OSF癌变侵袭转移的临床研究及其与Wnt途径异常激活关系的初步研究
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摘要
口腔黏膜下纤维性变(oral submucous fibrosis,OSF)是一种慢性、隐匿性、与咀嚼槟榔有关的口腔黏膜疾病,OSF可以癌变成口腔鳞状细胞癌(oral squamous cell carcinoma,OSCC)。临床上观察到此类患者的局部复发与颈部淋巴转移率要高于其它非OSF癌变鳞癌,预后较差,提示OSF癌变鳞癌可能存在有别于非OSF癌变鳞癌不同的生物学行为,然而目前关于OSF癌变鳞癌生物学行为的临床与基础研究甚少。
Wnt途径是一类在生物体进化过程中高度保守的信号转导途径,调节控制着众多生命活动过程,对细胞增殖和分化具有重要调节作用,与肿瘤的发生发展也有密切的关系,最近几年针对Wnt途径与肿瘤侵袭和转移关系的研究开始引起关注,却未见Wnt途径在OSF癌变鳞癌中的研究。
目的:本文旨在对OSF癌变鳞癌生物学行为进行临床与机制研究。通过已被确诊的OSF癌变鳞癌临床病例,对OSF癌变鳞癌病例与非OSF癌变鳞癌病例的临床特点与生物学行为进行对比研究,以补充与完善关于OSF癌变生物学行为方面的临床研究;采用免疫组化SP法以及荧光实时定量RT-PCR法对Wnt途径的几个关键分子在OSF癌变鳞癌等组织中的表达进行检测,观察其在mRNA水平及蛋白表达水平的改变,从而探讨Wnt信号途径在OSF癌变鳞癌侵袭转移机制中可能发挥的作用;通过比较不同手术方式治疗OSF癌变鳞癌病例后对其复发转移率控制的优劣,提出手术治疗OSF癌变鳞癌的推荐术式,以提高OSF癌变鳞癌患者的生存时间及生活质量。
材料与方法:对2002年1月～2008年12月在中南大学湘雅医院口腔颌面外科病房经手术治疗的口腔黏膜鳞癌患者进行回顾性分析,将其病例分为OSF癌变鳞癌组及非OSF癌变鳞癌组。对其病例分布、发病部位、临床特征、淋巴结转移及复发等进行统计比较分析;采用免疫组化SP法对52例OSF癌变鳞癌与48例非OSF癌变鳞癌组织及其癌旁组织的石蜡包埋切片进行染色,检测组织中β-catenin、Wnt2、E-cadherin、TCF-4以及CD44v6的蛋白表达水平的改变;采用实时荧光定量RT-PCR方法检测OSF癌变鳞癌组织与非OSF癌变鳞癌组织及各自癌旁组织中β-catenin、E-cadherin及TCF-4的mRNA水平的变化;收集45例OSF癌变鳞癌患者,对其中25例采用原发灶扩大癌旁组织、与颈部淋巴组织连续垂直切除、个体化皮瓣修复的手术方法并与传统手术方法进行临床疗效观察比较研究,将其研究结果供临床应用。所得结果通过统计学软件SPSS13.0进行统计学分析。
结果:一.OSF癌变鳞癌组复发转移率(43.12%)高于非OSF癌变鳞癌(30.77%),预后较差;组间差异有统计学意义,P＜0.05。
二.β-catenin的易位表达
1.正常口腔粘膜组织中,β-catenin的表达为细胞膜阳性(强染色率93.33%);
2.OSF癌变鳞癌组织呈现β-catenin胞膜染色减少乃至消失(强染色率7.69%),非OSF癌变鳞癌组织亦存在β-catenin胞膜染色减少(强染色率20%),二者差异无统计学意义(P＞0.05);OSF癌变鳞癌组织β-catenin胞浆内积聚率达61.5%,非OSF癌变鳞癌组织则达57.8%,二者差异无统计学意义(P＞0.05);OSF癌变鳞癌组织β-catenin核易位率达59.6%,非OSF癌变鳞癌组织则未发现β-catenin的核易位现象;
3.OSF癌变鳞癌癌旁组织与非OSF癌变鳞癌癌旁组织比较,β-catenin包膜强染色率差别有统计学意义(分别为57.7%,86.7%,P＜0.01);
4.荧光实时定量RT-PCR结果:OSF癌变鳞癌组织(1.10)与非OSF癌变鳞癌组织(1.70)之间β-catenin mRNA表达量差异无统计学意义(P＞0.05);OSF癌变鳞癌癌旁组织(0.87)与非OSF癌变鳞癌癌旁组织(0.85)之间β-catenin mRNA表达量差异无统计学意义(P＞0.05)。
三.Wnt2的异常表达
1.正常口腔粘膜组织中,Wnt2表达为阴性;
2.OSF癌变鳞癌组织可见Wnt2的高表达(染色率达78.84%)与非OSF癌变鳞癌组织的44%相比,差异有统计学意义(P＜0.01);OSF癌变鳞癌癌旁组织Wnt2染色率为34.62%,而非OSF癌变鳞癌癌旁组织无Wnt2染色;
3.Wnt2的表达与β-catenin膜染色呈负相关(r=-0.956,P=0.011),与β-catenin胞浆积聚呈正相关。
四.E-cadherin的表达
1.正常口腔粘膜组织中,E-cadherin的表达为细胞膜阳性,强染色率达93.33%;
2.OSF癌变鳞癌组织中E-cadherin膜表达明显减少,强染色率3.85%;非OSF癌变鳞癌组织中E-cadherin强染色率53.33%,二者差异有统计学意义(P＜0.01);OSF癌变鳞癌癌旁组织中E-cadherin强染色率57.69%,非OSF癌变鳞癌癌旁组织E-cadherin强染色率64.44%,二者差异无统计学意义(P＞0.05);
3.膜E-cadherin与β-catenin的膜表达呈正相关(r=0.962,P=0.038),Wnt2与膜E-cadherin的减少或消失存在负相关(r=-0.919,P=0.027),β-catenin的易位与膜E-cadherin的减少具有伴随关系。
4.荧光实时定量RT-PCR结果:OSF癌变鳞癌组、OSF癌变鳞癌癌旁组、非OSF癌变鳞癌组、非OSF癌变鳞癌癌旁组等4组中E-cadherinmRNA表达水平均低于正常黏膜组,差别有统计学意义(P＜0.01),但4组间差别无统计学意义(P＞0.05)。
五.TCF-4及CD44_v6的表达
1.正常口腔粘膜中,TCF-4的表达表现为细胞核弱阳性(20%);CD44_v6的表达表现为细胞膜阳性(40%);
2.TCF-4在OSF癌变鳞癌组织染色率69.23%,在非OSF癌变鳞癌组织48.89%,二者差异有统计学意义(P＜0.05);TCF-4在OSF癌变鳞癌癌旁组织染色率50%,在非OSF癌变鳞癌癌旁组织22.22%,二者差异有统计学意义(P＜0.05);
3.CD44_v6在OSF癌变鳞癌组织染色率40%,在非OSF癌变鳞癌组织82.7%,二者差异有统计学意义(P＜0.01);CD44_v6在OSF癌变鳞癌癌旁组织染色率57.7%,在非OSF癌变鳞癌癌旁组织48.89%,二者差异无统计学意义(P＞0.05);
4.CD44_v6的表达与TCF-4呈正相关(r=0.949,P=0.014)。
5.荧光实时定量RT-PCR结果:OSF癌变鳞癌TCF-4 mRNA表达量较其它4组高,差别有统计学意义(P＜0.01),其它各组间差别无统计学意义(P＞0.05)。
六.采用扩大癌旁组织切除、原发灶与颈部淋巴组织连续垂直切除、个体化皮瓣修复等与传统治疗手段相比,可以明显减少OSF癌变鳞癌的复发转移率(分别为12%与40%);
结论:一.OSF癌变鳞癌临床上表现为更具侵袭性和转移性的生物学行为;
二.Wnt途径在OSF癌变鳞癌中处于异常活化状态;
三.OSF癌变鳞癌中Wnt2的表达上调导致β-catenin在胞浆/胞核的积聚,促使Wnt/β-catenin途径的活化,该途径的活化在OSF癌变鳞癌形成和肿瘤播散上具有重要作用;
四.Wnt途径的活化导致细胞黏附分子E-cadherin与CD44v6表达的改变,进而促进OSF癌变鳞癌的侵袭与转移;
五.扩大原发灶切除边界以及原发灶-颈部连续垂直切除可获得较为满意的治疗效果,可作为手术治疗OSF癌变鳞癌的推荐术式。
Oral submucous fibrosis(OSF) is a kind of chronic,invisible,and betel nut chewing-related oral mucosal diseases,which can turn into oral squamous cell carcinoma(OSCC).It was observed clinically that the local recurrence rate and neck lymph node metastasis rate of such patients,with poor prognosis,are higher than those of OSCC non-originating from OSF.It indicates that there may be different biological behavior between OSCC originating from OSF and the other ones.However,there is little clinical and basic research regarding the biological behavior of OSCC originating from OSF.
Wnt pathway is a class of highly conserved signal transduction pathway in the evolution of organism.It controls numerous processes of life activities,regulates cell proliferation and differentiation,and relates to occurrence and development of tumor.In recent years,the study on the relationship between Wnt pathway and cancer invasion and metastasis has been paid close attention to.But there is no study on Wnt pathway in OSCC originating from OSF.
Objective:The purpose of this paper is to research the clinical feature and mechanisms on the biological behavior of OSCC originating from OSF.Using the existing clinical data,a comparative study about the clinical characteristics and biological behavior between OSCC originating from OSF and the other ones was made,so as to supplement and perfect the clinical research about the biological behavior of OSCC originating from OSF.The expressions of some key molecules of Wnt pathway in the tissues of OSCC originating from OSF were detected by immunohistochemistry SP method and Real-Time PCR,the expression changes of these molecules at mRNA level and protein level were observed,and then the possible role of Wnt signaling pathway in the mechanism of invasion and metastasis of OSCC originating from OSF was investigated.After the advantages and disadvantages on controlling the rate of recurrence and metastasis by different surgical methods were compared,the recommend surgery of OSCC originating from OSF was put forward,and the significance of mechanism research about the biological behavior of OSCC originating from OSF was validated clinically.
Materials & Methods:The patients with OSCC after surgical treatment (Jan 2002～Dec 2008) in the Department of Oral and Maxillofacial Surgery,Xiangya Hospital,Central South University were studied.The clinical data of these patients were analyzed retrospectively.They were divided into the group of OSCC originating from OSF and the group of OSCC non-originating from OSF.Their case distribution,site,clinical characteristics,lymphatic metastasis and recurrence were compared and analyzed.The expressions ofβ-catenin,Wnt2,E-cadherin,TCF-4 and CD44v6 were detected in the carcinoma and adjacent tissues of 52 OSCCs originating from OSF and 48 OSCCs non-originating from OSF by immunohistochemistry SP method,respectively.Then the expressions ofβ-catenin mRNA,E-cadherin mRNA and TCF-4 mRNA in these tissues were detected by Real-Time PCR,respectively.45 cases of OSCC originating from OSF were selected.25 of these cases were treated by the methods including resection of expanding adjacent tissues, successive and vertical removal of primary tumor and neck lymphoid tissue,restoration of individual flap and so on.The clinical efficacy of these methods were compared with traditional surgical methods.The results were analyzed by statistical software SPSS 13.0.
Results:
1.The rates of recurrence and metastasis of OSCC originating from OSF(43.12%) are higher than those of OSCC non-originating from OSF (30.77%).The patients with OSCC originating from OSF have poor prognosis.
2.Translocation expression ofβ-catenin
1) In normal oral mucosa,the expression ofβ-catenin performs membrane positive(strong staining rate:93.33%).
2) In the tissues of OSCC originating from OSF,the expression ofβ-catenin performed reduce or even disappearance of membrane staining (strong staining rate:7.69%);in the tissues of OSCC non-originating from OSF,the phenomenon of reduced membrane staining also existed (strong staining rate:20%);no statistically significant difference was found between the two groups(P＞0.05).There was no statistically significant difference about intracytoplasmic accumulation ofβ-catenin between OSCC originating from OSF group(61.5%) and OSCC non-originating from OSF(57.8%)(P＞0.05).The rate of nuclear translocation ofβ-catenin in OSCC originating from OSF was 59.6%, but the phenomenon of nuclear translocation ofβ-catenin in OSCC non-originating from OSF was not found.
