moesin在胰腺癌嗜神经性中的分子机制及与疼痛的相关性
|
摘要
研究背景：
近年来，胰腺癌发病率在全国乃至全世界均呈明显的上升趋势。大约40％的胰腺癌患者在诊断时就已经发生转移，而神经浸润转移是其最常见的转移途径和重要特点之一，也是导致胰腺癌病人术后复发率高和预后差的重要原因之一。目前认为神经浸润是引起胰腺癌复发和癌性疼痛的重要原因，是其独立预后指标。近年来，胰腺癌的侵袭与转移，尤其是胰腺癌的神经定向转移问题，日益成为临床与基础研究中的重点和热点。
自从1889年Peget首次提出癌转移的“种子与土壤”学说、1929年Ewing提出肿瘤转移的“机械与解剖”学说，多强调癌细胞自身的侵袭能力、运动能力等生物学特性的改变以及对组织、器官的被动适应。多年来，从亚细胞、细胞及其微环境、细胞与宿主机体的相互关系等诸多方面进行了深入广泛的研究，初步形成现代肿瘤转移理论：基因参与下的转移调控机制。该机制认为，肿瘤是由诸多因素决定的多步骤、序贯性的生物学过程。除强调肿瘤细胞自身因素外，更强调促转移因素与抑转移因素间网络调节的平衡性、宿主微环境的可塑性、宿主整体／局部免疫和肿瘤细胞的主动适应性变化等。
但胰腺癌神经组织浸润的确切分子机制至今尚不明朗。以往研究认为，主要是神经周围间隙中张力较低，易于肿瘤生长，胰腺癌神经浸润是在平面最小阻力处即神经束膜的薄弱部位侵入神经，并在神经周围间隙内连续浸润，到达远处形成新的转移灶。近年来的研究表明，某些表面特性分子和神经组织周围微环境成分在肿瘤的嗜神经性上可能起着重要作用。膜结构伸展刺突蛋白moesin，是ERM蛋白家族的成员之一，表达于许多细胞膜突出部位，如伪足、微绒毛等，对维持细胞骨架及运动都起着重要作用，参与人体生理状态下的许多基本生命活动，是近年来被广泛关注的一类特殊蛋白质。近年发现其广泛表达于多种肿瘤组织中，在肿瘤发生、浸润及转移过程中可能扮演着重要角色，这一观点近年来已在口腔鳞状上皮细胞癌、宫颈癌、头颈恶性肿瘤以及某些消化系统的恶性肿瘤组织中得到了证实。但moesin是否在胰腺癌转移途径中发挥了作用，其作用机制仍不太清楚。为此，本课题选择moesin——这一新近受到关注的指标作为研究切入点，探讨胰腺癌发生神经侵袭转移的原因和机制。
目的：
收集天津医科大学附属肿瘤医院病理科手术切除的胰腺癌组织标本，从免疫组织化学、RT-PCR、实时荧光定量PCR、ELISA等方法检测moesin、β-NGF和MMP-7在人胰腺癌组织中的表达分布，初步探讨moesin、β-NGF和MMP-7在人胰腺癌组织中的作用及其与临床病理学特征之间的关系。并在以上研究的基础上结合患者临床症状，探讨moesin、β-NGF和MMP-7与胰腺癌患者疼痛症状的关系，以及胰腺癌疼痛与其临床病理学改变的相关性，进一步明确其神经性疼痛产生的原因，并探索缓解胰腺癌患者疼痛的方法，提高其生存质量。
方法：
(1)采用免疫组织化学的方法检测胰腺癌组织中moesin、β-NGF和MMP-7各指标的表达、分布特点，并且分析其与临床病理学特征之间的关系。
(2)应用PT-PCR、实时荧光定量PCR、ELISA等分子生物学技术检测该组标本中moesin、β-NGF和MMP-7的蛋白表达，在验证免疫组化结果的同时，分析moesin对癌细胞中β-NGF和MMP-7表达的影响，以探索moesin对胰腺癌细胞侵袭转移作用的分子机制和此过程中moesin可能存在的调控机制。
(3)在上述二部分的基础上，初步探讨moesin、β-NGF和MMP-7与胰腺癌患者疼痛症状的关系，以及胰腺癌疼痛与其临床病理学改变的相关性，进一步明确其神经性疼痛产生的原因，并探索缓解胰腺癌患者疼痛的方法。
(4)采用SPSS15．0统计学软件包进行数据处理，以p＜0．05为有显著性差异。
结果：
(1)moesin、β-NGF、MMP-7均参与胰腺癌的发生发展。44例胰腺癌组织中有24例存在神经浸润(几率为54．55％)。侵入型8例，围神经型16例。moesin的表达在胰腺癌组织中明显高于正常组织，在胰体尾部癌组织中高于胰头癌，在有神经侵犯组明显高于无神经侵犯组，而且靠近神经组织的癌细胞moesin阳性程度高于远离神经组织的癌细胞。此外，随着癌细胞分化程度的降低和临床TNM分期的增加，moesin表达水平增加，moesin表达在有淋巴结转移组比无淋巴结转移组明显增加。β-NGF、MMP-7的表达与胰腺癌临床病理学特征的关系和moesin相似，经过相关性分析显示β-NGF、MMP-7和moesin的表达呈现正相关。
(2)运用RT-PCR、实时荧光定量PCR、ELISA等分子生物学检测方法从RNA转录、蛋白表达、基因表达等三个方面来验证胰腺癌细胞中moesin的表达情况。moesin在胰腺癌组织中高表达，且与β-NGF和MMP-7之间呈现正相关的表达，该结论与第一部分免疫组织化学方法得到的结论一致，从而进一步验证了moesin作为一个新近受到关注的指标与胰腺癌病情进展相关，并参与了胰腺癌的浸润转移机制。
(3)胰腺癌伴有疼痛者比不伴有疼痛者的moesin、3-NGF和MMP-7水平高，而且第一和第二部分结果证明moesin、β-NGF和MMP-7水平与胰腺癌嗜神经性有关，说明胰腺癌患者的疼痛发生和胰腺癌的嗜神经性、胰腺癌细胞的moesin、β-NGF和MMP-7表达水平有关。胰腺癌肿瘤位置、大小、TNM分期以及其对胰内神经、胰腺前方被膜和腹膜后组织的浸润与疼痛有显著相关性，而分化程度、淋巴结转移以及其对胰外神经、远端胆管和十二指肠壁的浸润与疼痛没有显著相关性。
结论：
(1)moesin、β-NGF、MMP-7均参与胰腺癌的发生发展，与胰腺癌嗜神经性成正相关，并且与临床病理学特征尤其与肿瘤发生部位、神经浸润、淋巴结转移、癌细胞低分化和临床分期密切相关，同时与胰腺癌患者的疼痛关系密切。
(2)从胰腺癌大体水平、分子生物学水平和患者临床症状等方面综合探讨了moesin参与胰腺癌嗜神经性生长的机理。
Background:Pancreatic carcinoma(PAC) is common malignant neoplasms ofdigestive system tumors.Perineural invasion is one of the important features forpatients with pancreatic carcinoma,and it thus cause the difficulity in curativeresection,high local recurrence and abdominal pain.Perineural invasion has becomethe research emphasis and focus on pancreatic carcinoma.The“seed and soil”theoryforwarded by Peget in 1889 and“machine and atomy”theory forwarded by Ewing in1929 had almost emphasized tumor cell' s progressiveness and invasion of itself,passive adaptability to tissue microenviroment,tissue and organ' s anatomicalfactors abouts tumor metastasis and ignored the active contributions of organism.Atpresent,through more than 100 year' s research,plentiful and substantial outcomeshave been made in the many levels and fields such as oncogene,biomacromolecule,subcell,cell,mesenchyma microenviroment and so on.On this basis,the modemtumor metastasis theory is formed gradually that tumor metastasis is a multisteps andsequential pathological process and emphasizes the balance between numerousmetastasis and antimetastasis factors,active plasticity and specificity of host targetorgan microenviroment and the whole and/or local immunity of the host.It wasbelieved that the tumor invasion appeared to follow the plane of least resistance of theperineural space,but recent reaearch shows that some molecules on the surface ofcancer cells may have effects on the progression of tumor perineural invasion.It isnecessary,therefore,to investigate the molecular mechanisms in patients withperineural invasion.Actin cytoskeleton reorganization is reportedly regulated byezrir/radixir/moesin(ERM) family.Moesin,one member of ERM family,mainlylocalizes on membrane structures such as microvillus or lamellipodia which are richin actin fibers.The functions of moesin proteins are regulated by its conformationalcharges:the intramolecular interaction between the N-and C-terminal domains of moesin protein charges masks several binding sites,leading to a dormant protein.When stimulated by extracellular signals,moesin protein changes its conformationand is activated as the bridge molecule crosslinking the actin with plasma membraneand initiating the reorganization of actin cytosleleton.In this manner,it regulates theprocess of cell growth and migration.Recently it has been reported that moesinprotein play important roles in several tumor development and metastasis.However,to the best of our knowledge,till now there is no research focused on the relevancebetween moesin protein and pancreatic carcinoma,in particular,the role andmechanism of moesin protein on pancreatic carcinoma metastasis.
Objective:To study the moesin protein's effects on the mechanism of pancreaticcarcinoma perineural invasion from operation tissue specimens.And to explore therelationship between moesin protein and the pain of the patients with pancreaticcarcinoma.Our study may provide in the future the novel therapeutic tools for thetreatment of PAC patients.
Methods:
(1) Expression and distribution of moesin,β-NGF and MMP-7 were detected inopration tissue specimens of pancreatic carcinoma with immunohistochemistry,RT-PCR,Real-time PCR and ELISA.The relations of moesin withβ-NGF andMMP-7 were analyzed.
(2) Exploration the relationship between moesin,β-NGF and MMP-7 and thepain of the patients with pancreatic carcinoma.
(3) All data were processed by SPSS version 15.0 analysis software.
Results:
(1) By immunohistochemistry,the expression of moesin,β-NGF and MMP-7 inthe well-,medium-and poor-differentiated PAC groups lie in the cytoplasm of tumorcell,higher than normal group (p＜0.05).The radio of PNI found was 54.55%.β-NGFand MMP-7 were correlated with perineural invasiveness.
(2) By RT-PCR,real-time PCR and ELISA,we found that moesin,β-NGF andMMP-7 expression of PAC samples were higher than the other.There was great significantly difference between two groups.The result by molecular biologytechnology was correlated with it by immunohistochemistry.
(3) We found that moesin,β-NGF and MMP-7 expression of in patients withpain were higher than those who without pain.Moesin,β-NGF and MMP-7 werecorrelated with perineural invasiveness.
