in serous ovarian carainoma patients[J].Gynecol Oncol,2003,90(8):273-81.
[15]Weber GF,Bronson RT,Lagan J,et al.Absence of the CD44geneprevents sarcoma metastasis[J].Cancer Res,2002,62(8):2281-86.
[16]荆雪宁.CD44与肿瘤的免疫逃逸.国外医学肿瘤学分册,2004,31(3):186-189.
[17]Dustin M.A supercede for inflammation[J].Immunity,2004,20:361-62.
[18]谷化平,尚培中,周翠玲.甲状腺肿瘤中CD44v6表达及其意义.中国普通外科杂志,2002,11(5):303-04.
[19]张连斌,孙玉鹗.人肺癌CD44蛋白和基金的异常表达与淋巴结转移的相关性.癌症,2001,20(6):595-98.
[20]周烨,朱慰祺,师英强.CD44s和CD44v6的mRNA在胃癌中的表达及其临床意义.肿瘤,2002,22(6):509-11.
[21]Yoshida R,Kimura N,Harada Y,et al.The loss of E2cadherin,alpha2 and beta2catenin expression is associated with metastasis and poor prognosis in invasive breast cancer[J].Int J Oncol,2001,18(3):513-20.
[22]孙喜文,申宝忠,石美森,等.CD44v6基因表达与胃癌危险因素的关系[J].世界华人消化杂志,2002,10(10):1129-32.
[23]Jun-Qiang Chen,Wen-Hua Zhan,et al.Expression of heparanase gene,CD44v6,MMP-7 and nm23 protein and their relationship with the invasion and metastasis of gastric carcinomas[J].World J Gastroenterol,2004,10(6):776-82.
[24]杨树成,胥传海.CD44v6在胃癌中的表达及临床意义探讨.江苏大学学报(医学版),2005,15(3):232-234.
[25]徐胜军,胡炳奎,凌志强,等.CD44v6在胃癌中的表达及其临床意义.中国普外基础与临床杂志,2006,13(1):42-44.
[26]Montgomery E,Abraham SC.CD44 loss in gastric stromal tumors as a prognostic marker[J].Am J Suyg Pathal,2004,28(2):168-77.
[27]Vizoso FJ,Femandez JC,Corte MD,er al.Expression and clinical significance CD44v5 and CD44v6 in respectable colorectal cancer[J].J Cancer Clin Oncol,2004,130(11):679-84.
[28]Yamamichi K,Uehara Y,Kitamura N,et al.Increased expression of CD44v6mRNA significantly correlates with distant metastasis and poor prognosis in gastric cancer[J].Int J Cancer,1998,79(3):256.
[29]Saito H,Tsujitara S,Katano K,et al.Serum concentration of CD44 variant 6 and its relation to prognosis in patients with gastric carcinoma[J].Cancer,1998,83(6):1094-101.
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