3) The strong membrane staining rate ofβ-catenin in adjacent tissues of OSCC originating from OSF(57.7%) was lower than that in OSCC non-originating from OSF(86.7%)(P＜0.01).
4) The result of Real-Time PCR showed that there was no significant difference about the expression ofβ-catenin mRNA between OSCC originating from OSF(1.10) and OSCC non-originating from OSF(1.70)(P＞0.05);in the same way,no significant difference was found about the expression ofβ-catenin mRNA in adjacent tissues between OSCC originating from OSF(0.87) and OSCC non-originating from OSF(0.85)(P＞0.05).
3.Abnormal expression of Wnt2
1) In normal oral mucosa,Wnt2 expressed as negative.
2) The positive staining rate of Wnt2 in the tissues of OSCC originating from OSF(78.84%) was higher than that in OSCC non-originating from OSF(44%)(P＜0.01).The positive staining rate of Wnt2 in adjacent tissues of OSCC originating from OSF was 34.62%, but the staining rate of Wnt2 in adjacent tissues of OSCC non-originating from OSF was negative.
3) There was a negative correlation between Wnt2 expression andβ-catenin membrane staining(r=-0.956,P=0.011).There was a positive correlation between Wnt2 expression and cytoplasmic accumulation ofβ-catenin.It Showed that the translocation ofβ-catenin related to the initiation of Wnt pathway.
4.Expression of E-cadherin
1) In normal oral mucosa,the expression of E-cadherin registered as membrane positive,and the strong staining rate was 93.33%.
2) The strong staining rate of E-cadherin in OSCC originating from OSF(3.85%) was significantly lower than that in OSCC non-originating from OSF(53.33%)(P＜0.01).No significant difference about the strong staining rate of E-cadherin was found in the adjacent tissues between OSCC originating from OSF(57.69%) and OSCC non-originating from OSF(64.44%)(P＞0.05).
3) There was a positive correlation between membrane E-cadherin and membrane expression ofβ-catenin(r=0.962,P=0.038).There was a negative correlation between Wnt2 and reduce or disappearance of E-cadherin(r=-0.919,P=0.027).The translocation ofβ-catenin accompanied by reduce of membrane E-cadherin.
4) The result of Real-Time PCR showed that the expression levels of E-cadherin mRNA in the 4 groups such as Group OSCC originating from OSF were significantly lower than that in normal group(P＜0.01); there was no significant difference about the expression levels of E-cadherin mRNA among the other groups(P＞0.05).
5.Expression of TCF-4 and CD44v6
1) In normal oral mucosa,the expression of TCF-4 was nucleus weakly positive,and the expression of CD44v6 performed membrane positive.
2) The positive rate of TCF-4 in Group OSCC originating from OSF(69.23%) was significantly higher than that in Group OSCC non-originating from OSF(48.89%)(P＜0.05).The staining rate of TCF-4 in the adjacent tissues of OSCC originating(50%) from OSF was significantly higher than that of OSCC non-originating from OSF (22.22%)(P＜0.05).
3) The positive rate of CD44v6 in Group OSCC originating from OSF(40%) was significantly lower than that in Group OSCC non-originating from OSF(82.7%)(P＜0.01).However,the staining rate of CD44v6 in the adjacent tissues showed no significant difference between OSCC originating from OSF(57.7%) and OSCC non-originating from OSF(48.89%)(P＞0.05).
4) There was a positive correlation between the expression of CD44v6 and TCF-4(r=0.949,P=0.014).
5) The result of Real-Time PCR showed that the expression of TCF-4 mRNA in Group OSCC non-originating from OSF was significantly higher than that in the other 4 groups(P＜0.01);the differences among the other groups were not statistically significant(P＞0.05).
6.Compared with using traditional treatment means(40%),using the new methods(12%),including resection of expanding adjacent tissues,vertical removal of primary tumor and neck lymphoid tissue, restoration of individual flap and so on,the rates of recurrence and metastasis of OSCC originating from OSF could be reduced significantly.
Conclusions:
1.Clinically,OSCC originating from OSF has a more invasive and metastatic biological behavior.
2.In OSCC originating from OSF,Wnt pathway is in the abnormal activation status.
3.Upregulation of Wnt2 in OSCC originating from OSF causes the accumulation ofβ-catenin in the cytoplasm/nucleus,prompts Wnt/β-catenin pathway to activate.This pathway plays a key role in carcinogenesis of OSF and dissemination of cancer.
4.The abnormal expressions of E-cadherin and CD44 resulting from the activation of Wnt signaling pathway could play an important role on the process of invasion and metastasis of OSCC originating from OSF.
5.To expand the resection border of adjacent tissues and successive vertical resection of tongue-the floor of mouth-neck could obtain a satisfying treatment effect.It can be used as a recommend surgical method of OSCC originating from OSF.
Wnt途径是一类在生物体进化过程中高度保守的信号转导途径,调节控制着众多生命活动过程,对细胞增殖和分化具有重要调节作用,与肿瘤的发生发展也有密切的关系,最近几年针对Wnt途径与肿瘤侵袭和转移关系的研究开始引起关注,却未见Wnt途径在OSF癌变鳞癌中的研究。
目的:本文旨在对OSF癌变鳞癌生物学行为进行临床与机制研究。通过已被确诊的OSF癌变鳞癌临床病例,对OSF癌变鳞癌病例与非OSF癌变鳞癌病例的临床特点与生物学行为进行对比研究,以补充与完善关于OSF癌变生物学行为方面的临床研究;采用免疫组化SP法以及荧光实时定量RT-PCR法对Wnt途径的几个关键分子在OSF癌变鳞癌等组织中的表达进行检测,观察其在mRNA水平及蛋白表达水平的改变,从而探讨Wnt信号途径在OSF癌变鳞癌侵袭转移机制中可能发挥的作用;通过比较不同手术方式治疗OSF癌变鳞癌病例后对其复发转移率控制的优劣,提出手术治疗OSF癌变鳞癌的推荐术式,以提高OSF癌变鳞癌患者的生存时间及生活质量。
材料与方法:对2002年1月～2008年12月在中南大学湘雅医院口腔颌面外科病房经手术治疗的口腔黏膜鳞癌患者进行回顾性分析,将其病例分为OSF癌变鳞癌组及非OSF癌变鳞癌组。对其病例分布、发病部位、临床特征、淋巴结转移及复发等进行统计比较分析;采用免疫组化SP法对52例OSF癌变鳞癌与48例非OSF癌变鳞癌组织及其癌旁组织的石蜡包埋切片进行染色,检测组织中β-catenin、Wnt2、E-cadherin、TCF-4以及CD44v6的蛋白表达水平的改变;采用实时荧光定量RT-PCR方法检测OSF癌变鳞癌组织与非OSF癌变鳞癌组织及各自癌旁组织中β-catenin、E-cadherin及TCF-4的mRNA水平的变化;收集45例OSF癌变鳞癌患者,对其中25例采用原发灶扩大癌旁组织、与颈部淋巴组织连续垂直切除、个体化皮瓣修复的手术方法并与传统手术方法进行临床疗效观察比较研究,将其研究结果供临床应用。所得结果通过统计学软件SPSS13.0进行统计学分析。
结果:一.OSF癌变鳞癌组复发转移率(43.12%)高于非OSF癌变鳞癌(30.77%),预后较差;组间差异有统计学意义,P＜0.05。
二.β-catenin的易位表达
1.正常口腔粘膜组织中,β-catenin的表达为细胞膜阳性(强染色率93.33%);
2.OSF癌变鳞癌组织呈现β-catenin胞膜染色减少乃至消失(强染色率7.69%),非OSF癌变鳞癌组织亦存在β-catenin胞膜染色减少(强染色率20%),二者差异无统计学意义(P＞0.05);OSF癌变鳞癌组织β-catenin胞浆内积聚率达61.5%,非OSF癌变鳞癌组织则达57.8%,二者差异无统计学意义(P＞0.05);OSF癌变鳞癌组织β-catenin核易位率达59.6%,非OSF癌变鳞癌组织则未发现β-catenin的核易位现象;
3.OSF癌变鳞癌癌旁组织与非OSF癌变鳞癌癌旁组织比较,β-catenin包膜强染色率差别有统计学意义(分别为57.7%,86.7%,P＜0.01);
4.荧光实时定量RT-PCR结果:OSF癌变鳞癌组织(1.10)与非OSF癌变鳞癌组织(1.70)之间β-catenin mRNA表达量差异无统计学意义(P＞0.05);OSF癌变鳞癌癌旁组织(0.87)与非OSF癌变鳞癌癌旁组织(0.85)之间β-catenin mRNA表达量差异无统计学意义(P＞0.05)。
三.Wnt2的异常表达
1.正常口腔粘膜组织中,Wnt2表达为阴性;
2.OSF癌变鳞癌组织可见Wnt2的高表达(染色率达78.84%)与非OSF癌变鳞癌组织的44%相比,差异有统计学意义(P＜0.01);OSF癌变鳞癌癌旁组织Wnt2染色率为34.62%,而非OSF癌变鳞癌癌旁组织无Wnt2染色;
3.Wnt2的表达与β-catenin膜染色呈负相关(r=-0.956,P=0.011),与β-catenin胞浆积聚呈正相关。
四.E-cadherin的表达
1.正常口腔粘膜组织中,E-cadherin的表达为细胞膜阳性,强染色率达93.33%;
2.OSF癌变鳞癌组织中E-cadherin膜表达明显减少,强染色率3.85%;非OSF癌变鳞癌组织中E-cadherin强染色率53.33%,二者差异有统计学意义(P＜0.01);OSF癌变鳞癌癌旁组织中E-cadherin强染色率57.69%,非OSF癌变鳞癌癌旁组织E-cadherin强染色率64.44%,二者差异无统计学意义(P＞0.05);
3.膜E-cadherin与β-catenin的膜表达呈正相关(r=0.962,P=0.038),Wnt2与膜E-cadherin的减少或消失存在负相关(r=-0.919,P=0.027),β-catenin的易位与膜E-cadherin的减少具有伴随关系。
4.荧光实时定量RT-PCR结果:OSF癌变鳞癌组、OSF癌变鳞癌癌旁组、非OSF癌变鳞癌组、非OSF癌变鳞癌癌旁组等4组中E-cadherinmRNA表达水平均低于正常黏膜组,差别有统计学意义(P＜0.01),但4组间差别无统计学意义(P＞0.05)。
五.TCF-4及CD44_v6的表达
1.正常口腔粘膜中,TCF-4的表达表现为细胞核弱阳性(20%);CD44_v6的表达表现为细胞膜阳性(40%);
2.TCF-4在OSF癌变鳞癌组织染色率69.23%,在非OSF癌变鳞癌组织48.89%,二者差异有统计学意义(P＜0.05);TCF-4在OSF癌变鳞癌癌旁组织染色率50%,在非OSF癌变鳞癌癌旁组织22.22%,二者差异有统计学意义(P＜0.05);
3.CD44_v6在OSF癌变鳞癌组织染色率40%,在非OSF癌变鳞癌组织82.7%,二者差异有统计学意义(P＜0.01);CD44_v6在OSF癌变鳞癌癌旁组织染色率57.7%,在非OSF癌变鳞癌癌旁组织48.89%,二者差异无统计学意义(P＞0.05);
4.CD44_v6的表达与TCF-4呈正相关(r=0.949,P=0.014)。
5.荧光实时定量RT-PCR结果:OSF癌变鳞癌TCF-4 mRNA表达量较其它4组高,差别有统计学意义(P＜0.01),其它各组间差别无统计学意义(P＞0.05)。
六.采用扩大癌旁组织切除、原发灶与颈部淋巴组织连续垂直切除、个体化皮瓣修复等与传统治疗手段相比,可以明显减少OSF癌变鳞癌的复发转移率(分别为12%与40%);
结论:一.OSF癌变鳞癌临床上表现为更具侵袭性和转移性的生物学行为;
二.Wnt途径在OSF癌变鳞癌中处于异常活化状态;
三.OSF癌变鳞癌中Wnt2的表达上调导致β-catenin在胞浆/胞核的积聚,促使Wnt/β-catenin途径的活化,该途径的活化在OSF癌变鳞癌形成和肿瘤播散上具有重要作用;
四.Wnt途径的活化导致细胞黏附分子E-cadherin与CD44v6表达的改变,进而促进OSF癌变鳞癌的侵袭与转移;
五.扩大原发灶切除边界以及原发灶-颈部连续垂直切除可获得较为满意的治疗效果,可作为手术治疗OSF癌变鳞癌的推荐术式。
Oral submucous fibrosis(OSF) is a kind of chronic,invisible,and betel nut chewing-related oral mucosal diseases,which can turn into oral squamous cell carcinoma(OSCC).It was observed clinically that the local recurrence rate and neck lymph node metastasis rate of such patients,with poor prognosis,are higher than those of OSCC non-originating from OSF.It indicates that there may be different biological behavior between OSCC originating from OSF and the other ones.However,there is little clinical and basic research regarding the biological behavior of OSCC originating from OSF.