Conclusions:
(1) Expression's change of moesin,β-NGF and MMP-7 may induce the formof PAC.They may play an important role on perineural invasion of human pancreaticcarcinoma.
(2) Moesin,β-NGF and MMP-7 expression have something to do with pain ofPAC patients.
近年来，胰腺癌发病率在全国乃至全世界均呈明显的上升趋势。大约40％的胰腺癌患者在诊断时就已经发生转移，而神经浸润转移是其最常见的转移途径和重要特点之一，也是导致胰腺癌病人术后复发率高和预后差的重要原因之一。目前认为神经浸润是引起胰腺癌复发和癌性疼痛的重要原因，是其独立预后指标。近年来，胰腺癌的侵袭与转移，尤其是胰腺癌的神经定向转移问题，日益成为临床与基础研究中的重点和热点。
自从1889年Peget首次提出癌转移的“种子与土壤”学说、1929年Ewing提出肿瘤转移的“机械与解剖”学说，多强调癌细胞自身的侵袭能力、运动能力等生物学特性的改变以及对组织、器官的被动适应。多年来，从亚细胞、细胞及其微环境、细胞与宿主机体的相互关系等诸多方面进行了深入广泛的研究，初步形成现代肿瘤转移理论：基因参与下的转移调控机制。该机制认为，肿瘤是由诸多因素决定的多步骤、序贯性的生物学过程。除强调肿瘤细胞自身因素外，更强调促转移因素与抑转移因素间网络调节的平衡性、宿主微环境的可塑性、宿主整体／局部免疫和肿瘤细胞的主动适应性变化等。
但胰腺癌神经组织浸润的确切分子机制至今尚不明朗。以往研究认为，主要是神经周围间隙中张力较低，易于肿瘤生长，胰腺癌神经浸润是在平面最小阻力处即神经束膜的薄弱部位侵入神经，并在神经周围间隙内连续浸润，到达远处形成新的转移灶。近年来的研究表明，某些表面特性分子和神经组织周围微环境成分在肿瘤的嗜神经性上可能起着重要作用。膜结构伸展刺突蛋白moesin，是ERM蛋白家族的成员之一，表达于许多细胞膜突出部位，如伪足、微绒毛等，对维持细胞骨架及运动都起着重要作用，参与人体生理状态下的许多基本生命活动，是近年来被广泛关注的一类特殊蛋白质。近年发现其广泛表达于多种肿瘤组织中，在肿瘤发生、浸润及转移过程中可能扮演着重要角色，这一观点近年来已在口腔鳞状上皮细胞癌、宫颈癌、头颈恶性肿瘤以及某些消化系统的恶性肿瘤组织中得到了证实。但moesin是否在胰腺癌转移途径中发挥了作用，其作用机制仍不太清楚。为此，本课题选择moesin——这一新近受到关注的指标作为研究切入点，探讨胰腺癌发生神经侵袭转移的原因和机制。
目的：
收集天津医科大学附属肿瘤医院病理科手术切除的胰腺癌组织标本，从免疫组织化学、RT-PCR、实时荧光定量PCR、ELISA等方法检测moesin、β-NGF和MMP-7在人胰腺癌组织中的表达分布，初步探讨moesin、β-NGF和MMP-7在人胰腺癌组织中的作用及其与临床病理学特征之间的关系。并在以上研究的基础上结合患者临床症状，探讨moesin、β-NGF和MMP-7与胰腺癌患者疼痛症状的关系，以及胰腺癌疼痛与其临床病理学改变的相关性，进一步明确其神经性疼痛产生的原因，并探索缓解胰腺癌患者疼痛的方法，提高其生存质量。
方法：
(1)采用免疫组织化学的方法检测胰腺癌组织中moesin、β-NGF和MMP-7各指标的表达、分布特点，并且分析其与临床病理学特征之间的关系。
(2)应用PT-PCR、实时荧光定量PCR、ELISA等分子生物学技术检测该组标本中moesin、β-NGF和MMP-7的蛋白表达，在验证免疫组化结果的同时，分析moesin对癌细胞中β-NGF和MMP-7表达的影响，以探索moesin对胰腺癌细胞侵袭转移作用的分子机制和此过程中moesin可能存在的调控机制。
(3)在上述二部分的基础上，初步探讨moesin、β-NGF和MMP-7与胰腺癌患者疼痛症状的关系，以及胰腺癌疼痛与其临床病理学改变的相关性，进一步明确其神经性疼痛产生的原因，并探索缓解胰腺癌患者疼痛的方法。
(4)采用SPSS15．0统计学软件包进行数据处理，以p＜0．05为有显著性差异。
结果：
(1)moesin、β-NGF、MMP-7均参与胰腺癌的发生发展。44例胰腺癌组织中有24例存在神经浸润(几率为54．55％)。侵入型8例，围神经型16例。moesin的表达在胰腺癌组织中明显高于正常组织，在胰体尾部癌组织中高于胰头癌，在有神经侵犯组明显高于无神经侵犯组，而且靠近神经组织的癌细胞moesin阳性程度高于远离神经组织的癌细胞。此外，随着癌细胞分化程度的降低和临床TNM分期的增加，moesin表达水平增加，moesin表达在有淋巴结转移组比无淋巴结转移组明显增加。β-NGF、MMP-7的表达与胰腺癌临床病理学特征的关系和moesin相似，经过相关性分析显示β-NGF、MMP-7和moesin的表达呈现正相关。
(2)运用RT-PCR、实时荧光定量PCR、ELISA等分子生物学检测方法从RNA转录、蛋白表达、基因表达等三个方面来验证胰腺癌细胞中moesin的表达情况。moesin在胰腺癌组织中高表达，且与β-NGF和MMP-7之间呈现正相关的表达，该结论与第一部分免疫组织化学方法得到的结论一致，从而进一步验证了moesin作为一个新近受到关注的指标与胰腺癌病情进展相关，并参与了胰腺癌的浸润转移机制。
(3)胰腺癌伴有疼痛者比不伴有疼痛者的moesin、3-NGF和MMP-7水平高，而且第一和第二部分结果证明moesin、β-NGF和MMP-7水平与胰腺癌嗜神经性有关，说明胰腺癌患者的疼痛发生和胰腺癌的嗜神经性、胰腺癌细胞的moesin、β-NGF和MMP-7表达水平有关。胰腺癌肿瘤位置、大小、TNM分期以及其对胰内神经、胰腺前方被膜和腹膜后组织的浸润与疼痛有显著相关性，而分化程度、淋巴结转移以及其对胰外神经、远端胆管和十二指肠壁的浸润与疼痛没有显著相关性。
结论：
(1)moesin、β-NGF、MMP-7均参与胰腺癌的发生发展，与胰腺癌嗜神经性成正相关，并且与临床病理学特征尤其与肿瘤发生部位、神经浸润、淋巴结转移、癌细胞低分化和临床分期密切相关，同时与胰腺癌患者的疼痛关系密切。
(2)从胰腺癌大体水平、分子生物学水平和患者临床症状等方面综合探讨了moesin参与胰腺癌嗜神经性生长的机理。
Background:Pancreatic carcinoma(PAC) is common malignant neoplasms ofdigestive system tumors.Perineural invasion is one of the important features forpatients with pancreatic carcinoma,and it thus cause the difficulity in curativeresection,high local recurrence and abdominal pain.Perineural invasion has becomethe research emphasis and focus on pancreatic carcinoma.The“seed and soil”theoryforwarded by Peget in 1889 and“machine and atomy”theory forwarded by Ewing in1929 had almost emphasized tumor cell' s progressiveness and invasion of itself,passive adaptability to tissue microenviroment,tissue and organ' s anatomicalfactors abouts tumor metastasis and ignored the active contributions of organism.Atpresent,through more than 100 year' s research,plentiful and substantial outcomeshave been made in the many levels and fields such as oncogene,biomacromolecule,subcell,cell,mesenchyma microenviroment and so on.On this basis,the modemtumor metastasis theory is formed gradually that tumor metastasis is a multisteps andsequential pathological process and emphasizes the balance between numerousmetastasis and antimetastasis factors,active plasticity and specificity of host targetorgan microenviroment and the whole and/or local immunity of the host.It wasbelieved that the tumor invasion appeared to follow the plane of least resistance of theperineural space,but recent reaearch shows that some molecules on the surface ofcancer cells may have effects on the progression of tumor perineural invasion.It isnecessary,therefore,to investigate the molecular mechanisms in patients withperineural invasion.Actin cytoskeleton reorganization is reportedly regulated byezrir/radixir/moesin(ERM) family.Moesin,one member of ERM family,mainlylocalizes on membrane structures such as microvillus or lamellipodia which are richin actin fibers.The functions of moesin proteins are regulated by its conformationalcharges:the intramolecular interaction between the N-and C-terminal domains of moesin protein charges masks several binding sites,leading to a dormant protein.When stimulated by extracellular signals,moesin protein changes its conformationand is activated as the bridge molecule crosslinking the actin with plasma membraneand initiating the reorganization of actin cytosleleton.In this manner,it regulates theprocess of cell growth and migration.Recently it has been reported that moesinprotein play important roles in several tumor development and metastasis.However,to the best of our knowledge,till now there is no research focused on the relevancebetween moesin protein and pancreatic carcinoma,in particular,the role andmechanism of moesin protein on pancreatic carcinoma metastasis.
Objective:To study the moesin protein's effects on the mechanism of pancreaticcarcinoma perineural invasion from operation tissue specimens.And to explore therelationship between moesin protein and the pain of the patients with pancreaticcarcinoma.Our study may provide in the future the novel therapeutic tools for thetreatment of PAC patients.
Methods:
(1) Expression and distribution of moesin,β-NGF and MMP-7 were detected inopration tissue specimens of pancreatic carcinoma with immunohistochemistry,RT-PCR,Real-time PCR and ELISA.The relations of moesin withβ-NGF andMMP-7 were analyzed.
(2) Exploration the relationship between moesin,β-NGF and MMP-7 and thepain of the patients with pancreatic carcinoma.
(3) All data were processed by SPSS version 15.0 analysis software.
Results:
(1) By immunohistochemistry,the expression of moesin,β-NGF and MMP-7 inthe well-,medium-and poor-differentiated PAC groups lie in the cytoplasm of tumorcell,higher than normal group (p＜0.05).The radio of PNI found was 54.55%.β-NGFand MMP-7 were correlated with perineural invasiveness.
(2) By RT-PCR,real-time PCR and ELISA,we found that moesin,β-NGF andMMP-7 expression of PAC samples were higher than the other.There was great significantly difference between two groups.The result by molecular biologytechnology was correlated with it by immunohistochemistry.
(3) We found that moesin,β-NGF and MMP-7 expression of in patients withpain were higher than those who without pain.Moesin,β-NGF and MMP-7 werecorrelated with perineural invasiveness.
Conclusions:
(1) Expression's change of moesin,β-NGF and MMP-7 may induce the formof PAC.They may play an important role on perineural invasion of human pancreaticcarcinoma.
(2) Moesin,β-NGF and MMP-7 expression have something to do with pain ofPAC patients.
引文
[1]Takahashi T,Ishikura H,Motohara T.Perineural invasion by ductal Adenocarcinoma of the pancreas[J].J Surg Oncol,1997,65(3):164-70.
[2]Kameda K,Shimada H,Ishikawa T,et al.Expression of highly polysialylated neural cell adhesion molecule in pancreatic cancer neural invasive lesion[J].Cancer Lett.1999,137(2):201-7.
[3]王启俊，祝伟星，邢秀梅，等．北京城区居民1982年-1997年癌症发病趋势[J]．中国肿瘤，2001，10(9)：507-509．
[4]胡家露．努力提高胰腺癌的早期诊断水平[J]．中华内科杂志，1999,38(2)：77-8．
[5]陆星华．胰腺癌研究现状与展望[J]．胰腺病学，2003，3：63-65．
[6]张群华，倪泉兴，张延龄．应加大胰腺癌诊治研究的力度[J]．中华医学杂志，2002，82：361-362．
[7]Hirai I,Kinura W,Ozawa K,et al.Perineural invasion in Pancreas[M].2002,24(1):15-25.
[8]于勇．小鼠肿瘤模型及其在胰腺癌治疗研究中的应用[J]．肿瘤研究与临床，2003，15(2)：139-143．
[9]Lindsay TH,Jonas BM,Sevcik MA,et al.Pancreatic cancer pain and its correlation with changes in tumor vasculature,macrophage infiltration,neuronal innervation,body weight and disease progression[J].Pain.2005 Decl5,119 (1-3).233-246.
[10]Tsukita S,Yonemura S.Cortical actin organization:lessons from ERM (ezrin/radixin/moesin) proteins[J].J Biol Chem 1999,274:34507-34510.
[11]Sophie LV.ERM proteins:From cellular architecture to cell signaling[J].Biology of the Cell 2000,92:305-316.
[12]唐平章．运用蛋白质组学的方法对甲状腺癌和正常甲状腺组织不同蛋白表达
[22]杨青峰，范明．神经营养因子的作用模式[J]．第三军医大学学报，2000，22(4)：400-402．
[23]Campos X,Munoz Y,Selman A,et al.Nerve growth factor and its high-affinity receptor trkA participate in the control of vascular endothelial growth factor expression in epithelial ovarian cancer[J].Gynecol Oncol.2007 Jan,104(1):168-175.
[24]Papatsoris AG,Liolitsa D,Deliveliotis C.Manipulation of the nerve growth factor network in prostate cancer[J].Expert Opin Investig Drugs.2007 Mar,16(3):303-309.
[25]花柱明，李真，罗东兰，等．神经生长因子在胰腺癌中的表达与癌细胞嗜神经侵袭和疼痛的关系[J]．南方医科大学学报，2006，26(8)：1251-1253．
[26]Chambers A F,Matrisian L M,et al.Changing views of the role of matix metalloproteinases in metastasis[J].J Natl Cancer Inst,1997,89:1260-1270.
[27]Papetti M,Herman I M.Mechanisms of normal and tumor-derived angiogenesis[J].Am J Physiol Cell Physiol,2002,282:947-970.
[28]Ray J M,Stetler-Stevenson W G.The role of matrix metalloproteases and their inhibitors in tumour invasion,metastasis and angiogensis[J].Eur Respir J,1994,7:2062-2072.
[29]Liotta LA,Steeg PS,Stetlei Stevenson WG.Cancer metastasis and angiogenesis:an imbalance of positive and negative regulation[J].Cell,1991,64:327.
[30]Bodey B,Bodey JB,Siegel SE,et al.Prognostic significance of matrix metalloproteinase expression in colorectal carcinomas[J].In Vivo,2000,14:659-666.
[31]Yamamoto H,Adachi Y,ItohF,et al.Association of matrilysinex pression with recurrence and poor prognosis in human esophagealsqua mous cell carcinoma[J].Cancer Res.1999,59:3313～3316.
[32]Jemal A,Thomas A,Murray T,et al.Cancer Statistics,2002[J].CA Cancer J Clin,2002,52(1):23-47.
[33]Hirai I,Kimura W,Ozawa K,et al.Perineural invasion in pancreatic cancer[J].Pancreas,2002,24:15-25.
[34]Nagakawa T,Kayahara M,Ueno K,et al.A clinicopathologic study on neural invasion in cancer of the pancreatic head[J].Cancer,1992,69:930-935.
[35]Hirai I,Kimura W,Ozawa K,et al.Perineural invasion in pancreatic cancer[J].Pancreas,2002,24(1):15-25.
[36]张华，林元问，顾乃群．“胰头丛”的应用解剖学研究[J]．临床应用解剖学杂志，1985，3(3)：140-143．
[37]徐恩多，何伪为，于频．外科解剖学(第一版)[M]．辽宁：辽宁教育出版社，1992，629-630．
[38]何平，石景森，陈武科．应用Cox模型分析影响胆管癌切除术后的预后因素[J]．中华肝胆外科杂志，2002，8(4)：219-221．
[39]党诚学．胰腺癌神经浸润的特点及临床意义[J]．普外基础与临床杂志，1997，4(4)：249-250．
[40]Zeelenberg IS,Ruuls-Van Stalle L,Roos E.The chemokine receptor CSCR4 is required for outgrowth of colon carcinoma micrometastases[J].Cancer Res,2003 Jul 1,63(13):3833-3839.
[41]程扬，何勉，李雯，等．血管内皮细胞因子C及膜突蛋白表达与宫颈癌恶性进展的相关性[J]．中山大学学报(医学科学版)，2008，29(2)：173-176．
[42]Macan R,Brandwein-Gensler M,Schlecht NF,et al.Differential tissue and subcellular expression of ERM proteins in normal and malignant tissues:cytoplasmic ezrin expression has prognostic significance for head and neck squamous cell carcinoma[J].Head Neck,2006,28(11):1018-1027.
[43]Kobayashi H,Sagara J,Kurita H,et al.Clinical significance of cellular distribution of moesin in patients with oral squamous cell carcinoma[J].Clin Cancer Res,2004,10:572-580.
[44]李婷婷，徐秀玉，王鑫．膜组织结构伸展刺突蛋白在喉癌中的表达[J]．中国耳鼻咽喉头颈外科，2007，14：37-40．
[45]Poppe D,Tiede I,Fritz G,et al.Azathioprine suppresses ezrin-radixin-moesin-dependent T cell-APC conjugation through inhibition of Vav guanosine exchange activity on Rac proteins[J].J Immunol,2006,176:640-651.
[46]Sala-Valdes M,Uras A,Charrin S,et al.EWI-2 and EWI-F link the tetraspanin web to the actin cytoskeleton through their direct association with ezrin-radixin-moesin proteins[J].J Biol Chem,2006,281:19665-19675.
[47]Speck O,Hughes SC,Noren NK,et al.Moesin functions antagonistically to the Rho pathway to maintain epithelial integrity[J].Nature,2003,421 (6918):83-87.
[48]陶晓峰，王齐敏，金晓明．肝细胞癌中Ezrin、Moesin表达的临床病理学意义[J]．临床与实验病理学杂志，2007 Feb，23(1)：30-32．
[49]Dolle L,EI Yazidi-Belkoura I,Adriaenssens E,et al.Nerve growth factor overexpression and autocrine loop in breast cancer[J].Oncogene,2003,22(36):5592-5601.
[50]Adriaenssens E,Vanhecke E,Saule P,et al.Nerve growth factor is a potential therapeutic target in breast cancer[J].Cancer Res.2008 Jan 15,68(2):346-351.
[51]Festuccia C,Muzi P,Gravina GL,et al.Tyrosine kinase inhibitor CEP-701 blocks the NTRK1/NGF receptor and limits the invasive capability of prostate cancer cells in vitro[J].Int J Oncol.2007 Jan,30(1):193-200.
[52]Tsunoda S,Okumura T,et al.Significance of nerve growth factor overexpression and its autocrine loop in oesophageal squamous cell carcinoma[J].Br J Cancer.2006 Aug 7,95 (3):322-330.
[53]Tee BK,Park KM,Surendran S,et al.KAII / CD82 suppresses tumor invasion by MMP—9 inactivation via TIMP1 up regulation in the H1299 human lung carcinoma cell line[J].Biochemi Biophys Res Commun,2006,342(2):655-661.
[54]Chambers A F,Matrisian L M,et al.Changing views of the role of matix metalloproteinases in memsmsis[J].J Natl Cancer Inst,1997,89:1260-1270.
[55]Kayahara M,Nagakawa T,Konishi I,et al.Clinicopathological study of pancreatic carcinoma with paticular referenee to the invasion of the extrapancreatic neural plexus[J].IntJPancreatol,1991,10(2):105-111.
[56]Okusaka T,Okada S,Ueno H,et al.Abdominal pain in patients with respectable pancreatic cancer with reference to clinicopathologic findings[J].Pancreas,2001,22(3):279.
[57]Exocrine pancreas.AJCC Cancer Staging Manual,6th edition[M].New York:Springer,2002,157-163.
[58]倪晓光，赵平，白晓枫．胰腺癌疼痛与其临床病理学关系的探讨[J]．实用癌症杂志，2003，18(4)：414-416．
[59]孙燕，顾慰萍，主编．癌症三阶梯止痛指导原则(第2版)[M]．北京：北京医科大学出版社，2002，21-23．
[60]Yamamoto M,Ohashi O,Saitoh Y.Japan pancreatic cancer registry:current status[J].Pancreas,1998,16(3):238.
[61]Krech RL,Walsh D.Symptoms of pancreatic cancer[J].J Pain Symptom Manage,1991,6(6):360.
[62]van Geenen RC,Keyzer-Dekker CM,van Tienhoven G,et al.Pain management of patients with unresectable peripancreatic carcinoma[J].Worle J Surg,2002,26:715-720.
[63]朱明华，胡先贵，郑建，等．249例外分泌源性胰腺癌临床病理和免疫组化研究[J]．胰腺病学，2003，3(4)：193-197．
[64]Grahm AL,Andren-Sandberg A.Prospective evaluation of pain in exocrine pancreatic cancer[J].Digestion,1997,58(6):542.