Wnt pathway is a class of highly conserved signal transduction pathway in the evolution of organism.It controls numerous processes of life activities,regulates cell proliferation and differentiation,and relates to occurrence and development of tumor.In recent years,the study on the relationship between Wnt pathway and cancer invasion and metastasis has been paid close attention to.But there is no study on Wnt pathway in OSCC originating from OSF.
Objective:The purpose of this paper is to research the clinical feature and mechanisms on the biological behavior of OSCC originating from OSF.Using the existing clinical data,a comparative study about the clinical characteristics and biological behavior between OSCC originating from OSF and the other ones was made,so as to supplement and perfect the clinical research about the biological behavior of OSCC originating from OSF.The expressions of some key molecules of Wnt pathway in the tissues of OSCC originating from OSF were detected by immunohistochemistry SP method and Real-Time PCR,the expression changes of these molecules at mRNA level and protein level were observed,and then the possible role of Wnt signaling pathway in the mechanism of invasion and metastasis of OSCC originating from OSF was investigated.After the advantages and disadvantages on controlling the rate of recurrence and metastasis by different surgical methods were compared,the recommend surgery of OSCC originating from OSF was put forward,and the significance of mechanism research about the biological behavior of OSCC originating from OSF was validated clinically.
Materials & Methods:The patients with OSCC after surgical treatment (Jan 2002～Dec 2008) in the Department of Oral and Maxillofacial Surgery,Xiangya Hospital,Central South University were studied.The clinical data of these patients were analyzed retrospectively.They were divided into the group of OSCC originating from OSF and the group of OSCC non-originating from OSF.Their case distribution,site,clinical characteristics,lymphatic metastasis and recurrence were compared and analyzed.The expressions ofβ-catenin,Wnt2,E-cadherin,TCF-4 and CD44v6 were detected in the carcinoma and adjacent tissues of 52 OSCCs originating from OSF and 48 OSCCs non-originating from OSF by immunohistochemistry SP method,respectively.Then the expressions ofβ-catenin mRNA,E-cadherin mRNA and TCF-4 mRNA in these tissues were detected by Real-Time PCR,respectively.45 cases of OSCC originating from OSF were selected.25 of these cases were treated by the methods including resection of expanding adjacent tissues, successive and vertical removal of primary tumor and neck lymphoid tissue,restoration of individual flap and so on.The clinical efficacy of these methods were compared with traditional surgical methods.The results were analyzed by statistical software SPSS 13.0.
Results:
1.The rates of recurrence and metastasis of OSCC originating from OSF(43.12%) are higher than those of OSCC non-originating from OSF (30.77%).The patients with OSCC originating from OSF have poor prognosis.
2.Translocation expression ofβ-catenin
1) In normal oral mucosa,the expression ofβ-catenin performs membrane positive(strong staining rate:93.33%).
2) In the tissues of OSCC originating from OSF,the expression ofβ-catenin performed reduce or even disappearance of membrane staining (strong staining rate:7.69%);in the tissues of OSCC non-originating from OSF,the phenomenon of reduced membrane staining also existed (strong staining rate:20%);no statistically significant difference was found between the two groups(P＞0.05).There was no statistically significant difference about intracytoplasmic accumulation ofβ-catenin between OSCC originating from OSF group(61.5%) and OSCC non-originating from OSF(57.8%)(P＞0.05).The rate of nuclear translocation ofβ-catenin in OSCC originating from OSF was 59.6%, but the phenomenon of nuclear translocation ofβ-catenin in OSCC non-originating from OSF was not found.
3) The strong membrane staining rate ofβ-catenin in adjacent tissues of OSCC originating from OSF(57.7%) was lower than that in OSCC non-originating from OSF(86.7%)(P＜0.01).
4) The result of Real-Time PCR showed that there was no significant difference about the expression ofβ-catenin mRNA between OSCC originating from OSF(1.10) and OSCC non-originating from OSF(1.70)(P＞0.05);in the same way,no significant difference was found about the expression ofβ-catenin mRNA in adjacent tissues between OSCC originating from OSF(0.87) and OSCC non-originating from OSF(0.85)(P＞0.05).
3.Abnormal expression of Wnt2
1) In normal oral mucosa,Wnt2 expressed as negative.
2) The positive staining rate of Wnt2 in the tissues of OSCC originating from OSF(78.84%) was higher than that in OSCC non-originating from OSF(44%)(P＜0.01).The positive staining rate of Wnt2 in adjacent tissues of OSCC originating from OSF was 34.62%, but the staining rate of Wnt2 in adjacent tissues of OSCC non-originating from OSF was negative.
3) There was a negative correlation between Wnt2 expression andβ-catenin membrane staining(r=-0.956,P=0.011).There was a positive correlation between Wnt2 expression and cytoplasmic accumulation ofβ-catenin.It Showed that the translocation ofβ-catenin related to the initiation of Wnt pathway.
4.Expression of E-cadherin
1) In normal oral mucosa,the expression of E-cadherin registered as membrane positive,and the strong staining rate was 93.33%.
2) The strong staining rate of E-cadherin in OSCC originating from OSF(3.85%) was significantly lower than that in OSCC non-originating from OSF(53.33%)(P＜0.01).No significant difference about the strong staining rate of E-cadherin was found in the adjacent tissues between OSCC originating from OSF(57.69%) and OSCC non-originating from OSF(64.44%)(P＞0.05).
3) There was a positive correlation between membrane E-cadherin and membrane expression ofβ-catenin(r=0.962,P=0.038).There was a negative correlation between Wnt2 and reduce or disappearance of E-cadherin(r=-0.919,P=0.027).The translocation ofβ-catenin accompanied by reduce of membrane E-cadherin.
4) The result of Real-Time PCR showed that the expression levels of E-cadherin mRNA in the 4 groups such as Group OSCC originating from OSF were significantly lower than that in normal group(P＜0.01); there was no significant difference about the expression levels of E-cadherin mRNA among the other groups(P＞0.05).
5.Expression of TCF-4 and CD44v6
1) In normal oral mucosa,the expression of TCF-4 was nucleus weakly positive,and the expression of CD44v6 performed membrane positive.
2) The positive rate of TCF-4 in Group OSCC originating from OSF(69.23%) was significantly higher than that in Group OSCC non-originating from OSF(48.89%)(P＜0.05).The staining rate of TCF-4 in the adjacent tissues of OSCC originating(50%) from OSF was significantly higher than that of OSCC non-originating from OSF (22.22%)(P＜0.05).
3) The positive rate of CD44v6 in Group OSCC originating from OSF(40%) was significantly lower than that in Group OSCC non-originating from OSF(82.7%)(P＜0.01).However,the staining rate of CD44v6 in the adjacent tissues showed no significant difference between OSCC originating from OSF(57.7%) and OSCC non-originating from OSF(48.89%)(P＞0.05).
4) There was a positive correlation between the expression of CD44v6 and TCF-4(r=0.949,P=0.014).
5) The result of Real-Time PCR showed that the expression of TCF-4 mRNA in Group OSCC non-originating from OSF was significantly higher than that in the other 4 groups(P＜0.01);the differences among the other groups were not statistically significant(P＞0.05).
6.Compared with using traditional treatment means(40%),using the new methods(12%),including resection of expanding adjacent tissues,vertical removal of primary tumor and neck lymphoid tissue, restoration of individual flap and so on,the rates of recurrence and metastasis of OSCC originating from OSF could be reduced significantly.
Conclusions:
1.Clinically,OSCC originating from OSF has a more invasive and metastatic biological behavior.
2.In OSCC originating from OSF,Wnt pathway is in the abnormal activation status.
3.Upregulation of Wnt2 in OSCC originating from OSF causes the accumulation ofβ-catenin in the cytoplasm/nucleus,prompts Wnt/β-catenin pathway to activate.This pathway plays a key role in carcinogenesis of OSF and dissemination of cancer.
4.The abnormal expressions of E-cadherin and CD44 resulting from the activation of Wnt signaling pathway could play an important role on the process of invasion and metastasis of OSCC originating from OSF.
5.To expand the resection border of adjacent tissues and successive vertical resection of tongue-the floor of mouth-neck could obtain a satisfying treatment effect.It can be used as a recommend surgical method of OSCC originating from OSF.
引文
[1]Tilakaratne WM,Klinikowski MF,Saku T,et al.Oral submucous fibrosis:review on aetiology and pathogenesis.Oral Oncol,2006,42(6):561-568
[2]Paymaster JC.Cancer of the buccal mucosa:a clinical study of cases in India patients.Cancer,1956,9:431-435
[3]Pindborg JJ,Mufti PR,Bhonsle RB,et al.Oral submucous fibrosis as a precancerous condition.Scand J Dent Res,1984,92(3):224-229
[4]Murti PR,Bhonsle RB,Pindborg JJ,et al.Malignant transformation rates in oral submucous fibrosis over a 17 year periodJ.Community Dent Oral Epidemiol,1985(4),13:340-341
[5]翦新春,沈子华,刘蜀凡.口腔黏膜下纤维性变(附二例报告).临床口腔医学杂志,1985,1(1):12-13
[6]翦新春,彭解英,唐瞻贵.口腔黏膜下纤维性变癌变(附3例报告).华西口腔医学杂志,2000,18(2):130-131
[7]高义军,凌天牖,尹晓敏,等.口腔黏膜下纤维性变癌变的回顾性研究.临床口腔医学杂志,2005,21(2):119-120
[8]Pingborg JJ.Oral submucous fibrosis:a review.Ann Acad Med Singapore,1989,18(5):603-607
[9]Tang JG,Jian XF,Gao ML,et al.Epidemiological survey of oral submucous fibrosis in Xiangtan City,Hunan Province,China.Community Dent Oral Epidemiol,1997,25(2):177-180
[10]Shah N,Sharma PP.Role of chewing and smoking habits in the etiology of oral submucous fibrosis(OSF):a case-control study.J Oral Pathol Med,1998,27(10):475-479
[11]Zhou S,Guo F,Li L,et al.Multiple logistic regression analysis of risk factors for carcinogenesis of oral submucous fibrosis in mainland China.Int J Oral Maxillofac Surg,2008,37(12):1094-1098
[12]Shieh DH,Chiang LC,Shieh TY.Augmented mRNA expression of tissue inhibitor of metalloproteinase-1 in buccal mucosal fibroblasts by arecoline and safrole as a possible pathogenesis for oral submucous fibrosis.Oral Oncol,2003,39(7):728-735
[13]胡延佳,翦新春,刘斌杰,等.两种基因芯片数据分析软件在口腔黏膜下纤维化差异表达基因分析中的应用.中华口腔医学杂志,2008,43(3):168-171
[14]李宁,翦新春.软骨寡聚基质蛋白、趋化因子-9和细胞角蛋白19在口腔黏膜下纤维化中的表达.中华口腔医学杂志,2008,43(9):551-555
[15]Li N,Jian X,Hu Y,et al.Discovery of novel biomarkers in oral submucous fibosis by microarray analysis.Cancer Epidemiol Biomarkers Prev,2008,17(9):2249-2259
[16]Bienz M,Clevers H.Linking colorectal cancer to Wnt signaling.Cell,2000,103:311-320
[17]Verras M,Sun Z.Roles and regulation of Wnt signaling and beta 2 catenin in prostate cancer.Cancer Lett,2006,237(1):22-32
[18]Barth AI,Nathke IS,Nelson WJ.Cadherins,catenins and APC protein:interplay between cytoskeletal complexes and signaling pathways.Curr Opin Cell Biol,1997,9(5):683-690
[19]Ramesh S,Nash J,Mcculloch PG.Reduction in membranous expression of beta-catenin and increased cytoplasmic E-cadherin expression predict poor survival in gastric cancer.Br J Cancer,1999,81(8):1392-1397
[20]Ebert MP,Fei G,Kahmann S,et al.Increased beta-catenin mRNA levels and mutational alterations of the APC and beta-catenin gene are present in intestinal-type gastric cancer.Carcinogenesis,2002,23(1):87-91
[21]Ebert MP,Yu J,Hoffmann J,et al.Loss of beta-catenin expression in metastatic gastric cancer.J Clin Oncol,2003,21(9):1708-1714
[22]van Noort M,Clevers H.TCF transcription factors,mediators of Wnt-signaling in development and cancer.Dev Biol,2002,244(1):1-8
[23]Lustig B,Behrens J.The Wnt signaling pathway and its role in tumor development.J Cancer Res Clin Oncol,2003,129(4):199-221
[24]van de Wetering M,Cavallo R,DooijesD,et al.Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gened dTCF.Cell,1997,88(6):789-799
[25]Wielenga V J,Smits R,Korinek,et al.Expression of CD44 in Apc and Tcf mutant mice implies regulation by the WNT pathway.Am J Pathol,1999,154(2):515-523
[26]Ougolkov AV,Yamashita K,Mai M,et al.Oncogenic beta-catenin and MMP-7(matrilysin) cosegregate in late-stage clinical colon cancer.Gastroenterology,2002,122(1):60-71
[27]Herzig M,Savarese F,Novatchkova M,et al.Tumor progression induced by the loss of E-cadhedn independent of beta-catenin/ Tcf-mediated Wnt signaling.Oncogene,2007,26(16):2290-2298
[28]Maier TJ,Janssen A,Schmidt R,et al.Targeting the beta-catenin/APC pathway:a novel mechanism to explain the cyclooxygenase-2-independent anticarcinogenic effects of celecoxib in human colon carcinoma cells.FASEB J,2005,19(10):1353-1355
[29]Lim SC,Lee MS.Significance of E-cadherin/oeta-catenin complex and cyclinD 1 in breast cancer.Oncol Rep,2002,9(5):915-928
[30]Cheng XX,Wang ZC,Chen XY,et al.Correlation of wnt-2 expression and beta-catenin intracellular accumulation in chinese gastric cancers:relevance with tumor dissemination.Cancer Lett,2005,223:339-347
[31]Fujioka T,Takebayashi Y,Kihana T,et al.Expression of E-cadherin and beta-catenin in primary and peritoneal metastatic ovarian carcinoma.Oncol Rep,2001,8(2):249-255
[32]Tanaka N,Odajima T,Ogi K,et al.Expression of cadherins and catenins in oral epithelial dysplasia and squamous cell carcinoma.Brit J Cancer,2003,89:557-563
[33]翦新春,周晌辉,马文涛,等.口腔黏膜下纤维性变癌变病例体征的分析研究.华西口腔医学杂志,2005,(增刊):145-148
[34]Shiu MN,Chen TH,Chang SH,et al.Risk factors for leukoplakia and malignant transformation to oral carcinoma:a leukoplakia cohort in Taiwan.Br J Cancer.2000,82(11):1871-1874
[35]Llewellyn CD,Johnson NW,Warnakulasuriya KA.Risk factors for squamous cell carcinoma of the oral cavity in young people--a comprehensive literature review.Oral Oneol,2001,37(5;):401-418
[36]Gupta PC.Mouth cancer in India:a new epidemic?.J Indian Med Assoe,1999,97(9):370-3
[37]Byers RM.Squamous cell carcinoma of the oral tongue in patients less than thirty years of age.Am J Surg,1.975,130(4):475-478
[38]Rosenquist K.Risk factors in oral and oropharyngeal squarnous cell carcinoma:a population-based case-control study in southern Sweden.Swed Dent J Suppl,2005,179:1-66
[39]Dumper J,Kerr P.Recurrent squamous cell carcinoma of the tongue in pregnancy.J Otolaryngol,2005,34(4):242-243
[40]Tsukuda M,Ooishi K,Moehimatsu I,et al.Head and neck carcinomas in patients under the age of forty 3,ears.Jpn J Cancer Res,1993,84(7):748-752
[41]Llewellyn CD,Linklater K,Bell J,et al.Squamous cell carcinoma of the oral cavity in patients aged 45 years and under:a descriptive analysis of 116 eases diagnosed in the South East of England from 1990 to 1997.Oral Oncol,2003,39(2):106-114
[42]Livak K J,Sehmittgen YD.A:aalysis of relative gene expression data using real-time quantitative PCR and the 2~(-ΔΔCt) method.Methods,2001,25(4):402-408
[43]Rijsewijk F,Sehuermann M,Wagenear E,et al.The drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless.Cell.1987,50(40):649-657
[44]Sharpe C,Lawrence N,Martinez Arias.Wnt signaling:a theme with nuclear variations.Bioessays.2001,23(4):311-318
[45]Kimelman D and Xu W.W.eta-catenin destruction complex:insights and questions from a structural per:;peetive.Oneogene,2006,25(57):7482-7491
[46]Henderson BR,Fagotto E The ins and outs of APC and beta-catenin nuclear transport. EMBO Rep. 2002,3(9):834-839
[47] Huber O, Bierkamp C, Kemler R. Cadherins and catenins in development. Curr Opin Cell Biol.1996,8(5):685-691
[48] Muller T, Choidas A, Reichmann E, et al. Phosphorylation and free pool of beta-catenin are regulated by tyrosine kinase and tyrosine phosphatases during epithelial cell migration. J Biol Chem. 1999,274(15):10173-10183
[49] Rubinfeld B, Robbins P, E1-Gamil M, et al. Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science,1997;275(5307):1790-1792
[50] Morin PJ, Sparks AB, Korinek V, et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science, 1997,275(5307): 1787-1790
[51] Clements WM, Wang J, Sarnaik A, et al. Beta-catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Cancer Res,2002,62(12):3503-3506
[52] Behrens J, von Kries JP, Kuhl M, et al. Functional interaction of beta-catenin with the transcription factor LEF-1. Nature, 1996, 382 (6592):638-642
[53] Molenar M, van de Wetering M, Osterwegel M, et al. XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos.Cell,1996,86(3):391-399
[54] Brabletz T, Jung A, Dag S, et al. Beta-catenin regulates the expression of the matrix metalloproteinase-7 in human colorectal cancer. Am J Pathol,1999, 155:1033-1038
[55] He TC, Sparks AB, Rago C, et al. Identification of c-MYC as a target of the APC pathway. Science,1998,281:1509-1512
[56] Zhang X, Gaspard JP, Chung DC. Regulation of vascular endothelial growth factor by the wnt and K-ras pathways in colonic neoplasia. Cancer Res,2001,61-.6050-6054
[57] Tetsu O, McCormick F. Beta-catenin regulates expression of cyclinDl in colon carcinoma cells. Nature,1999,398:422-426
[58] Zhang T, Otevrel T, Gao Z, et al. Evidence that APC regulates surviving expression: A possible mechanism contributing to the stem cell origin of colon cancer. Cancer Res,2001,61:8664-8667
[59] Boussioutas A, Li H, Liu J, et al. Distinctive patterns of gene expression in premalignant gastric mucosa and gastric cancer. Cancer Res,2003,63 (10):2569-2577
[60] Tanaka M, Kitajima Y, Edakurd G, et al. Abnormal expression of E-cadherin and beta-catenin may be a molecular marker of submucosal invasion and lymph node metastasis in early gastric cancer. Br J Surg, 2002,89(2):236-244
[61] Miller JR. The Wnts. Genome Biol, 2002,3(1):3001-3015
[62] Koppert LB, van der Velden AW, van de Wetering, et al. Frequent loss of the AXIN1 locus but absence of AXIN1 gene mutations in adenocarcinomas of the gastro-oesophageal junction with nuclear beta-catenin expression. Br J Cancer,2004,90(4):892-899
[63] Shimizu M, Suzui M, Moriwaki H, et al. No involvement of beta-catenin gene mutation in gastric carcinomas induced by N-methyl-N-nitrosourea in male F344 rats. Cancer Lett,2003,195(2):147-152
[64] Ozawa M ,Baribault H,Kemler R .The cytoplasmic domain of the cell adhesion molecule uvomorulin associates with three independent proteins structurally related indifferent species. EMBO J, 1989, 8(6):1711 - 1717
[65] Nathke IS, Hinck L, Swedlow JR, et al. Defining interactions and distributions of cadherin and catenin complexes in polarized epithelial cells. J Cell Biol, 1994 ,125(6):1341-1352
[66] Conacci-Sorrell M, Zhurinsky J, Ben-Z(?)ev A. The cadherin-catenin adhesion system in signaling and cancer. J Clin Invest, 2002,109 (8):987-991
[67] Mareel M, Leroy A. Clinical, cellular, and molecular aspects of cancer invasion. Physiol Rev,2003,83(2):337-376
[68] Gumbier BM. Cell adherin: The molecular basis of tissue architecture and morphogenesis. Cell, 1996,84(3):345-357
[69] Cox RT, Kirkpatrick C, Peifer M. Armadillo is required for adherens junction assembly, cell polarity, and morphogenesis during Drosophila embryogenesis. J Cell Biol,1996,134(l):133-148
[70] Graff JR., Herman JG, Lapidus RG, et al. E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas. Cancer Res. 1995,55(22):5195-5199
[71] Schipper JH, Unger A, Jahnke K. E-cadherin as a functional marker of the differentiation and invasiveness of squamous cell carcinoma of the head and neck. Clin Otolaryngol Allied Sci. 1994,19(5):381-384
[72] Batlle E, Sancho E, Franci C, et al. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumor cells. Nat Cell Biol,2000,2(2):84-89
[73] Hajra KM, Chen DY, Fearon ER. The slug zinc-finger protein represses E-cadherin in breast cancer. Cancer Res, 2002,62(6): 1613-1618