[65]Ridder G J,Klempnauer J.Back pain in patients with ductal pancreatic cancer.Its impact on respectability and prognosis after reaection[J].Scand J Gastroenterol,1995,30(12):1216.
[66]Kelsen DP,Portenoy R,Thaler H,et al.Pain as a predictor of outcome in patients with operable pancreatic carcinoma[J].Surgery,1997,122(1):53.
[67]倪晓光，赵平，白晓枫．胰腺癌疼痛与其临床病理学关系的探讨[J]．实用癌症杂志，2003，18(4)：414-416．
[68]严相默．神经阻滞及药物治疗疼痛性疾病的进展[J]．中国疼痛医学杂志，2003，9(4)：225-229．
[69]王晓，孙靖中，毕冬松．高能聚焦超声缓解晚期胰腺癌疼痛的疗效分析[J]．癌症，2002，21(5)：554．
[70]el Kamar FG,Grossbard ML,Kozuch PS,et al.Metastatic pancreatic cancer:emerging strategies in chemotherapy and palliative care[J].Oncologist,2003,8(1):18-34.
[71]Morganti AG,Trodella L,Valentini V,et al.Pain relief with short-term irradiation in locally advanced carcinoma of the pancreas[J].J Palliat Care,2003,19(4):258-262.
[72]石玉生，徐素俊，郑小康，等．局部晚期胰腺癌三维适形放射治疗疗效观察[J]．第一军医大学学报，2004，24(2)：213-215，219．
[73]el Kamar FG,Grossbard ML,Kozuch PS,et al.Metastatic pancreatic cancer:emerging strategies in chemotherapy and palliative care[J].Oncologist,2003,8(1):18-34.
[74]Ueno H,Okusaka T,Ikeda M,et al.Phase Ⅰ study of hyperfractionated radiation therapy with protracted 5-fluorouracil infusion in patients with locally advanced pancreatic cancer[J].Oncology,2004,67(3-4):215-221.
[1] Tsukita S, Yonemura S. Cortical actin organization: lessons from ERM (ezrin/radixin/moesin) proteins[J]. J Biol Chem,1999, 274: 34507-34510.
[2] Sophie LV. ERM proteins: From cellular architecture to cell signaling[J]. Biology of the Cell,2000,92: 305-316.
[3] Chishti AH, Kim AC, Marfatia SM, et al. The FERM domain: a unique module involved in the linkage of cytoplasmic proteins to the membrane[J]. Trends Biochem Sci,1998,23: 281-282.
[4] Ivetic A, Ridley AJ. Ezrin/radixin/moesin proteins and Rho GTPase signaling in leucocytes [J]. Immunology,2004,112:165-176.
[5] Pestonjamasp K, Amieva MR, Strassel CP, et al. Moesin, ezrin, and p205 are actin-binding proteins associated with neutrophil plasma membranes [J].Mol.Biol.Cell, 1995,6: 247-259.
[6] Bretscher A, Gary R, Berryman M. Soluble ezrin purified from placenta exists as stable monomers and elongated dimmers with masked C-terminal ezrin-radixin-moesin association domains[J]. Biochemistry, 1995, 34:16830-16837.
[7] Gautreau A, Louvard D, Arpin M. Morphogenic effects of ezrin require a phosphorylation-induced transition from oligomers to monomers at the plasma membrane[J]. J Cell Biol,2000,l50:193-203.
[8] Barret C, Roy C, Montcourrier P, et al. Mutagenesis of the phosphatidylinositol 4,5-bisphosphate PIP(2) binding site in the NH(2)-terminal domain of ezrin correlates with its altered cellular distribution[J]. J Cell Biol,2000,151:1067-1080.
[9] Niggli V, Andreoli C, Roy C, et al. Identification of a phosphatidylinositol-4,5-bisphosphate-binding domain in the N-terminal region of ezrin[J]. FEBS Lett, 1995,376:172-176.
[10] Bonilha VL, Finnemann SC, Rodriguez-Boulan E.Ezrin promotes morphogenesis of apical microvilli and basal infoldings in retinal pigment epithelium[J]. Cell Biol,1999,147,1533-1548.
[11] Speck .O, et al.Moesin functions antagonistically to the Rho pathway to maintain epithelial integrity[J]. Nature,2003,421:83-87.
[12] Paglini G, Kunda P, Quiroga S, et al. Suppression of radixin and moesin alters growth cone morphology,motility,and process formation in primary cultured neurons[J].J Cell Biot,1998,143:443-455.
[13] Yokoyama T, Goto H, Izawa I, et al. Aurora-B and Rho-Kinase/ROCK, the two cleavage furrow kinases, independently regulate the progression of cytokinesis :possible existence of a novel cleavage furrow kinase phosphorylates ezrin/radixin/moesin (ERM) [J]. Genes Cell,2005,10(2):127-137.
[14] Kishore R, Qin G, Luedemann C, et al. The cytoskeletal protein ezrin regulates EC proliferation and angiogenesis via TNF-alpha-induced transcriptional repression of cyclin[J].J Clin Invest.2005,115(7):1785-1796.
[15] Ng T, Parsons M, Hughes W, et al.Ezrin is a downstream effector of trafficking PKC/integrin complexes involved in the control of cell motility[J]. EMBO J 2001,20:2723-2741.
[16] Eugene E, Hoffmann I, Pujol C, et al. Microvilli-like structures are associated with the internalization of virulent capsulated Neisseria meningitides into vascular endothelial celIs[J]. J Cell Sci.2002,115:1231-1241.
[17] Guoquan L, Voyno-Yasenetskaya TA. Radixin stimulates Racl and Ca2+/calmodulin dependent kinase, CaMKⅡ :Crosstalk with G α/ 13[J].J BiolChem,2005 Sep 26, (Epub ahead of print) .
[18] Hecker C, Weise J, Schneider-Schaulies HC, et al. Specific binding of HIV-1 envelope protein gp120 to the structural membrane proteins ezrin and moesin[J]. Virus Res, 1997, 49:215-223.
[19] Tohme ZN, Amar S, Dyke TV, et al. Moesin functions as a lipopolysaccharide receptor on human monocytes[J]. Infect Immun,1999,67(7):3 215-3 220.
[20] Sebo TJ, Cheville JC, Riehle DL, et al. Perineural invasion and MIB-1 positivity in addition to Gleason score are significant preoperative predictors of progression after radical retropubic prostatectomy for prostate cancer[J].Am J Surg Pathol, 2002,26(4): 431-439.
[21] Regis De Brito Santos I, Kowalski LP, Araujo VC, et al. Multivariate analysis of risk factors for neck metastases in surgically treated parotid carcinomas[J].Arch Otolaryngeol Head Neck Surg, 2001,127(1):56-60.
[22] Duraker N, Sisman S, Can G. The significance of perineural invasion as a prognostic factor in patients with gastric carcinoma[J]. Surg Today,2003,33:95-100.
[23] Ayala GE, Dai H, Li R, et al. Bystin in perineural invasion of prostate cancer[J]. Prostate, 2006,66:266-272.
[24] Hassanein AM, Proper SA, Depeik-Smith ND, et al. Peritumoral fibrosis in basal cell and squamous cell carcinoma mimicking perineural invasion: Potential pitfall in mohs micrographic surgery [J]. Dermatol Surg,2005,31:1101-1106.
[25] Chen-Tsai CP, Colome-Grimmer M, Wagner RF Jr. Correlations among neural cell adhesion molecule, nerve growth factor, and its receptors, TrkA, TrkB,TrkC, and p75, in perineural invasion by basal cell and cutaneous squamous cell carcinomas[J]. Dermatol Surg, 2004,30:1009-1016.
[26] Kameda K, Shimada H, Ishikawa T, et al. Expression of highly polysialylated neural cell adhesion molecule in pancreatic cancer neural invasive lesion[J].Cancer Lett, 1999,137:201-207.
[27] Murakawa K, Tada M, Takada M, et al. Prediction of lymph node metastasis and perineural invasion of biliary tract cancer by selected features from cDNA array data[J].J Surg Res, 2004,122:184-194.
[28] Lee MA, Park GS, Lee HJ, et al. Survivin expression and its clinical significance in pancreatic cancer[J]. BMC Cancer, 2005,5:127.
[29] Kham OA, Alexiou C, Soomro I, et al. Pathological determinants of survival in node-negative oesophageal cancerl[J]. Br J Surg, 2004,91:1586-1591.
[30] Giuliani A, Caporale A, Di Bari M, et al. Maximum gastric cancer diameter as a prognostic indicator: Univariate and multi-variate analysis[J]. J Exp Clin Cancer Res,2003,22:531-538.
[31] Miknyoczki SJ, Klein Szanto AJ, Ruggeri BA. Neutotrophin-Trk receptor interactions in neoplasia: a possible role in interstitial and perineural invasion in ductal pancreatic cancer[J]. Crit-Rev-Oncog, 1996,7(1-2): 89-100.
[32] Yang G, Wheeler TM, Kattan MW, et al. Perineural invasion of prostate carcinoma cells is associated with reduced apoptotic index[J]. Cancer,1996,78(6): 1267-1271.
[33] Geldof AA, De Kleijn MA, Rao BR, et al. Nerve growth factor stimulates in vitro invasive capacity of DU145 human prostatic cancer cells [J]. J Cancer Res Clin Oncol, 1997,123(2): 107-112.
[34] Walch ET, Marchetti D. Role of neurotrophins and neurotrophins receptors in the vitro invasion and heparanase production of human prostate cancer cells[J].Clin Exp Metastasis, 1999,17(4): 307-314.
[35] Weeranatna AT, Dalrymple SL, Lamb JC, et al. Pan-trk inhibition decreases metatasis and enhances host survival in experimental models as a result of its selective induction of apoptosis of prostate cancer cells[J]. Clin Cancer Res,2001,7(8): 2237-2245.
[36] Sakamoto Y, Kitajima Y, Edakuni G, et al. Expression of Trk tyrosine kinase receptor is a biologic mkarker for cell proliferation and perineural invasion of human pancreatic ductal adenocarcinoma[J]. Oncol-Rep, 2001,8(3): 477-484.
[37] Marchetti D, Nicolson GL. Human melanoma cell invasion: selected neurotrophin enhancement of invasion and heparanase activity[J]. J Investig Dermatol Symp Proc, 1997,2(1):99-105.
[38] Missale C, Codignol A, Sigala S, et al. Nerve growth factor abrogates the tumorigenicity of human small cell lung cancer cell lines[J]. Proc Natl Acad Sci U S A, 1998,95(9): 5366-5371.
[39] Giese A, Kluwe L, Laube B, et al. Migration of human glioma cells on myelin[J]. Neurosurgery, 1996,38(4): 755-764.