[74] Mei JM, Borchert GL, Donald SP, et al. Matrix metalloproteinase mediates NO-induced dissociation of P-catenin from membrane bound E-cadherin and formation of nuclear P-catenin/LEF-1 complex. Carcinogenesis, 2002,23(12):2119-2122
[75] Fagotto F, Funayama N, Gluck U, et al. Binding to cadherins antagonizes the signaling activity of beta-catenin during axis formation in Xenopus. J Cell Biol,1996,132(6):1105-1114
[76] Conacci-Sorrell M, Simcha I,Ben-Yedidia T,et al.Autoregulation of E-cadherin expression by cadherin-cadherin interaction: the roles of beta-catenin signaling, Slug and MAPK.J Cell Biol,2003,163(4):847-857
[77] Naor D, Sionov RV, Ish-Shalom D. CD44: structure, function, and association with the malignant process. Adv Cancer Res,1997,71.241-319
[78] Bourguignon LY, Zhu D, Zhu H. CD44 isoform-cytoskeleton interaction in oncogenic signaling and tumor progression. Front Biosci, 1998, 3: 637 -649
[79] Ming SC. Cellular and molecular pathology of gastric carcinoma and precursor lesions: A critical review. Gastric Cancer, 1998,1:31-50
[80] Yamaguchi A, Goi T, Seki K, et al. Clinical significance of combined immunohistochemical detection of CD44v and sialyl LeX expression for colorectal cancer patients undergoing curative resection.Oncology,1998,55:400-403
[81]Liu YJ,Yan PS,Li J,et al.Expression and significance of CD44s,CD44v6,and nm23 mRNA in human cancer.World J Gastroenterol,2005,11:6601-6606
[82]Seiter S,Arch R,Reber S,et al.Prevention of tumor metastasis formation by anti-variant CD44.J Exp Med,1993,177(2):443-455
[83]Yasuda M,Tanaka Y,Fujii K,et al.CD44 stimulation down-regulates Fas expression and Fas-mediated apoptosis of lung cancer cells.Int Immunol,2001,13(10):1309-1319
[84]邱蔚六.口腔颌面外科理论与实践.北京:人民卫生出版社,1998.643-651
[85]Matsuura K,Hirokawa Y,Fujita M,.etal.Treatment result of stage Ⅰ and Ⅱ oral tongue cancer with interstitial brachytherapy:maximum tumor thickness is prognostic of nodal metastasis.Int J Radial Oncol Biol Phys,1998,40(3):535-539
[86]Rouviere H.Anatomy of the human lymphatic system(translation by Tobies MJ).Ann Arbor,MI:Edwards Brother,Inc,1938:250
[87]Blondeel PN,Morris SF,Hallock GG,et al.Perforator flaps:anatomy,technique,and clinical applications.St Louis,Missouri:Quality Medical Publishing,Inc,2006
[88]Allen RJ,Treece P.Deep interior epigastric artery perforator flap for breast reconstruction.Ann Plast Surg,1994,32:32-38
[89]Wei FC,Jain V,Celik N,et al.Have we found an ideal soft-tissue flap? an experience with 672 anterolateral thigh flaps.Plast Reconstr Surg,2002,109:2219-2226
[1]Cavallaro U and Christofori G.Cell adhesion in tumor invasion and metastasis:loss of the glue is not enough.Biochim Biophys Acta,2001,1552(1):39-44
[2]Perez-Moreno M,Jamora C,and Fuchs E.Sticky business:orchestrating cellular signals at adherens junctions.Cell,2003,112(4):535-548
[3]Wijnhoven BP,Dinjens WN,and Pignatelli M.E-cadherin-catenin cell-cell complex and human cancer. Br J Surg, 2000, 87(8):992- 1005
[4] Wong AS and Gumbiner BM. Adhesion-independent mechanism for suppression of tumor cell invasion by E-cadherin. J Cell Biol, 2003,161 (6): 1191-1203
[5] Kowalczyk AP and Reynolds AB. Protecting your tail: regulation of cadherin degradation by p120-catenin. Curr Opin Cell Biol,2004, 16(5):522-527
[6] Frixen UH,Behrens J,Sachs M,et al. E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cell.J Cell Biol,1991,113(1):173- 185
[7] De Leeuw WJ,Berx G,Vos CB,et al.Simultaneous loss of E-cadherin and catenin on invasive lobular breast cancer and lobular carcinoma in situ.J Pathol,1997,183(4):404-411
[8] Reynolds AB and Carnahan RH. Regulation of cadherin stability and turnover by p120~(ctn):implications in disease and cancer.Semin Cell Dev Biol, 2004,15(6):657-663
[9] Reynolds AB. p120-catenin:Past and present.Biochim Bilphys Acta,2007, 1773(1):2-7
[10] van Hengel J and van Roy F.Diverse functions of pl20~(ctn) in tumors.Biochim Biophs Acta,2007,1773(1):78-38
[11] Rask K, Nilsson A, Brannstrom M,et al. Wnt-signalling pathway in ovarian epithelial tumors: increased expression of beta-catenin and GSK3 beta. Br J Cancer,2003,89(7):1298-304
[12] Lu Z and Hunter T. Wnt-independent beta-catenin transactivation in tumor development. Cell Cycle,2004,3(5):571-573
[13] Barker N and Clevers H. Catenins, Wnt signaling and cancer. Bioessays, 2000,22(11):961-965
[14] Ozawa M ,Baribault H ,Kemler R .The cytoplasmic domain of the cell adhesion molecule uvomorulin associates with three independent proteins structurally related indifferent species. EMBO J, 1989, 8(6):1711 - 1717
[15] Joo M,Lee HK,Kang YK.Expression of E-cadherin, beta-catenin, CD44s and CD44v6 in gastric adenocarcinoma: relationship with lymph node metastasis[J]. AnticancerRes , 2003, 23(2): 1581-1588
[16] Polakis P. Wnt signaling and cancer. Genes Dev, 2000, 14(15): 1837-1851
[17] Peifer M, Polakis P. Wnt signaling in oncogenesis and embryogenesis -a look outside the nucleus. Science, 2000, 287(3): 1606-1609
[18] Akiyama T and Kawasaki Y. Wnt signaling and the actin cytoskeleton. Oncogene,2006,25(57):7538-7544
[19] Luu HH, Zhang R, Haydon RC, et al. Wnt/beta-catenin signaling pathway as anovel cancer drug target. Curr Cancer Drug Targets, 2004,4(8): 653-671
[20] Kolligs FT , Bommer G, and Goke B . Wnt/beta-catenin/tcf signaling: a critical pathway in gastrointestinal tumorigenesis. Digestion, 2002, 66(3): 131 - 144
[21] Conacci-Sorrell M, Simcha I,Ben-Yedidia T,et al.Autoregulation of E-cadherin expression by cadherin-cadherin interaction: the roles of beta-catenin signaling, Slug and MAPK.J Cell Biol,2003,163(4):847-857
[22] Chan AO.E-cadherin in gastric cancer.World J Gastroenterol, 2006, 12(2):199-203
[23] Leung WK, Yu J, Ng EK, et al. Concurrent hypermethylation multiple tumor-related genes in gastric carcinoma and adjacent normal tissues. Cancer,2001,91(12):2294-2301
[24] Ombaerts M, Middeldorp JW, Van der Weide E, et al. Infiltrating leukocytes confound the detection of E-cadherin promoter methylation in tumors. Biochem Bilphys Res Commun, 2004,319(2):697-704
[25] Kimelman D and Xu W. Beta-catenin destruction complex: insights and questions from a structural perspective. Oncogene,2006,25(57): 7482-7491
[26] Moon HS, Choi EA, Park HY, et al. Expression and tyrosine phosphorylation of E-cadherin, beta- and gamma-catenin, and epidermal growth factor receptor in cervical cancer cells. Gynecol Oncol, 2001, 81(3):355-359
[27] Ackland ML, Newgreen DF, Fridman M, et al. Epidermal growth factor-induced epithelio-mesenchymal transition in human breast carcinoma cells. Lab Invest, 2003,83(3):435-448
[28] Yasmeen A, Bismar TA and Moustafa AE. ErbB receptors and epithelial-cadherin-catenin complex in human carcinomas. Future Oncol, 2006,2(6):765-781
[29] Lobo MV, Alonso FJ, Redondo C, et al. Cellular characterization of epidermal growth factor-expanded free-floating neurospheres .J Histochem Cytochem, 2003,51(1):89-103
[30] Li G, Schaider H, Satyamoorthy K,et al. Downregulation of E-cadherin and Desmogeinl by autocrine hepatocyte growth factor during melanoma development. Oncogene, 2001,20(56):8125-8135
[31] Muller T, Choidas A, Reichmarin E, et al. Phosphorylation and free pool of beta-catenin are regulated by tyrosine phosphatase during epithelial cell migration. J Biol Chem, 1999,274:10173-10183
[32] Aberle H, Schwartz H and Kemler R. Cadherin-catenin complex: protein interactions and their implications for cadherin function. J Cell Bilchem, 1996,61(4):514-523
[33] Royal I, Lamarche Vane N, Lamorte L, et al. Activation of Cdc42, Rac,PAK,and Rho-kinase in response to hepatocyte growth factor differentially regulates epithelial cell colony spreading and dissociation. Mol Biol Cell, 2000,11(5):1709-1725
[34] Evers EE, Zondag GC, Malliri A. et al. Rho family proteins in cell adhesion and cell migration. Eur J Cancer,2000,36(10): 1269-1274
[35] Lu Z, Ghosh S, Wang Z, et al. Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion. Cancer Cell,2003, 4(6):499-515
[36] Galbiati F, Volonte D, Browm AM, et al. Caveolin-1 expression inhibits Wnt/beta-catenin/Lef-1 signaling by recruiting beta-catenin to caveolae membrane domains. J Biol Chem,2000,275(30):23368-23377
[37] Harris TJ, Peifer M. Adherens junction-dependent and junction-independent steps in the establishment of epithelial cell polarity in Drosophila. J Cell Biol, 2004, 167(1):135-147
[38] Zhu B, Chappuis FS, Wong E, et al. Functional analysis of the structural basis of homophilic cadherin adhesion. Bilphys J, 2003, 84(6): 4033-4042
[39] Andersen H, Mejlvang J, Mahmood S, et al. Immediate and delayed effects of E-cadherin inhibition on gene regulation and cell motility in human epidermoid carcinoma cells. Mol Cell Biol, 2005, 25(20):9138-9150
[40] Slater M, Barden JA. Differentiating keratoacanthoma from squamous cell carcinoma by the use of apoptotic and cell adhesion markers. Histopathology, 2005, 47(2):170-178
[41] Ferreira P, Oliveira MJ, Beraldi E, et al. Loss of functional E-cadherin renders cells more resistant to the apoptotic agent taxol in vitro. Exp Cell Res, 2005, 310(1):99-104
[42] Margulis A, Zhang W, Alt-Holland A, et al. Loss of intercellular adhesion activates a transition from low- to high-grade human squamous cell carcinoma. Int J Cancer, 2006, 118(4):821-831
[43] Zhang G, Zhou X, Xue L, et al. Accumulation of cytoplasmic beta-catenin correlates with reduced expression of E-cadherin, but not with phosphorylated Akt in esophageal squamous cell carcinoma: immunohistochemical study. PatholInt, 2005, 55(6):310-317
[44] Marchenko GN, Marchenko ND, Leng J, et al. Promoter characterization of the novel human matrix metalloproteinase-26 gene: regulation by the T-cell factor-4 implies specific exprsssion of the gene in cancer cells of epithelial origin. BiochemJ, 2002, 363(2):253-262
[45] Cheng XX, Wang ZC, Chen XY, et al. Frequent loss of membranous N-cadherin in gastric cancers: A cross-talk with Wnt in determining the fate of beta-catenin. Clin Exp Metastasis, 2005, 22(1):85-93
[46] Pena C, Garcia JM, Silva, et al. E-cadherin and vitamin D receptor regulation by SNAIL and ZEB1 in colon cancer: clinicopathological correlations. Hum Mol Genet, 2005, 14(22):3361-3370
[47] Jiao W, Miyazaki K, Kitajima Y. Inverse correlation between E-cadherin and Snail expression in hepatocellular carcinoma cell lines in vitro and in vivo. Br J Cancer, 2002, 86(1):98-101
[48] Kim HS, Hong EK, Park SY, et al. Expression of beta-catenin and E-cadherin in the adenoma-carcinoma sequence of the stomach. Anticance Res, 2003, 23(3):2863-2868
[49] Spina D, Vindigni C, Presenti L. et al. Cell proliferation, cell death, E-cadherin, metalloproteinase expression and angiogenesis in gastric cancer precursors and early cancer of the intestinal type. Int J Oncol, 2001, 18(6):1251-1258
[50] Gabbert HE, Mueller W, Schneiders A, et al. Prognostic value of E-cadherin expression in 413 gastric carcinomas. Int J Cancer, 1996, 69(3):184-189
[51] Behrens J, Weidner KM, Frixen UH, et al. The role of E-cadherin and scatter factor in tumor invasion and cell motility. EXS, 1991, 59:109-126
[52] Chen Q, Lipkina G, Song Q, et al. Promoter methylation regulates cadherin in squamous cell carcinoma. Bilchem Biophys Res Commun , 2004,315 (4):850-856
[53] Kudo Y, Kitajima S, Ogawa I, et al. Invasion and metastasis of oral cancer cells require methylation of E-cadherin and/or degradation of membranous beat-catenin. Clin Cancer Res,2004,10(16):5455-5463
[54] Downer CS, Speight PM. E-cadherin expression in normal, hyperplastic and malignant oral epithelium. Eur J Cancer B Oral Oncol, 1993,29B(4): 303-305
[55] Morin PJ. Beta-catenin signaling and cancer. Bioessays, 1999, 21(12): 1021-1030
[56] Tanaka N, Odajima T, Ogi K, et al.Exprssion of E-cadherin, alpha-catenin, and beta-catenin in the process of lymph node metastasis in oral squamous cell carcinoma. Br J Cancer, 2003,89(3):557-563
[57] Chow V, Yuen AP, Lam KY, et al. A comparative study of the clinicopathological significance of E-cadherin and catenins (alpha,beta,gamma) expression in the surgical management of oral tongue carcinoma. J Cancer Res Clin Oncol, 2001,127(1):59-63
[58] Okamoto M, Nishimine M, Kishi M, et al. Prediction of delayed neck metastasis in patents with stage Ⅰ /Ⅱ squamous cell carcinoma of the tongue. J Oral Pathol Med,2002,31(4):227-233
[59] Brabletz T, Jung A, Reu S, et al. Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc Natl AcadSci USA, 2001, 98(18):10356-10361
[60] Novak A, Dedhar S. Signaling through beta-catenin and Lef/Tcf. Cell Mol Life Sci, 1999, 56:523-537
[61] Clevers H, van de Wetering M. TCF/LEF factors earn their wings. Trends Genent, 1997, 13:485-489
[62] Lustig B, Behrens J. The Wnt signaling pathway and its role in tumor development. J Cancer Res Clin Oncol, 2003, 129:199-221
[63] He TC, Sparks AB, Rago C, et al. Identification of c-MYC as a target of the APC pathway. Science, 1998, 281:1509-1512
[64] Shtutman M, Zhurinsky J, Simcha I, et al. The cyclin Dl gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci USA, 1999, 96(16):5522-5527
[65] Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin Dl in colon carcinoma cells. Nature, 1999, 398:422-426
[66] Zhang X, Gaspard JP, Chung DC. Regulation of vascular endothelial growth factor by the Wnt and K-ras pathways in colonic neoplasia. Cancer Res, 2001, 61:6050-6054
[67] Koh TJ, Bulitta CJ, Fleming JV, et al. Gastrin is a target of the beta-catenin/TCF-4 growth-singaling pathway inaa model of intestinal polyposis. J Xlin Invest, 2000, 106:533-539
[68] Watson SA, Smith AM. Hypergastrinemia promotes adenoma progression in the APC(Min-/+) mouse model of familial adenomatous polyposis. Cancer Res, 2001, 61:625-631
[69] Boon EM, van der Neut R, van de Wetering M, et al. Wnt signaling regulates expression of the receptor tyrosine kinase met in colorectal cancer. Cancer Res, 2002, 62:5126-5128
[70] Brabletz T, Jung A, Dag S,et al.Beta-catenin regulates the expression of the matrix metalloproteinase-7 in human colorectal cancer. Am J Pathol, 1999, 155:1033-1038
[71] Crawford HC, Fingleton BM, Rudolph-Owen LA, et al. The metalloproteinase matrilysin is a target of beta-catenin transactivation in intestinal tumors. Oncogene, 1999, 18:2883-2891
[72] Conacci-Sorrell ME, Ben-Yedidia T, Shtutman M, et al. Nr-CAM is a target gene of the beta-catenin/LEF-1 pathway in melanoma and colon cancer and its expression enhances motility and confers tumorigenesis. Genes Dev, 2002, 16:2058-2072
[73] Wielenga VJ, van der Neut R, Offerhaus GJ, et al. CD44 glycoproteins in colorectal cancer: expression, function,and prognostic value. Adv Cancer Res, 2000, 77:169-187
[74] Kolligs FT, Nieman MT, Winer I, et al. ITF-2, a downstream target of the Wnt/TCF pathway, is activated in human cancers with beta-catenin defects and promotes neoplastic transformation. Cancer Cell, 2002, 1:145-155
[75] Rockman SP, Currie SA, Ciavarella M, et al. Id2 is a target of the beta-catenin/T cell factor pathway in colon carcinoma. J Biol Chem, 2001, 276:45113-45119
[76] Zhang T, Otevrel T,Gao Z, et al. Evidence that APC regulates surviving expression: a possible mechanism contributing to the stem cell origin of colon cancer. Cancer Res, 2001, 61:8664-8667
[77] Weber GF, Ashkar S. Stress response genes: the genes that make cancer metastasize. J Mol Med, 2000, 78(8):404-408
[78] Ishikawa T, Ichikawa Y, Mitsuhashi M, et al. Matrilysin is associated with progression of colorectal tumor. Gincer Lett, 1996, 107 (1 ):5-10
[79] Hasegawa S, Koshikawa N, Momiyama N, et al. Matrilysin-specific antisense oligonucleotide inhibits liver metastasis of human colon cancer cells in a nude mouse model. Int J Cancer, 1998, 76(6):812-816
[80] Adachi Y, Yamamoto H, Itoh F, et al. Contribution of matrilysin (MMP-7) to the metastatic pathway of human colorectal cancers. Gut, 1999, 45(2):252-258
[81] Zeng ZS, Shu WP, Cohen AM, et al. Matrix metalloproteinase-7 expression in
colorectal cancer liver metastases: evidence for involvement of MMP-7
activation in human cancer metastases. Clin Cancer Res, 2002, 8(1): 144-148 [82] Mareel M, Leroy A. Clinical, cellular, and molecular aspects of cancer invasion.
PhysiolRev, 2003, 83(2):337-376 [83] Davidson B, Gotlieb WH, Ben-Baruch G, et al. E-cadherin complex protein
expression and survival in ovarian carcinoma. Gynecol Oncol,2000,79
(3):362-371 [84] Beavon IRG The E-cadherin-catenin complex in tumor metastasis: structure,
function and regulation. European Journal of Cancer, 2000,3 6:1607-1620
90
[2]Paymaster JC.Cancer of the buccal mucosa:a clinical study of cases in India patients.Cancer,1956,9:431-435
[3]Pindborg JJ,Mufti PR,Bhonsle RB,et al.Oral submucous fibrosis as a precancerous condition.Scand J Dent Res,1984,92(3):224-229
[4]Murti PR,Bhonsle RB,Pindborg JJ,et al.Malignant transformation rates in oral submucous fibrosis over a 17 year periodJ.Community Dent Oral Epidemiol,1985(4),13:340-341
[5]翦新春,沈子华,刘蜀凡.口腔黏膜下纤维性变(附二例报告).临床口腔医学杂志,1985,1(1):12-13
[6]翦新春,彭解英,唐瞻贵.口腔黏膜下纤维性变癌变(附3例报告).华西口腔医学杂志,2000,18(2):130-131
[7]高义军,凌天牖,尹晓敏,等.口腔黏膜下纤维性变癌变的回顾性研究.临床口腔医学杂志,2005,21(2):119-120
[8]Pingborg JJ.Oral submucous fibrosis:a review.Ann Acad Med Singapore,1989,18(5):603-607
[9]Tang JG,Jian XF,Gao ML,et al.Epidemiological survey of oral submucous fibrosis in Xiangtan City,Hunan Province,China.Community Dent Oral Epidemiol,1997,25(2):177-180
[10]Shah N,Sharma PP.Role of chewing and smoking habits in the etiology of oral submucous fibrosis(OSF):a case-control study.J Oral Pathol Med,1998,27(10):475-479
[11]Zhou S,Guo F,Li L,et al.Multiple logistic regression analysis of risk factors for carcinogenesis of oral submucous fibrosis in mainland China.Int J Oral Maxillofac Surg,2008,37(12):1094-1098
[12]Shieh DH,Chiang LC,Shieh TY.Augmented mRNA expression of tissue inhibitor of metalloproteinase-1 in buccal mucosal fibroblasts by arecoline and safrole as a possible pathogenesis for oral submucous fibrosis.Oral Oncol,2003,39(7):728-735
[13]胡延佳,翦新春,刘斌杰,等.两种基因芯片数据分析软件在口腔黏膜下纤维化差异表达基因分析中的应用.中华口腔医学杂志,2008,43(3):168-171
[14]李宁,翦新春.软骨寡聚基质蛋白、趋化因子-9和细胞角蛋白19在口腔黏膜下纤维化中的表达.中华口腔医学杂志,2008,43(9):551-555
[15]Li N,Jian X,Hu Y,et al.Discovery of novel biomarkers in oral submucous fibosis by microarray analysis.Cancer Epidemiol Biomarkers Prev,2008,17(9):2249-2259
[16]Bienz M,Clevers H.Linking colorectal cancer to Wnt signaling.Cell,2000,103:311-320
[17]Verras M,Sun Z.Roles and regulation of Wnt signaling and beta 2 catenin in prostate cancer.Cancer Lett,2006,237(1):22-32
[18]Barth AI,Nathke IS,Nelson WJ.Cadherins,catenins and APC protein:interplay between cytoskeletal complexes and signaling pathways.Curr Opin Cell Biol,1997,9(5):683-690
[19]Ramesh S,Nash J,Mcculloch PG.Reduction in membranous expression of beta-catenin and increased cytoplasmic E-cadherin expression predict poor survival in gastric cancer.Br J Cancer,1999,81(8):1392-1397
[20]Ebert MP,Fei G,Kahmann S,et al.Increased beta-catenin mRNA levels and mutational alterations of the APC and beta-catenin gene are present in intestinal-type gastric cancer.Carcinogenesis,2002,23(1):87-91
[21]Ebert MP,Yu J,Hoffmann J,et al.Loss of beta-catenin expression in metastatic gastric cancer.J Clin Oncol,2003,21(9):1708-1714
[22]van Noort M,Clevers H.TCF transcription factors,mediators of Wnt-signaling in development and cancer.Dev Biol,2002,244(1):1-8
[23]Lustig B,Behrens J.The Wnt signaling pathway and its role in tumor development.J Cancer Res Clin Oncol,2003,129(4):199-221
[24]van de Wetering M,Cavallo R,DooijesD,et al.Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gened dTCF.Cell,1997,88(6):789-799
[25]Wielenga V J,Smits R,Korinek,et al.Expression of CD44 in Apc and Tcf mutant mice implies regulation by the WNT pathway.Am J Pathol,1999,154(2):515-523
[26]Ougolkov AV,Yamashita K,Mai M,et al.Oncogenic beta-catenin and MMP-7(matrilysin) cosegregate in late-stage clinical colon cancer.Gastroenterology,2002,122(1):60-71
[27]Herzig M,Savarese F,Novatchkova M,et al.Tumor progression induced by the loss of E-cadhedn independent of beta-catenin/ Tcf-mediated Wnt signaling.Oncogene,2007,26(16):2290-2298
[28]Maier TJ,Janssen A,Schmidt R,et al.Targeting the beta-catenin/APC pathway:a novel mechanism to explain the cyclooxygenase-2-independent anticarcinogenic effects of celecoxib in human colon carcinoma cells.FASEB J,2005,19(10):1353-1355
[29]Lim SC,Lee MS.Significance of E-cadherin/oeta-catenin complex and cyclinD 1 in breast cancer.Oncol Rep,2002,9(5):915-928
[30]Cheng XX,Wang ZC,Chen XY,et al.Correlation of wnt-2 expression and beta-catenin intracellular accumulation in chinese gastric cancers:relevance with tumor dissemination.Cancer Lett,2005,223:339-347
[31]Fujioka T,Takebayashi Y,Kihana T,et al.Expression of E-cadherin and beta-catenin in primary and peritoneal metastatic ovarian carcinoma.Oncol Rep,2001,8(2):249-255
[32]Tanaka N,Odajima T,Ogi K,et al.Expression of cadherins and catenins in oral epithelial dysplasia and squamous cell carcinoma.Brit J Cancer,2003,89:557-563
[33]翦新春,周晌辉,马文涛,等.口腔黏膜下纤维性变癌变病例体征的分析研究.华西口腔医学杂志,2005,(增刊):145-148
[34]Shiu MN,Chen TH,Chang SH,et al.Risk factors for leukoplakia and malignant transformation to oral carcinoma:a leukoplakia cohort in Taiwan.Br J Cancer.2000,82(11):1871-1874
[35]Llewellyn CD,Johnson NW,Warnakulasuriya KA.Risk factors for squamous cell carcinoma of the oral cavity in young people--a comprehensive literature review.Oral Oneol,2001,37(5;):401-418
[36]Gupta PC.Mouth cancer in India:a new epidemic?.J Indian Med Assoe,1999,97(9):370-3
[37]Byers RM.Squamous cell carcinoma of the oral tongue in patients less than thirty years of age.Am J Surg,1.975,130(4):475-478
[38]Rosenquist K.Risk factors in oral and oropharyngeal squarnous cell carcinoma:a population-based case-control study in southern Sweden.Swed Dent J Suppl,2005,179:1-66
[39]Dumper J,Kerr P.Recurrent squamous cell carcinoma of the tongue in pregnancy.J Otolaryngol,2005,34(4):242-243