[40] Hensel T, Amberger VR, Schwab ME. A metalloprotease activity from C6 glioma cells inactivates the myelin-associated neurite growth inhibitors and can be neutralized by antibodies[J]. Br-J-Cancer, 1998,78(12): 1564-1572.
[41] Hensel T, Amberger VR, Schwab ME. A metalloprotease activity from C6 glioma cells inactivates the myelin-associated neurite growth inhibitors and can be neutralized by antibodies[J]. Br-J-Cancer, 1998,78(12): 1564-1572.
[42] Nagakawa O, Murakami K, Yamaura T, et al. Expressio of membrane-type 1 matrix metalloproteinase (MT1-MMP) on prostate cancer cell lines[J].Cancer-Lett, 2000,155(2):173-179.
[43] Hotary K, Allen E, Punturieri A, et al. Regulation of cell invasion and morphogenesis in a three-dimensional type 1 collagen matrix by membrane-type matrix metalloproteinases 1,2 and 3[J]. J Cell Biol,2000,149(6): 1309-1323.
[44] Fillmore HL, Van Meter TE, Broaddus WC. Membrane-type matrix metalloproteinases (MT-MMPs): expression and function during glioma invasion[J]. J Neurooncol, 2001,53(2): 187-202.
[45] Franca CM, Jaeger MM, Jaeger RG, et al. The role of basement membrane proteins on the expression of neural cell adhesion molecule (N-CAM) in an adenoid cystic carcinoma cell line[J].Oral Oncol, 2000,36(2):248-252.
[46] Gandour ER, Kapadia SB, Barnes L, et al. Nueral cell adhesion molecule in adenoid cystic carcinoma invading the skull base[J]. Otolaryngol Head Neck Surg, 1997,117(5): 453-458.
[47] Hutcheson JA, Vural E, Korourian S, et al. Neural cell adhesion molecule expression in adenoid cystic carcinoma of the head and neck[J]. Laryngoscope,2000,110(6):946-948.
[48] Kameda K, Shimada H, Lesionlshikawa T, et al. Expression of highly polysialylated neural cell adhesion molecule in pancreatic cancer neural invasive[J]. Cancer-Lett, 1999,137(2):201-207.
[49] Franca CM, Jaeger RG, Freitas VM, et al. Effect of N-CAM on in vitro invasion of human adenoid cystic carcinoma cells[J]. Oral Oncol, 2001,37(8):638-642.
[50] Cavallaro U, Niedermayer J, Fuxa M, et al. N-CAM modulates tumor-cell adhesion to matrix by inducing FGF-receptor signaling[J]. Nat Cell Biol,2001,3(7):650-657.
[51] Giese A, Kluwe L, Laube B, et al. Migration of human glioma cells on myelin[J]. Neurosurgery, 1996,38(4): 755-764.
[52] Mathew J, Hines J E, Obafunwa J O, et al. CD44 is expressed in hepatocellular carcinomas showing vascular invasion[J].J Pathol, 1996,179(1): 74-79.
[53] Yu Y, Khan J, Khanna C, et al. Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators[J].Nat Med,2004,10(2):175-181.
[54]Carmeci C,Thompson D A,Kuang W W,et al.Moesin expression is associated with the estrogen receptor-negative breast cancer phenotype[J].Surgery,1998,124(2):211-217.
[55]陶晓峰，王齐敏，金晓明．肝细胞癌中Ezrin、Moesin表达的临床病理学意义[J]．临床与实验病理学杂志，2007 Feb，23(1)：30-32．
[56]唐平章．运用蛋白质组学的方法对甲状腺癌和正常甲状腺组织不同蛋白表达的分析[D]．北京：中国协和医科大学,2007．
[57]Robbins J,Memo MJ,Boice JD,Jr.,et al.Thyroid cancer:a lethal endocrine neoplasm[J].Ann Intern Med 1991,115(2):133-147.
[58]Jernal A TA,Murray T Surveillance,Epidemiology,and End Results (SEER) Incidence and U.S.Mortality Statistics[J].CA Cancer J Clin 2002,52:23-47.
[59]钱碧云，何敏，董淑芬．1981年至2001年天津市甲状腺癌的发病率和死亡率[J]．中华内分泌代谢杂志，2005,21：432-434．
[60]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 protein[J].J Cell Boil,1999,145:1497-1509.
[61]Carmeci C,Thompson DA,Kuang WW,Lightdale N,Furthmayr H,Weigel RJ.Moesin expression is associated with the estrogen receptor-negative breast cancer phenotype[J].Surgery 1998,124(2):211-217.
[62]Kobayashi H,Sagara J,Kurita H,et al.Clinical significance of cellular distribution of moesin in patients with oral squamous cell carcinoma[J].Clin Cancer Res,2004,10:572-580.
[63]李婷婷，徐秀玉，王鑫．膜组织结构伸展刺突蛋白在喉癌中的表达[J]．中国耳鼻咽喉头颈外科，2007，14：37-40．
[64] Sato N, Funayama N, NagafuchiA, et al. A gene family consisting of ezrin,radixin and moesin. Its specific localization at actin filament/plasma membrane association sites[J]. J Cell Sci, 1992,103:131-143.
[65] Yonemura S, Hirao M, Doi Y, et al. Ezrin/radixin/moesin (ERM) protein bind to a positively charged amino acid cluster in the juxta-membrane cytoplasmic domain of CD44, CD43, and ICAM-2[J]. J Cell Biol, 1998,140:885-895.
[66] Bretscher A, Edwards K, Fehon RG. ERM proteins and merlin: integrators at the cell cortes[J]. Nat Rev Mol Cell Biol, 2002,3: 586-599.
[67] Simoncini T, Scorticati C, Mannella P, et al. Estrogen receptor alpha interacts with Galphal 3 to drive actin remodeling and endothelial cell migration via the RhoA/Rho kinase/moesin pathway[J]. Mol Endocrinol, 2006,20:1756-1771.
[68] Poppe D, Tiede I, Fritz G, et al. Azathioprine suppresses ezrin-radixin-moesin-dependent T cell-APC conjugation through inhibition of Vav guanosine exchange activity on Rac proteins[J]. J Immunol, 2006,176:640-651.
[69] Sala-Valdes M, Uras A, Charrin S, et al. EWI-2 and EWI-F link the tetraspanin web to the actin cytoskeleton through their direct association with ezrin-radixin-moesin proteins[J].J Biol Chem,2006,281:19665-19675.
[70] Ohtani K, Sakamoto H, Rutherford T, et al. Ezrin, a membrane-cytoskeletal linking protein, is involved in the process of invasion of endometrial cancer cells[J].Cancer Lett, 1999,147:31-38.
[71] 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[J]. Cancer Lett,2002,179:79-86.
[72] Chen Z, Fadiel A, Feng Y, et al. Ovarian epithelial carcinoma tyrosine phosphorylation cell proliferation, and ezrin translocation are stimulated by interleukin 1 alpha and epidermal growth factor[J].Cancer.2001,92(12):3068-3975.
[73]Song J,Fadiel A,Edusa V,et al.Estradiol-induced ezrin overexpressin in ovarian cancer:a new signaling domain for estrogen[J].Cancer Lett,2005,220(1):57-65.
[74]Moilanen J,Lassus H,Leminen A,et al.Ezrin immunoreactivity in relation to survival in serous ovarian carcimona patients[J].Gynecol Oncol.2003,90(2):273-281.
[75]Martin TA,Harrison G,Mansel RE,et al.The role of the CD44/ezrin complex in cancer metastasis[J].Crit Rev Oncol Hematol,2003,46(2):165-186.
[76]Paglini G,Kunda P,Quiroga S,et al.Suppression of radixin and moesin alters growth cone morphology,motility,and process formation in primary cultured neurons[J].J Cell Biol,1998,143 (2):443-455.
[77]程扬，何勉，李雯，等．血管内皮细胞因子C及膜突蛋白表达与宫颈癌恶性进展的相关性[J]．中山大学学报(医学科学版)，2008，29(2)：173-176．
[78]Macan R,Brandwein-Gensler M,Schlecht NF,et al.Differential tissue and subcellular expression of ERM proteins in normal and malignant tissues:cytoplasmic ezrin expression has prognostic significance for head and neck squamous cell carcinoma[J].Head Neck,2006,28(11):1018-1027.
[79]Khanna C,Wan X,Bose S,et al.The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis[J].Nat Med,2004,10(2):182-186.
[80]Moilanen J,Lassus H,Leminen A,et al.Ezrin immunoreactivity in relation to survival in serous ovarian carcinoma patients[J].Gynecol Oncol,2003,90(2):273-281.
[81]Makitie T,Carpen O,Vaheri A,et al.Ezrin as a prognostic indicator and its relationship to tumor characteristics in uveal malignant melanoma[J].Invest Ophthalmol Vis Sci,2001,42(11):2442-2449.
[82]陶晓峰、金晓明、王齐敏，等．Ezrin、Moesin在肝细胞癌中表达的研究[J]．诊断病理学杂志，2007，14(6)：456-458．
[83]Hefler LA,Concin N,Mincham D,et al.The prognostic value of immunohistochemically detected CD44v3 and CD44v6 expression in patients with surgically staged vulvar carcinoma:a multicenter study[J].Cancer,2002,94(1):125-130.
[84]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):2181-2191.
[85]Xu Y,Yu Q.E-cadherin negatively regulates CD44-hyaluronan interaction and CD44-mediated tumor invasion and branching morphogenesis[J].J Biol Chem,2003,278(10):8661-8668.
[86]Speck O,Hughes SC,Noren NK,et al.Moesin functions antagonistically to the Rho pathway to maintain epithelial integrity[J],Nature,2003,421(6918):83-87.
[87]李莹杰，陶晓峰，贺岩，等．Ezrin和Moesin在胃癌中的表达及其临床意义[J]．中国肿瘤，2007，16：550-552．
[88]Yu Y,Khan J,Khanna C,et al.Expression profiling identifies the cytoskeletal organizer Ezrin and the developmental homeoprotein Six-1 as key metastatic regulators[J].Nat Med,2004,10(2):175-181.
[89]Khanna C,Wan X,Bose S,et al.The membrane-cytoskeleton linker Ezrin is necessary for osteosarcoma metastasis[J].Nat Med,2004,10(2):182-186.
[90]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):273-281.
[91] Akisawa N, Nishimori I, Iwamura T, et al. High levels of ezrin expressed by human pancrestic adenocarcinoma cell line with high metastatic potential[J].Biochem Biophys Res Commun,1999,258(2):395-400.
[92] Martin TA, Harrison G, Mansel RE, et al. The role of the CD44/ezrin complex in cancer metastasis[J]. Crit Rev Oncol Hematol, 2003,46(2): 165-186.