[40]Tsukuda M,Ooishi K,Moehimatsu I,et al.Head and neck carcinomas in patients under the age of forty 3,ears.Jpn J Cancer Res,1993,84(7):748-752
[41]Llewellyn CD,Linklater K,Bell J,et al.Squamous cell carcinoma of the oral cavity in patients aged 45 years and under:a descriptive analysis of 116 eases diagnosed in the South East of England from 1990 to 1997.Oral Oncol,2003,39(2):106-114
[42]Livak K J,Sehmittgen YD.A:aalysis of relative gene expression data using real-time quantitative PCR and the 2~(-ΔΔCt) method.Methods,2001,25(4):402-408
[43]Rijsewijk F,Sehuermann M,Wagenear E,et al.The drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless.Cell.1987,50(40):649-657
[44]Sharpe C,Lawrence N,Martinez Arias.Wnt signaling:a theme with nuclear variations.Bioessays.2001,23(4):311-318
[45]Kimelman D and Xu W.W.eta-catenin destruction complex:insights and questions from a structural per:;peetive.Oneogene,2006,25(57):7482-7491
[46]Henderson BR,Fagotto E The ins and outs of APC and beta-catenin nuclear transport. EMBO Rep. 2002,3(9):834-839
[47] Huber O, Bierkamp C, Kemler R. Cadherins and catenins in development. Curr Opin Cell Biol.1996,8(5):685-691
[48] Muller T, Choidas A, Reichmann E, et al. Phosphorylation and free pool of beta-catenin are regulated by tyrosine kinase and tyrosine phosphatases during epithelial cell migration. J Biol Chem. 1999,274(15):10173-10183
[49] Rubinfeld B, Robbins P, E1-Gamil M, et al. Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science,1997;275(5307):1790-1792
[50] Morin PJ, Sparks AB, Korinek V, et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science, 1997,275(5307): 1787-1790
[51] Clements WM, Wang J, Sarnaik A, et al. Beta-catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Cancer Res,2002,62(12):3503-3506
[52] Behrens J, von Kries JP, Kuhl M, et al. Functional interaction of beta-catenin with the transcription factor LEF-1. Nature, 1996, 382 (6592):638-642
[53] Molenar M, van de Wetering M, Osterwegel M, et al. XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos.Cell,1996,86(3):391-399
[54] Brabletz T, Jung A, Dag S, et al. Beta-catenin regulates the expression of the matrix metalloproteinase-7 in human colorectal cancer. Am J Pathol,1999, 155:1033-1038
[55] He TC, Sparks AB, Rago C, et al. Identification of c-MYC as a target of the APC pathway. Science,1998,281:1509-1512
[56] Zhang X, Gaspard JP, Chung DC. Regulation of vascular endothelial growth factor by the wnt and K-ras pathways in colonic neoplasia. Cancer Res,2001,61-.6050-6054
[57] Tetsu O, McCormick F. Beta-catenin regulates expression of cyclinDl in colon carcinoma cells. Nature,1999,398:422-426
[58] Zhang T, Otevrel T, Gao Z, et al. Evidence that APC regulates surviving expression: A possible mechanism contributing to the stem cell origin of colon cancer. Cancer Res,2001,61:8664-8667
[59] Boussioutas A, Li H, Liu J, et al. Distinctive patterns of gene expression in premalignant gastric mucosa and gastric cancer. Cancer Res,2003,63 (10):2569-2577
[60] Tanaka M, Kitajima Y, Edakurd G, et al. Abnormal expression of E-cadherin and beta-catenin may be a molecular marker of submucosal invasion and lymph node metastasis in early gastric cancer. Br J Surg, 2002,89(2):236-244
[61] Miller JR. The Wnts. Genome Biol, 2002,3(1):3001-3015
[62] Koppert LB, van der Velden AW, van de Wetering, et al. Frequent loss of the AXIN1 locus but absence of AXIN1 gene mutations in adenocarcinomas of the gastro-oesophageal junction with nuclear beta-catenin expression. Br J Cancer,2004,90(4):892-899
[63] Shimizu M, Suzui M, Moriwaki H, et al. No involvement of beta-catenin gene mutation in gastric carcinomas induced by N-methyl-N-nitrosourea in male F344 rats. Cancer Lett,2003,195(2):147-152
[64] Ozawa M ,Baribault H,Kemler R .The cytoplasmic domain of the cell adhesion molecule uvomorulin associates with three independent proteins structurally related indifferent species. EMBO J, 1989, 8(6):1711 - 1717
[65] Nathke IS, Hinck L, Swedlow JR, et al. Defining interactions and distributions of cadherin and catenin complexes in polarized epithelial cells. J Cell Biol, 1994 ,125(6):1341-1352
[66] Conacci-Sorrell M, Zhurinsky J, Ben-Z(?)ev A. The cadherin-catenin adhesion system in signaling and cancer. J Clin Invest, 2002,109 (8):987-991
[67] Mareel M, Leroy A. Clinical, cellular, and molecular aspects of cancer invasion. Physiol Rev,2003,83(2):337-376
[68] Gumbier BM. Cell adherin: The molecular basis of tissue architecture and morphogenesis. Cell, 1996,84(3):345-357
[69] Cox RT, Kirkpatrick C, Peifer M. Armadillo is required for adherens junction assembly, cell polarity, and morphogenesis during Drosophila embryogenesis. J Cell Biol,1996,134(l):133-148
[70] Graff JR., Herman JG, Lapidus RG, et al. E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas. Cancer Res. 1995,55(22):5195-5199
[71] Schipper JH, Unger A, Jahnke K. E-cadherin as a functional marker of the differentiation and invasiveness of squamous cell carcinoma of the head and neck. Clin Otolaryngol Allied Sci. 1994,19(5):381-384
[72] Batlle E, Sancho E, Franci C, et al. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumor cells. Nat Cell Biol,2000,2(2):84-89
[73] Hajra KM, Chen DY, Fearon ER. The slug zinc-finger protein represses E-cadherin in breast cancer. Cancer Res, 2002,62(6): 1613-1618
[74] Mei JM, Borchert GL, Donald SP, et al. Matrix metalloproteinase mediates NO-induced dissociation of P-catenin from membrane bound E-cadherin and formation of nuclear P-catenin/LEF-1 complex. Carcinogenesis, 2002,23(12):2119-2122
[75] Fagotto F, Funayama N, Gluck U, et al. Binding to cadherins antagonizes the signaling activity of beta-catenin during axis formation in Xenopus. J Cell Biol,1996,132(6):1105-1114
[76] Conacci-Sorrell M, Simcha I,Ben-Yedidia T,et al.Autoregulation of E-cadherin expression by cadherin-cadherin interaction: the roles of beta-catenin signaling, Slug and MAPK.J Cell Biol,2003,163(4):847-857
[77] Naor D, Sionov RV, Ish-Shalom D. CD44: structure, function, and association with the malignant process. Adv Cancer Res,1997,71.241-319
[78] Bourguignon LY, Zhu D, Zhu H. CD44 isoform-cytoskeleton interaction in oncogenic signaling and tumor progression. Front Biosci, 1998, 3: 637 -649
[79] Ming SC. Cellular and molecular pathology of gastric carcinoma and precursor lesions: A critical review. Gastric Cancer, 1998,1:31-50
[80] Yamaguchi A, Goi T, Seki K, et al. Clinical significance of combined immunohistochemical detection of CD44v and sialyl LeX expression for colorectal cancer patients undergoing curative resection.Oncology,1998,55:400-403
[81]Liu YJ,Yan PS,Li J,et al.Expression and significance of CD44s,CD44v6,and nm23 mRNA in human cancer.World J Gastroenterol,2005,11:6601-6606
[82]Seiter S,Arch R,Reber S,et al.Prevention of tumor metastasis formation by anti-variant CD44.J Exp Med,1993,177(2):443-455
[83]Yasuda M,Tanaka Y,Fujii K,et al.CD44 stimulation down-regulates Fas expression and Fas-mediated apoptosis of lung cancer cells.Int Immunol,2001,13(10):1309-1319
[84]邱蔚六.口腔颌面外科理论与实践.北京:人民卫生出版社,1998.643-651
[85]Matsuura K,Hirokawa Y,Fujita M,.etal.Treatment result of stage Ⅰ and Ⅱ oral tongue cancer with interstitial brachytherapy:maximum tumor thickness is prognostic of nodal metastasis.Int J Radial Oncol Biol Phys,1998,40(3):535-539
[86]Rouviere H.Anatomy of the human lymphatic system(translation by Tobies MJ).Ann Arbor,MI:Edwards Brother,Inc,1938:250
[87]Blondeel PN,Morris SF,Hallock GG,et al.Perforator flaps:anatomy,technique,and clinical applications.St Louis,Missouri:Quality Medical Publishing,Inc,2006
[88]Allen RJ,Treece P.Deep interior epigastric artery perforator flap for breast reconstruction.Ann Plast Surg,1994,32:32-38
[89]Wei FC,Jain V,Celik N,et al.Have we found an ideal soft-tissue flap? an experience with 672 anterolateral thigh flaps.Plast Reconstr Surg,2002,109:2219-2226
[1]Cavallaro U and Christofori G.Cell adhesion in tumor invasion and metastasis:loss of the glue is not enough.Biochim Biophys Acta,2001,1552(1):39-44
[2]Perez-Moreno M,Jamora C,and Fuchs E.Sticky business:orchestrating cellular signals at adherens junctions.Cell,2003,112(4):535-548
[3]Wijnhoven BP,Dinjens WN,and Pignatelli M.E-cadherin-catenin cell-cell complex and human cancer. Br J Surg, 2000, 87(8):992- 1005
[4] Wong AS and Gumbiner BM. Adhesion-independent mechanism for suppression of tumor cell invasion by E-cadherin. J Cell Biol, 2003,161 (6): 1191-1203
[5] Kowalczyk AP and Reynolds AB. Protecting your tail: regulation of cadherin degradation by p120-catenin. Curr Opin Cell Biol,2004, 16(5):522-527
[6] Frixen UH,Behrens J,Sachs M,et al. E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cell.J Cell Biol,1991,113(1):173- 185
[7] De Leeuw WJ,Berx G,Vos CB,et al.Simultaneous loss of E-cadherin and catenin on invasive lobular breast cancer and lobular carcinoma in situ.J Pathol,1997,183(4):404-411
[8] Reynolds AB and Carnahan RH. Regulation of cadherin stability and turnover by p120~(ctn):implications in disease and cancer.Semin Cell Dev Biol, 2004,15(6):657-663
[9] Reynolds AB. p120-catenin:Past and present.Biochim Bilphys Acta,2007, 1773(1):2-7
[10] van Hengel J and van Roy F.Diverse functions of pl20~(ctn) in tumors.Biochim Biophs Acta,2007,1773(1):78-38
[11] Rask K, Nilsson A, Brannstrom M,et al. Wnt-signalling pathway in ovarian epithelial tumors: increased expression of beta-catenin and GSK3 beta. Br J Cancer,2003,89(7):1298-304
[12] Lu Z and Hunter T. Wnt-independent beta-catenin transactivation in tumor development. Cell Cycle,2004,3(5):571-573
[13] Barker N and Clevers H. Catenins, Wnt signaling and cancer. Bioessays, 2000,22(11):961-965
[14] Ozawa M ,Baribault H ,Kemler R .The cytoplasmic domain of the cell adhesion molecule uvomorulin associates with three independent proteins structurally related indifferent species. EMBO J, 1989, 8(6):1711 - 1717
[15] Joo M,Lee HK,Kang YK.Expression of E-cadherin, beta-catenin, CD44s and CD44v6 in gastric adenocarcinoma: relationship with lymph node metastasis[J]. AnticancerRes , 2003, 23(2): 1581-1588
[16] Polakis P. Wnt signaling and cancer. Genes Dev, 2000, 14(15): 1837-1851
[17] Peifer M, Polakis P. Wnt signaling in oncogenesis and embryogenesis -a look outside the nucleus. Science, 2000, 287(3): 1606-1609
[18] Akiyama T and Kawasaki Y. Wnt signaling and the actin cytoskeleton. Oncogene,2006,25(57):7538-7544
[19] Luu HH, Zhang R, Haydon RC, et al. Wnt/beta-catenin signaling pathway as anovel cancer drug target. Curr Cancer Drug Targets, 2004,4(8): 653-671
[20] Kolligs FT , Bommer G, and Goke B . Wnt/beta-catenin/tcf signaling: a critical pathway in gastrointestinal tumorigenesis. Digestion, 2002, 66(3): 131 - 144
[21] Conacci-Sorrell M, Simcha I,Ben-Yedidia T,et al.Autoregulation of E-cadherin expression by cadherin-cadherin interaction: the roles of beta-catenin signaling, Slug and MAPK.J Cell Biol,2003,163(4):847-857