[93] Pujuguel P, Del Maeslro L, Gautreau A, et al. Expression of CD44s,MMP-9 and Ki67: possible association with invasion, metastasis and recurrence of osteosarcoma[J].Ai Zheng, 2002,21(7):745-750.
[2]Kameda K,Shimada H,Ishikawa T,et al.Expression of highly polysialylated neural cell adhesion molecule in pancreatic cancer neural invasive lesion[J].Cancer Lett.1999,137(2):201-7.
[3]王启俊，祝伟星，邢秀梅，等．北京城区居民1982年-1997年癌症发病趋势[J]．中国肿瘤，2001，10(9)：507-509．
[4]胡家露．努力提高胰腺癌的早期诊断水平[J]．中华内科杂志，1999,38(2)：77-8．
[5]陆星华．胰腺癌研究现状与展望[J]．胰腺病学，2003，3：63-65．
[6]张群华，倪泉兴，张延龄．应加大胰腺癌诊治研究的力度[J]．中华医学杂志，2002，82：361-362．
[7]Hirai I,Kinura W,Ozawa K,et al.Perineural invasion in Pancreas[M].2002,24(1):15-25.
[8]于勇．小鼠肿瘤模型及其在胰腺癌治疗研究中的应用[J]．肿瘤研究与临床，2003，15(2)：139-143．
[9]Lindsay TH,Jonas BM,Sevcik MA,et al.Pancreatic cancer pain and its correlation with changes in tumor vasculature,macrophage infiltration,neuronal innervation,body weight and disease progression[J].Pain.2005 Decl5,119 (1-3).233-246.
[10]Tsukita S,Yonemura S.Cortical actin organization:lessons from ERM (ezrin/radixin/moesin) proteins[J].J Biol Chem 1999,274:34507-34510.
[11]Sophie LV.ERM proteins:From cellular architecture to cell signaling[J].Biology of the Cell 2000,92:305-316.
[12]唐平章．运用蛋白质组学的方法对甲状腺癌和正常甲状腺组织不同蛋白表达
[22]杨青峰，范明．神经营养因子的作用模式[J]．第三军医大学学报，2000，22(4)：400-402．
[23]Campos X,Munoz Y,Selman A,et al.Nerve growth factor and its high-affinity receptor trkA participate in the control of vascular endothelial growth factor expression in epithelial ovarian cancer[J].Gynecol Oncol.2007 Jan,104(1):168-175.
[24]Papatsoris AG,Liolitsa D,Deliveliotis C.Manipulation of the nerve growth factor network in prostate cancer[J].Expert Opin Investig Drugs.2007 Mar,16(3):303-309.
[25]花柱明，李真，罗东兰，等．神经生长因子在胰腺癌中的表达与癌细胞嗜神经侵袭和疼痛的关系[J]．南方医科大学学报，2006，26(8)：1251-1253．
[26]Chambers A F,Matrisian L M,et al.Changing views of the role of matix metalloproteinases in metastasis[J].J Natl Cancer Inst,1997,89:1260-1270.
[27]Papetti M,Herman I M.Mechanisms of normal and tumor-derived angiogenesis[J].Am J Physiol Cell Physiol,2002,282:947-970.
[28]Ray J M,Stetler-Stevenson W G.The role of matrix metalloproteases and their inhibitors in tumour invasion,metastasis and angiogensis[J].Eur Respir J,1994,7:2062-2072.
[29]Liotta LA,Steeg PS,Stetlei Stevenson WG.Cancer metastasis and angiogenesis:an imbalance of positive and negative regulation[J].Cell,1991,64:327.
[30]Bodey B,Bodey JB,Siegel SE,et al.Prognostic significance of matrix metalloproteinase expression in colorectal carcinomas[J].In Vivo,2000,14:659-666.
[31]Yamamoto H,Adachi Y,ItohF,et al.Association of matrilysinex pression with recurrence and poor prognosis in human esophagealsqua mous cell carcinoma[J].Cancer Res.1999,59:3313～3316.
[32]Jemal A,Thomas A,Murray T,et al.Cancer Statistics,2002[J].CA Cancer J Clin,2002,52(1):23-47.
[33]Hirai I,Kimura W,Ozawa K,et al.Perineural invasion in pancreatic cancer[J].Pancreas,2002,24:15-25.
[34]Nagakawa T,Kayahara M,Ueno K,et al.A clinicopathologic study on neural invasion in cancer of the pancreatic head[J].Cancer,1992,69:930-935.
[35]Hirai I,Kimura W,Ozawa K,et al.Perineural invasion in pancreatic cancer[J].Pancreas,2002,24(1):15-25.
[36]张华，林元问，顾乃群．“胰头丛”的应用解剖学研究[J]．临床应用解剖学杂志，1985，3(3)：140-143．
[37]徐恩多，何伪为，于频．外科解剖学(第一版)[M]．辽宁：辽宁教育出版社，1992，629-630．
[38]何平，石景森，陈武科．应用Cox模型分析影响胆管癌切除术后的预后因素[J]．中华肝胆外科杂志，2002，8(4)：219-221．
[39]党诚学．胰腺癌神经浸润的特点及临床意义[J]．普外基础与临床杂志，1997，4(4)：249-250．
[40]Zeelenberg IS,Ruuls-Van Stalle L,Roos E.The chemokine receptor CSCR4 is required for outgrowth of colon carcinoma micrometastases[J].Cancer Res,2003 Jul 1,63(13):3833-3839.
[41]程扬，何勉，李雯，等．血管内皮细胞因子C及膜突蛋白表达与宫颈癌恶性进展的相关性[J]．中山大学学报(医学科学版)，2008，29(2)：173-176．
[42]Macan R,Brandwein-Gensler M,Schlecht NF,et al.Differential tissue and subcellular expression of ERM proteins in normal and malignant tissues:cytoplasmic ezrin expression has prognostic significance for head and neck squamous cell carcinoma[J].Head Neck,2006,28(11):1018-1027.
[43]Kobayashi H,Sagara J,Kurita H,et al.Clinical significance of cellular distribution of moesin in patients with oral squamous cell carcinoma[J].Clin Cancer Res,2004,10:572-580.
[44]李婷婷，徐秀玉，王鑫．膜组织结构伸展刺突蛋白在喉癌中的表达[J]．中国耳鼻咽喉头颈外科，2007，14：37-40．
[45]Poppe D,Tiede I,Fritz G,et al.Azathioprine suppresses ezrin-radixin-moesin-dependent T cell-APC conjugation through inhibition of Vav guanosine exchange activity on Rac proteins[J].J Immunol,2006,176:640-651.
[46]Sala-Valdes M,Uras A,Charrin S,et al.EWI-2 and EWI-F link the tetraspanin web to the actin cytoskeleton through their direct association with ezrin-radixin-moesin proteins[J].J Biol Chem,2006,281:19665-19675.
[47]Speck O,Hughes SC,Noren NK,et al.Moesin functions antagonistically to the Rho pathway to maintain epithelial integrity[J].Nature,2003,421 (6918):83-87.
[48]陶晓峰，王齐敏，金晓明．肝细胞癌中Ezrin、Moesin表达的临床病理学意义[J]．临床与实验病理学杂志，2007 Feb，23(1)：30-32．
[49]Dolle L,EI Yazidi-Belkoura I,Adriaenssens E,et al.Nerve growth factor overexpression and autocrine loop in breast cancer[J].Oncogene,2003,22(36):5592-5601.
[50]Adriaenssens E,Vanhecke E,Saule P,et al.Nerve growth factor is a potential therapeutic target in breast cancer[J].Cancer Res.2008 Jan 15,68(2):346-351.
[51]Festuccia C,Muzi P,Gravina GL,et al.Tyrosine kinase inhibitor CEP-701 blocks the NTRK1/NGF receptor and limits the invasive capability of prostate cancer cells in vitro[J].Int J Oncol.2007 Jan,30(1):193-200.
[52]Tsunoda S,Okumura T,et al.Significance of nerve growth factor overexpression and its autocrine loop in oesophageal squamous cell carcinoma[J].Br J Cancer.2006 Aug 7,95 (3):322-330.
[53]Tee BK,Park KM,Surendran S,et al.KAII / CD82 suppresses tumor invasion by MMP—9 inactivation via TIMP1 up regulation in the H1299 human lung carcinoma cell line[J].Biochemi Biophys Res Commun,2006,342(2):655-661.
[54]Chambers A F,Matrisian L M,et al.Changing views of the role of matix metalloproteinases in memsmsis[J].J Natl Cancer Inst,1997,89:1260-1270.
[55]Kayahara M,Nagakawa T,Konishi I,et al.Clinicopathological study of pancreatic carcinoma with paticular referenee to the invasion of the extrapancreatic neural plexus[J].IntJPancreatol,1991,10(2):105-111.
[56]Okusaka T,Okada S,Ueno H,et al.Abdominal pain in patients with respectable pancreatic cancer with reference to clinicopathologic findings[J].Pancreas,2001,22(3):279.
[57]Exocrine pancreas.AJCC Cancer Staging Manual,6th edition[M].New York:Springer,2002,157-163.
[58]倪晓光，赵平，白晓枫．胰腺癌疼痛与其临床病理学关系的探讨[J]．实用癌症杂志，2003，18(4)：414-416．
[59]孙燕，顾慰萍，主编．癌症三阶梯止痛指导原则(第2版)[M]．北京：北京医科大学出版社，2002，21-23．
[60]Yamamoto M,Ohashi O,Saitoh Y.Japan pancreatic cancer registry:current status[J].Pancreas,1998,16(3):238.
[61]Krech RL,Walsh D.Symptoms of pancreatic cancer[J].J Pain Symptom Manage,1991,6(6):360.
[62]van Geenen RC,Keyzer-Dekker CM,van Tienhoven G,et al.Pain management of patients with unresectable peripancreatic carcinoma[J].Worle J Surg,2002,26:715-720.
[63]朱明华，胡先贵，郑建，等．249例外分泌源性胰腺癌临床病理和免疫组化研究[J]．胰腺病学，2003，3(4)：193-197．
[64]Grahm AL,Andren-Sandberg A.Prospective evaluation of pain in exocrine pancreatic cancer[J].Digestion,1997,58(6):542.
[65]Ridder G J,Klempnauer J.Back pain in patients with ductal pancreatic cancer.Its impact on respectability and prognosis after reaection[J].Scand J Gastroenterol,1995,30(12):1216.
[66]Kelsen DP,Portenoy R,Thaler H,et al.Pain as a predictor of outcome in patients with operable pancreatic carcinoma[J].Surgery,1997,122(1):53.