[22] Chan AO.E-cadherin in gastric cancer.World J Gastroenterol, 2006, 12(2):199-203
[23] Leung WK, Yu J, Ng EK, et al. Concurrent hypermethylation multiple tumor-related genes in gastric carcinoma and adjacent normal tissues. Cancer,2001,91(12):2294-2301
[24] Ombaerts M, Middeldorp JW, Van der Weide E, et al. Infiltrating leukocytes confound the detection of E-cadherin promoter methylation in tumors. Biochem Bilphys Res Commun, 2004,319(2):697-704
[25] Kimelman D and Xu W. Beta-catenin destruction complex: insights and questions from a structural perspective. Oncogene,2006,25(57): 7482-7491
[26] Moon HS, Choi EA, Park HY, et al. Expression and tyrosine phosphorylation of E-cadherin, beta- and gamma-catenin, and epidermal growth factor receptor in cervical cancer cells. Gynecol Oncol, 2001, 81(3):355-359
[27] Ackland ML, Newgreen DF, Fridman M, et al. Epidermal growth factor-induced epithelio-mesenchymal transition in human breast carcinoma cells. Lab Invest, 2003,83(3):435-448
[28] Yasmeen A, Bismar TA and Moustafa AE. ErbB receptors and epithelial-cadherin-catenin complex in human carcinomas. Future Oncol, 2006,2(6):765-781
[29] Lobo MV, Alonso FJ, Redondo C, et al. Cellular characterization of epidermal growth factor-expanded free-floating neurospheres .J Histochem Cytochem, 2003,51(1):89-103
[30] Li G, Schaider H, Satyamoorthy K,et al. Downregulation of E-cadherin and Desmogeinl by autocrine hepatocyte growth factor during melanoma development. Oncogene, 2001,20(56):8125-8135
[31] Muller T, Choidas A, Reichmarin E, et al. Phosphorylation and free pool of beta-catenin are regulated by tyrosine phosphatase during epithelial cell migration. J Biol Chem, 1999,274:10173-10183
[32] Aberle H, Schwartz H and Kemler R. Cadherin-catenin complex: protein interactions and their implications for cadherin function. J Cell Bilchem, 1996,61(4):514-523
[33] Royal I, Lamarche Vane N, Lamorte L, et al. Activation of Cdc42, Rac,PAK,and Rho-kinase in response to hepatocyte growth factor differentially regulates epithelial cell colony spreading and dissociation. Mol Biol Cell, 2000,11(5):1709-1725
[34] Evers EE, Zondag GC, Malliri A. et al. Rho family proteins in cell adhesion and cell migration. Eur J Cancer,2000,36(10): 1269-1274
[35] Lu Z, Ghosh S, Wang Z, et al. Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion. Cancer Cell,2003, 4(6):499-515
[36] Galbiati F, Volonte D, Browm AM, et al. Caveolin-1 expression inhibits Wnt/beta-catenin/Lef-1 signaling by recruiting beta-catenin to caveolae membrane domains. J Biol Chem,2000,275(30):23368-23377
[37] Harris TJ, Peifer M. Adherens junction-dependent and junction-independent steps in the establishment of epithelial cell polarity in Drosophila. J Cell Biol, 2004, 167(1):135-147
[38] Zhu B, Chappuis FS, Wong E, et al. Functional analysis of the structural basis of homophilic cadherin adhesion. Bilphys J, 2003, 84(6): 4033-4042
[39] Andersen H, Mejlvang J, Mahmood S, et al. Immediate and delayed effects of E-cadherin inhibition on gene regulation and cell motility in human epidermoid carcinoma cells. Mol Cell Biol, 2005, 25(20):9138-9150
[40] Slater M, Barden JA. Differentiating keratoacanthoma from squamous cell carcinoma by the use of apoptotic and cell adhesion markers. Histopathology, 2005, 47(2):170-178
[41] Ferreira P, Oliveira MJ, Beraldi E, et al. Loss of functional E-cadherin renders cells more resistant to the apoptotic agent taxol in vitro. Exp Cell Res, 2005, 310(1):99-104
[42] Margulis A, Zhang W, Alt-Holland A, et al. Loss of intercellular adhesion activates a transition from low- to high-grade human squamous cell carcinoma. Int J Cancer, 2006, 118(4):821-831
[43] Zhang G, Zhou X, Xue L, et al. Accumulation of cytoplasmic beta-catenin correlates with reduced expression of E-cadherin, but not with phosphorylated Akt in esophageal squamous cell carcinoma: immunohistochemical study. PatholInt, 2005, 55(6):310-317
[44] Marchenko GN, Marchenko ND, Leng J, et al. Promoter characterization of the novel human matrix metalloproteinase-26 gene: regulation by the T-cell factor-4 implies specific exprsssion of the gene in cancer cells of epithelial origin. BiochemJ, 2002, 363(2):253-262
[45] Cheng XX, Wang ZC, Chen XY, et al. Frequent loss of membranous N-cadherin in gastric cancers: A cross-talk with Wnt in determining the fate of beta-catenin. Clin Exp Metastasis, 2005, 22(1):85-93
[46] Pena C, Garcia JM, Silva, et al. E-cadherin and vitamin D receptor regulation by SNAIL and ZEB1 in colon cancer: clinicopathological correlations. Hum Mol Genet, 2005, 14(22):3361-3370
[47] Jiao W, Miyazaki K, Kitajima Y. Inverse correlation between E-cadherin and Snail expression in hepatocellular carcinoma cell lines in vitro and in vivo. Br J Cancer, 2002, 86(1):98-101
[48] Kim HS, Hong EK, Park SY, et al. Expression of beta-catenin and E-cadherin in the adenoma-carcinoma sequence of the stomach. Anticance Res, 2003, 23(3):2863-2868
[49] Spina D, Vindigni C, Presenti L. et al. Cell proliferation, cell death, E-cadherin, metalloproteinase expression and angiogenesis in gastric cancer precursors and early cancer of the intestinal type. Int J Oncol, 2001, 18(6):1251-1258
[50] Gabbert HE, Mueller W, Schneiders A, et al. Prognostic value of E-cadherin expression in 413 gastric carcinomas. Int J Cancer, 1996, 69(3):184-189
[51] Behrens J, Weidner KM, Frixen UH, et al. The role of E-cadherin and scatter factor in tumor invasion and cell motility. EXS, 1991, 59:109-126
[52] Chen Q, Lipkina G, Song Q, et al. Promoter methylation regulates cadherin in squamous cell carcinoma. Bilchem Biophys Res Commun , 2004,315 (4):850-856
[53] Kudo Y, Kitajima S, Ogawa I, et al. Invasion and metastasis of oral cancer cells require methylation of E-cadherin and/or degradation of membranous beat-catenin. Clin Cancer Res,2004,10(16):5455-5463
[54] Downer CS, Speight PM. E-cadherin expression in normal, hyperplastic and malignant oral epithelium. Eur J Cancer B Oral Oncol, 1993,29B(4): 303-305
[55] Morin PJ. Beta-catenin signaling and cancer. Bioessays, 1999, 21(12): 1021-1030
[56] Tanaka N, Odajima T, Ogi K, et al.Exprssion of E-cadherin, alpha-catenin, and beta-catenin in the process of lymph node metastasis in oral squamous cell carcinoma. Br J Cancer, 2003,89(3):557-563
[57] Chow V, Yuen AP, Lam KY, et al. A comparative study of the clinicopathological significance of E-cadherin and catenins (alpha,beta,gamma) expression in the surgical management of oral tongue carcinoma. J Cancer Res Clin Oncol, 2001,127(1):59-63
[58] Okamoto M, Nishimine M, Kishi M, et al. Prediction of delayed neck metastasis in patents with stage Ⅰ /Ⅱ squamous cell carcinoma of the tongue. J Oral Pathol Med,2002,31(4):227-233
[59] Brabletz T, Jung A, Reu S, et al. Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc Natl AcadSci USA, 2001, 98(18):10356-10361
[60] Novak A, Dedhar S. Signaling through beta-catenin and Lef/Tcf. Cell Mol Life Sci, 1999, 56:523-537
[61] Clevers H, van de Wetering M. TCF/LEF factors earn their wings. Trends Genent, 1997, 13:485-489
[62] Lustig B, Behrens J. The Wnt signaling pathway and its role in tumor development. J Cancer Res Clin Oncol, 2003, 129:199-221
[63] He TC, Sparks AB, Rago C, et al. Identification of c-MYC as a target of the APC pathway. Science, 1998, 281:1509-1512
[64] Shtutman M, Zhurinsky J, Simcha I, et al. The cyclin Dl gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci USA, 1999, 96(16):5522-5527
[65] Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin Dl in colon carcinoma cells. Nature, 1999, 398:422-426
[66] Zhang X, Gaspard JP, Chung DC. Regulation of vascular endothelial growth factor by the Wnt and K-ras pathways in colonic neoplasia. Cancer Res, 2001, 61:6050-6054
[67] Koh TJ, Bulitta CJ, Fleming JV, et al. Gastrin is a target of the beta-catenin/TCF-4 growth-singaling pathway inaa model of intestinal polyposis. J Xlin Invest, 2000, 106:533-539
[68] Watson SA, Smith AM. Hypergastrinemia promotes adenoma progression in the APC(Min-/+) mouse model of familial adenomatous polyposis. Cancer Res, 2001, 61:625-631
[69] Boon EM, van der Neut R, van de Wetering M, et al. Wnt signaling regulates expression of the receptor tyrosine kinase met in colorectal cancer. Cancer Res, 2002, 62:5126-5128
[70] Brabletz T, Jung A, Dag S,et al.Beta-catenin regulates the expression of the matrix metalloproteinase-7 in human colorectal cancer. Am J Pathol, 1999, 155:1033-1038
[71] Crawford HC, Fingleton BM, Rudolph-Owen LA, et al. The metalloproteinase matrilysin is a target of beta-catenin transactivation in intestinal tumors. Oncogene, 1999, 18:2883-2891
[72] Conacci-Sorrell ME, Ben-Yedidia T, Shtutman M, et al. Nr-CAM is a target gene of the beta-catenin/LEF-1 pathway in melanoma and colon cancer and its expression enhances motility and confers tumorigenesis. Genes Dev, 2002, 16:2058-2072
[73] Wielenga VJ, van der Neut R, Offerhaus GJ, et al. CD44 glycoproteins in colorectal cancer: expression, function,and prognostic value. Adv Cancer Res, 2000, 77:169-187
[74] Kolligs FT, Nieman MT, Winer I, et al. ITF-2, a downstream target of the Wnt/TCF pathway, is activated in human cancers with beta-catenin defects and promotes neoplastic transformation. Cancer Cell, 2002, 1:145-155
[75] Rockman SP, Currie SA, Ciavarella M, et al. Id2 is a target of the beta-catenin/T cell factor pathway in colon carcinoma. J Biol Chem, 2001, 276:45113-45119
[76] Zhang T, Otevrel T,Gao Z, et al. Evidence that APC regulates surviving expression: a possible mechanism contributing to the stem cell origin of colon cancer. Cancer Res, 2001, 61:8664-8667
[77] Weber GF, Ashkar S. Stress response genes: the genes that make cancer metastasize. J Mol Med, 2000, 78(8):404-408
[78] Ishikawa T, Ichikawa Y, Mitsuhashi M, et al. Matrilysin is associated with progression of colorectal tumor. Gincer Lett, 1996, 107 (1 ):5-10
[79] Hasegawa S, Koshikawa N, Momiyama N, et al. Matrilysin-specific antisense oligonucleotide inhibits liver metastasis of human colon cancer cells in a nude mouse model. Int J Cancer, 1998, 76(6):812-816
[80] Adachi Y, Yamamoto H, Itoh F, et al. Contribution of matrilysin (MMP-7) to the metastatic pathway of human colorectal cancers. Gut, 1999, 45(2):252-258
[81] Zeng ZS, Shu WP, Cohen AM, et al. Matrix metalloproteinase-7 expression in
colorectal cancer liver metastases: evidence for involvement of MMP-7
activation in human cancer metastases. Clin Cancer Res, 2002, 8(1): 144-148 [82] Mareel M, Leroy A. Clinical, cellular, and molecular aspects of cancer invasion.
PhysiolRev, 2003, 83(2):337-376 [83] Davidson B, Gotlieb WH, Ben-Baruch G, et al. E-cadherin complex protein
expression and survival in ovarian carcinoma. Gynecol Oncol,2000,79
(3):362-371 [84] Beavon IRG The E-cadherin-catenin complex in tumor metastasis: structure,
function and regulation. European Journal of Cancer, 2000,3 6:1607-1620
90