[67]倪晓光，赵平，白晓枫．胰腺癌疼痛与其临床病理学关系的探讨[J]．实用癌症杂志，2003，18(4)：414-416．
[68]严相默．神经阻滞及药物治疗疼痛性疾病的进展[J]．中国疼痛医学杂志，2003，9(4)：225-229．
[69]王晓，孙靖中，毕冬松．高能聚焦超声缓解晚期胰腺癌疼痛的疗效分析[J]．癌症，2002，21(5)：554．
[70]el Kamar FG,Grossbard ML,Kozuch PS,et al.Metastatic pancreatic cancer:emerging strategies in chemotherapy and palliative care[J].Oncologist,2003,8(1):18-34.
[71]Morganti AG,Trodella L,Valentini V,et al.Pain relief with short-term irradiation in locally advanced carcinoma of the pancreas[J].J Palliat Care,2003,19(4):258-262.
[72]石玉生，徐素俊，郑小康，等．局部晚期胰腺癌三维适形放射治疗疗效观察[J]．第一军医大学学报，2004，24(2)：213-215，219．
[73]el Kamar FG,Grossbard ML,Kozuch PS,et al.Metastatic pancreatic cancer:emerging strategies in chemotherapy and palliative care[J].Oncologist,2003,8(1):18-34.
[74]Ueno H,Okusaka T,Ikeda M,et al.Phase Ⅰ study of hyperfractionated radiation therapy with protracted 5-fluorouracil infusion in patients with locally advanced pancreatic cancer[J].Oncology,2004,67(3-4):215-221.
[1] Tsukita S, Yonemura S. Cortical actin organization: lessons from ERM (ezrin/radixin/moesin) proteins[J]. J Biol Chem,1999, 274: 34507-34510.
[2] Sophie LV. ERM proteins: From cellular architecture to cell signaling[J]. Biology of the Cell,2000,92: 305-316.
[3] Chishti AH, Kim AC, Marfatia SM, et al. The FERM domain: a unique module involved in the linkage of cytoplasmic proteins to the membrane[J]. Trends Biochem Sci,1998,23: 281-282.
[4] Ivetic A, Ridley AJ. Ezrin/radixin/moesin proteins and Rho GTPase signaling in leucocytes [J]. Immunology,2004,112:165-176.
[5] Pestonjamasp K, Amieva MR, Strassel CP, et al. Moesin, ezrin, and p205 are actin-binding proteins associated with neutrophil plasma membranes [J].Mol.Biol.Cell, 1995,6: 247-259.
[6] Bretscher A, Gary R, Berryman M. Soluble ezrin purified from placenta exists as stable monomers and elongated dimmers with masked C-terminal ezrin-radixin-moesin association domains[J]. Biochemistry, 1995, 34:16830-16837.
[7] Gautreau A, Louvard D, Arpin M. Morphogenic effects of ezrin require a phosphorylation-induced transition from oligomers to monomers at the plasma membrane[J]. J Cell Biol,2000,l50:193-203.
[8] Barret C, Roy C, Montcourrier P, et al. Mutagenesis of the phosphatidylinositol 4,5-bisphosphate PIP(2) binding site in the NH(2)-terminal domain of ezrin correlates with its altered cellular distribution[J]. J Cell Biol,2000,151:1067-1080.
[9] Niggli V, Andreoli C, Roy C, et al. Identification of a phosphatidylinositol-4,5-bisphosphate-binding domain in the N-terminal region of ezrin[J]. FEBS Lett, 1995,376:172-176.
[10] Bonilha VL, Finnemann SC, Rodriguez-Boulan E.Ezrin promotes morphogenesis of apical microvilli and basal infoldings in retinal pigment epithelium[J]. Cell Biol,1999,147,1533-1548.
[11] Speck .O, et al.Moesin functions antagonistically to the Rho pathway to maintain epithelial integrity[J]. Nature,2003,421:83-87.
[12] Paglini G, Kunda P, Quiroga S, et al. Suppression of radixin and moesin alters growth cone morphology,motility,and process formation in primary cultured neurons[J].J Cell Biot,1998,143:443-455.
[13] Yokoyama T, Goto H, Izawa I, et al. Aurora-B and Rho-Kinase/ROCK, the two cleavage furrow kinases, independently regulate the progression of cytokinesis :possible existence of a novel cleavage furrow kinase phosphorylates ezrin/radixin/moesin (ERM) [J]. Genes Cell,2005,10(2):127-137.
[14] Kishore R, Qin G, Luedemann C, et al. The cytoskeletal protein ezrin regulates EC proliferation and angiogenesis via TNF-alpha-induced transcriptional repression of cyclin[J].J Clin Invest.2005,115(7):1785-1796.
[15] Ng T, Parsons M, Hughes W, et al.Ezrin is a downstream effector of trafficking PKC/integrin complexes involved in the control of cell motility[J]. EMBO J 2001,20:2723-2741.
[16] Eugene E, Hoffmann I, Pujol C, et al. Microvilli-like structures are associated with the internalization of virulent capsulated Neisseria meningitides into vascular endothelial celIs[J]. J Cell Sci.2002,115:1231-1241.
[17] Guoquan L, Voyno-Yasenetskaya TA. Radixin stimulates Racl and Ca2+/calmodulin dependent kinase, CaMKⅡ :Crosstalk with G α/ 13[J].J BiolChem,2005 Sep 26, (Epub ahead of print) .
[18] Hecker C, Weise J, Schneider-Schaulies HC, et al. Specific binding of HIV-1 envelope protein gp120 to the structural membrane proteins ezrin and moesin[J]. Virus Res, 1997, 49:215-223.
[19] Tohme ZN, Amar S, Dyke TV, et al. Moesin functions as a lipopolysaccharide receptor on human monocytes[J]. Infect Immun,1999,67(7):3 215-3 220.
[20] Sebo TJ, Cheville JC, Riehle DL, et al. Perineural invasion and MIB-1 positivity in addition to Gleason score are significant preoperative predictors of progression after radical retropubic prostatectomy for prostate cancer[J].Am J Surg Pathol, 2002,26(4): 431-439.
[21] Regis De Brito Santos I, Kowalski LP, Araujo VC, et al. Multivariate analysis of risk factors for neck metastases in surgically treated parotid carcinomas[J].Arch Otolaryngeol Head Neck Surg, 2001,127(1):56-60.
[22] Duraker N, Sisman S, Can G. The significance of perineural invasion as a prognostic factor in patients with gastric carcinoma[J]. Surg Today,2003,33:95-100.
[23] Ayala GE, Dai H, Li R, et al. Bystin in perineural invasion of prostate cancer[J]. Prostate, 2006,66:266-272.
[24] Hassanein AM, Proper SA, Depeik-Smith ND, et al. Peritumoral fibrosis in basal cell and squamous cell carcinoma mimicking perineural invasion: Potential pitfall in mohs micrographic surgery [J]. Dermatol Surg,2005,31:1101-1106.
[25] Chen-Tsai CP, Colome-Grimmer M, Wagner RF Jr. Correlations among neural cell adhesion molecule, nerve growth factor, and its receptors, TrkA, TrkB,TrkC, and p75, in perineural invasion by basal cell and cutaneous squamous cell carcinomas[J]. Dermatol Surg, 2004,30:1009-1016.
[26] Kameda K, Shimada H, Ishikawa T, et al. Expression of highly polysialylated neural cell adhesion molecule in pancreatic cancer neural invasive lesion[J].Cancer Lett, 1999,137:201-207.
[27] Murakawa K, Tada M, Takada M, et al. Prediction of lymph node metastasis and perineural invasion of biliary tract cancer by selected features from cDNA array data[J].J Surg Res, 2004,122:184-194.
[28] Lee MA, Park GS, Lee HJ, et al. Survivin expression and its clinical significance in pancreatic cancer[J]. BMC Cancer, 2005,5:127.
[29] Kham OA, Alexiou C, Soomro I, et al. Pathological determinants of survival in node-negative oesophageal cancerl[J]. Br J Surg, 2004,91:1586-1591.
[30] Giuliani A, Caporale A, Di Bari M, et al. Maximum gastric cancer diameter as a prognostic indicator: Univariate and multi-variate analysis[J]. J Exp Clin Cancer Res,2003,22:531-538.
[31] Miknyoczki SJ, Klein Szanto AJ, Ruggeri BA. Neutotrophin-Trk receptor interactions in neoplasia: a possible role in interstitial and perineural invasion in ductal pancreatic cancer[J]. Crit-Rev-Oncog, 1996,7(1-2): 89-100.
[32] Yang G, Wheeler TM, Kattan MW, et al. Perineural invasion of prostate carcinoma cells is associated with reduced apoptotic index[J]. Cancer,1996,78(6): 1267-1271.
[33] Geldof AA, De Kleijn MA, Rao BR, et al. Nerve growth factor stimulates in vitro invasive capacity of DU145 human prostatic cancer cells [J]. J Cancer Res Clin Oncol, 1997,123(2): 107-112.
[34] Walch ET, Marchetti D. Role of neurotrophins and neurotrophins receptors in the vitro invasion and heparanase production of human prostate cancer cells[J].Clin Exp Metastasis, 1999,17(4): 307-314.
[35] Weeranatna AT, Dalrymple SL, Lamb JC, et al. Pan-trk inhibition decreases metatasis and enhances host survival in experimental models as a result of its selective induction of apoptosis of prostate cancer cells[J]. Clin Cancer Res,2001,7(8): 2237-2245.
[36] Sakamoto Y, Kitajima Y, Edakuni G, et al. Expression of Trk tyrosine kinase receptor is a biologic mkarker for cell proliferation and perineural invasion of human pancreatic ductal adenocarcinoma[J]. Oncol-Rep, 2001,8(3): 477-484.
[37] Marchetti D, Nicolson GL. Human melanoma cell invasion: selected neurotrophin enhancement of invasion and heparanase activity[J]. J Investig Dermatol Symp Proc, 1997,2(1):99-105.
[38] Missale C, Codignol A, Sigala S, et al. Nerve growth factor abrogates the tumorigenicity of human small cell lung cancer cell lines[J]. Proc Natl Acad Sci U S A, 1998,95(9): 5366-5371.
[39] Giese A, Kluwe L, Laube B, et al. Migration of human glioma cells on myelin[J]. Neurosurgery, 1996,38(4): 755-764.
[40] Hensel T, Amberger VR, Schwab ME. A metalloprotease activity from C6 glioma cells inactivates the myelin-associated neurite growth inhibitors and can be neutralized by antibodies[J]. Br-J-Cancer, 1998,78(12): 1564-1572.
[41] Hensel T, Amberger VR, Schwab ME. A metalloprotease activity from C6 glioma cells inactivates the myelin-associated neurite growth inhibitors and can be neutralized by antibodies[J]. Br-J-Cancer, 1998,78(12): 1564-1572.
[42] Nagakawa O, Murakami K, Yamaura T, et al. Expressio of membrane-type 1 matrix metalloproteinase (MT1-MMP) on prostate cancer cell lines[J].Cancer-Lett, 2000,155(2):173-179.
[43] Hotary K, Allen E, Punturieri A, et al. Regulation of cell invasion and morphogenesis in a three-dimensional type 1 collagen matrix by membrane-type matrix metalloproteinases 1,2 and 3[J]. J Cell Biol,2000,149(6): 1309-1323.
[44] Fillmore HL, Van Meter TE, Broaddus WC. Membrane-type matrix metalloproteinases (MT-MMPs): expression and function during glioma invasion[J]. J Neurooncol, 2001,53(2): 187-202.
[45] Franca CM, Jaeger MM, Jaeger RG, et al. The role of basement membrane proteins on the expression of neural cell adhesion molecule (N-CAM) in an adenoid cystic carcinoma cell line[J].Oral Oncol, 2000,36(2):248-252.
[46] Gandour ER, Kapadia SB, Barnes L, et al. Nueral cell adhesion molecule in adenoid cystic carcinoma invading the skull base[J]. Otolaryngol Head Neck Surg, 1997,117(5): 453-458.
[47] Hutcheson JA, Vural E, Korourian S, et al. Neural cell adhesion molecule expression in adenoid cystic carcinoma of the head and neck[J]. Laryngoscope,2000,110(6):946-948.
[48] Kameda K, Shimada H, Lesionlshikawa T, et al. Expression of highly polysialylated neural cell adhesion molecule in pancreatic cancer neural invasive[J]. Cancer-Lett, 1999,137(2):201-207.
[49] Franca CM, Jaeger RG, Freitas VM, et al. Effect of N-CAM on in vitro invasion of human adenoid cystic carcinoma cells[J]. Oral Oncol, 2001,37(8):638-642.
[50] Cavallaro U, Niedermayer J, Fuxa M, et al. N-CAM modulates tumor-cell adhesion to matrix by inducing FGF-receptor signaling[J]. Nat Cell Biol,2001,3(7):650-657.
[51] Giese A, Kluwe L, Laube B, et al. Migration of human glioma cells on myelin[J]. Neurosurgery, 1996,38(4): 755-764.
[52] Mathew J, Hines J E, Obafunwa J O, et al. CD44 is expressed in hepatocellular carcinomas showing vascular invasion[J].J Pathol, 1996,179(1): 74-79.
[53] Yu Y, Khan J, Khanna C, et al. Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators[J].Nat Med,2004,10(2):175-181.
[54]Carmeci C,Thompson D A,Kuang W W,et al.Moesin expression is associated with the estrogen receptor-negative breast cancer phenotype[J].Surgery,1998,124(2):211-217.
[55]陶晓峰，王齐敏，金晓明．肝细胞癌中Ezrin、Moesin表达的临床病理学意义[J]．临床与实验病理学杂志，2007 Feb，23(1)：30-32．
[56]唐平章．运用蛋白质组学的方法对甲状腺癌和正常甲状腺组织不同蛋白表达的分析[D]．北京：中国协和医科大学,2007．
[57]Robbins J,Memo MJ,Boice JD,Jr.,et al.Thyroid cancer:a lethal endocrine neoplasm[J].Ann Intern Med 1991,115(2):133-147.
[58]Jernal A TA,Murray T Surveillance,Epidemiology,and End Results (SEER) Incidence and U.S.Mortality Statistics[J].CA Cancer J Clin 2002,52:23-47.
[59]钱碧云，何敏，董淑芬．1981年至2001年天津市甲状腺癌的发病率和死亡率[J]．中华内分泌代谢杂志，2005,21：432-434．
[60]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 protein[J].J Cell Boil,1999,145:1497-1509.
[61]Carmeci C,Thompson DA,Kuang WW,Lightdale N,Furthmayr H,Weigel RJ.Moesin expression is associated with the estrogen receptor-negative breast cancer phenotype[J].Surgery 1998,124(2):211-217.
[62]Kobayashi H,Sagara J,Kurita H,et al.Clinical significance of cellular distribution of moesin in patients with oral squamous cell carcinoma[J].Clin Cancer Res,2004,10:572-580.
[63]李婷婷，徐秀玉，王鑫．膜组织结构伸展刺突蛋白在喉癌中的表达[J]．中国耳鼻咽喉头颈外科，2007，14：37-40．
[64] Sato N, Funayama N, NagafuchiA, et al. A gene family consisting of ezrin,radixin and moesin. Its specific localization at actin filament/plasma membrane association sites[J]. J Cell Sci, 1992,103:131-143.
[65] Yonemura S, Hirao M, Doi Y, et al. Ezrin/radixin/moesin (ERM) protein bind to a positively charged amino acid cluster in the juxta-membrane cytoplasmic domain of CD44, CD43, and ICAM-2[J]. J Cell Biol, 1998,140:885-895.
[66] Bretscher A, Edwards K, Fehon RG. ERM proteins and merlin: integrators at the cell cortes[J]. Nat Rev Mol Cell Biol, 2002,3: 586-599.
[67] Simoncini T, Scorticati C, Mannella P, et al. Estrogen receptor alpha interacts with Galphal 3 to drive actin remodeling and endothelial cell migration via the RhoA/Rho kinase/moesin pathway[J]. Mol Endocrinol, 2006,20:1756-1771.
[68] Poppe D, Tiede I, Fritz G, et al. Azathioprine suppresses ezrin-radixin-moesin-dependent T cell-APC conjugation through inhibition of Vav guanosine exchange activity on Rac proteins[J]. J Immunol, 2006,176:640-651.
[69] Sala-Valdes M, Uras A, Charrin S, et al. EWI-2 and EWI-F link the tetraspanin web to the actin cytoskeleton through their direct association with ezrin-radixin-moesin proteins[J].J Biol Chem,2006,281:19665-19675.
[70] Ohtani K, Sakamoto H, Rutherford T, et al. Ezrin, a membrane-cytoskeletal linking protein, is involved in the process of invasion of endometrial cancer cells[J].Cancer Lett, 1999,147:31-38.
[71] 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[J]. Cancer Lett,2002,179:79-86.
[72] Chen Z, Fadiel A, Feng Y, et al. Ovarian epithelial carcinoma tyrosine phosphorylation cell proliferation, and ezrin translocation are stimulated by interleukin 1 alpha and epidermal growth factor[J].Cancer.2001,92(12):3068-3975.
[73]Song J,Fadiel A,Edusa V,et al.Estradiol-induced ezrin overexpressin in ovarian cancer:a new signaling domain for estrogen[J].Cancer Lett,2005,220(1):57-65.
[74]Moilanen J,Lassus H,Leminen A,et al.Ezrin immunoreactivity in relation to survival in serous ovarian carcimona patients[J].Gynecol Oncol.2003,90(2):273-281.
[75]Martin TA,Harrison G,Mansel RE,et al.The role of the CD44/ezrin complex in cancer metastasis[J].Crit Rev Oncol Hematol,2003,46(2):165-186.
[76]Paglini G,Kunda P,Quiroga S,et al.Suppression of radixin and moesin alters growth cone morphology,motility,and process formation in primary cultured neurons[J].J Cell Biol,1998,143 (2):443-455.
[77]程扬，何勉，李雯，等．血管内皮细胞因子C及膜突蛋白表达与宫颈癌恶性进展的相关性[J]．中山大学学报(医学科学版)，2008，29(2)：173-176．
[78]Macan R,Brandwein-Gensler M,Schlecht NF,et al.Differential tissue and subcellular expression of ERM proteins in normal and malignant tissues:cytoplasmic ezrin expression has prognostic significance for head and neck squamous cell carcinoma[J].Head Neck,2006,28(11):1018-1027.
[79]Khanna C,Wan X,Bose S,et al.The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis[J].Nat Med,2004,10(2):182-186.
[80]Moilanen J,Lassus H,Leminen A,et al.Ezrin immunoreactivity in relation to survival in serous ovarian carcinoma patients[J].Gynecol Oncol,2003,90(2):273-281.
[81]Makitie T,Carpen O,Vaheri A,et al.Ezrin as a prognostic indicator and its relationship to tumor characteristics in uveal malignant melanoma[J].Invest Ophthalmol Vis Sci,2001,42(11):2442-2449.
[82]陶晓峰、金晓明、王齐敏，等．Ezrin、Moesin在肝细胞癌中表达的研究[J]．诊断病理学杂志，2007，14(6)：456-458．
[83]Hefler LA,Concin N,Mincham D,et al.The prognostic value of immunohistochemically detected CD44v3 and CD44v6 expression in patients with surgically staged vulvar carcinoma:a multicenter study[J].Cancer,2002,94(1):125-130.
[84]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):2181-2191.
[85]Xu Y,Yu Q.E-cadherin negatively regulates CD44-hyaluronan interaction and CD44-mediated tumor invasion and branching morphogenesis[J].J Biol Chem,2003,278(10):8661-8668.
[86]Speck O,Hughes SC,Noren NK,et al.Moesin functions antagonistically to the Rho pathway to maintain epithelial integrity[J],Nature,2003,421(6918):83-87.
[87]李莹杰，陶晓峰，贺岩，等．Ezrin和Moesin在胃癌中的表达及其临床意义[J]．中国肿瘤，2007，16：550-552．
[88]Yu Y,Khan J,Khanna C,et al.Expression profiling identifies the cytoskeletal organizer Ezrin and the developmental homeoprotein Six-1 as key metastatic regulators[J].Nat Med,2004,10(2):175-181.
[89]Khanna C,Wan X,Bose S,et al.The membrane-cytoskeleton linker Ezrin is necessary for osteosarcoma metastasis[J].Nat Med,2004,10(2):182-186.
[90]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):273-281.
[91] Akisawa N, Nishimori I, Iwamura T, et al. High levels of ezrin expressed by human pancrestic adenocarcinoma cell line with high metastatic potential[J].Biochem Biophys Res Commun,1999,258(2):395-400.
[92] Martin TA, Harrison G, Mansel RE, et al. The role of the CD44/ezrin complex in cancer metastasis[J]. Crit Rev Oncol Hematol, 2003,46(2): 165-186.
[93] Pujuguel P, Del Maeslro L, Gautreau A, et al. Expression of CD44s,MMP-9 and Ki67: possible association with invasion, metastasis and recurrence of osteosarcoma[J].Ai Zheng, 2002,21(7):745-750.