肺癌组织中KAI1/CD82和整合素α5表达的临床意义及二者相关性的研究
摘要
目的
浸润和转移是恶性肿瘤的重要特征，也是引起肿瘤病例死亡的主要原因。尽管肿瘤的诊断和治疗方法不断改善，但总的治疗效果并不令人满意。目前，全部肺癌患者的5年生存率只有15％；未接受治疗的转移性NSCLC的中位生存仅4～5个月，1年生存率为10％。其根本原因在于我们无法控制、阻断肿瘤的浸润和转移。随着分子生物学的深入研究，人们对肿瘤发生基础有了明确的认识。然而，对肿瘤的浸润和转移的分子基础仍了解较少，这使得肿瘤浸润和转移问题成为分子生物学研究的热点及难点。目前已知肿瘤的浸润和转移与肿瘤发生一样，不仅有促进基因的激活，还有抑制基因的失活，同时伴有细胞粘附因子的参与。
1995年，Dong等首先从转移到前列腺癌细胞系AT6.1中的人第11号染色体中分离出特异性抑制肿瘤转移的基因，命名为KAI 1(取中文抗癌Kang ai)基因。KAI1基因定位于人染色体的11p11.2，长约80Kb，DNA序列分析证明KAI1与CD82基因是相同的，其cDNA片段为2.4Kb，编码一种267个氨基酸的蛋白质，分子量为29.61KD。故并称为KAI1／CD82。KAI1／CD82属四次跨膜超家族(transmembrance 4 superfamily，TM4SF)的成员，其结构为细胞膜糖蛋白。KAI1／CD82基因在前列腺癌转移中的抑制作用已经得到公认。经过多年的研究，在多种肿瘤中均证实了转移的肿瘤往往伴随有KAI1／CD82基因的表达下降或缺失。整合素是最重要的一种细胞粘附受体，1987年Hynes等首先提出。它有不同的α亚单位和β亚单位，是一种膜镶嵌糖蛋白。其功能是多种多样的，它们通过介导细胞粘附来锚定细胞，帮助转换细胞的迁移及传导信号。作为整合素家族中的一员，整合素α5是一种纤维结合受体，其功能为参与细胞信号传导、调整细胞粘附和迁移。研究表明高表达的α5与肿瘤转移呈负相关。尽管如此，国外文献有关KAI1／CD82和α5在肺癌方面的研究报道尚少；国内缺乏相关报道；且实验方法单一，结论也有矛盾之处。最新研究发现KAI1／CD82可与整合素形成复合体，从而调节整合素的粘附功
能并影响整合素介导的细胞转移〔’8，‘，，20〕;国内目前尚无报道。因此，有必
要进一步研究，增加人们对KAll/CD82及as作用的认识。本实验研究通
过检测KAll/CD82及整合素a5在肺癌组织中的表达，探讨KAll/CD82及
as与肺癌临床特征之间的关系，并分析KAn/CD82与a5的相关性，阐述
其在肺癌浸润和转移方面的意义。
方法
44例肺癌组织标本包括NSCLC组37例和SCLC组7例，按1 997版国
际肺癌TNM分期进行分期〔川，应用RT一PcR方法和免疫组化方法(IH)分
别检测KAll/CD82及as的表达水平，同时应用SPSSIO.O版统计软件包进
行数据处理及统计分析。
结果
44例肺癌组织中，RT一PCR法测得KAn/CD82表达阳性为20例，阳
性率为45.5%。免疫组化法测得KAn/CD82表达阳性为24例，阳性率为
54.5%。统计学分析显示，两种方法的所测得结果有显著性意义，P<0.05。
44例肺癌组织中，RT一PCR法测得as表达阳性为22例，阳性率为50.
O%。免疫组化法测得as表达阳性为27例，阳性率为61.4%。统计学分
析显示，两种方法的所测得结果有显著性意义，P<0.05。两种方法检测NO
病例的KAn/CD82表达水平与Nl+NZ病例的表达水平相比较，结果有显
著性意义，P<0.05，相关系数r>0。I期病例的KAll/CD82表达水平与n
+nI+W期病例的表达水平比较，其结果有显著性意义，P<0.05，r>0。高
分化病例的KAll/CD82表达水平比中+低分化病例高，统计学分析二者之
间的差异有显著性意义，P<0.05，r>0。在病理分型上，NSCLC病例组
KAll/CD82的表达水平与 SCLc病例组的表达水平比较，RT一PCR法所测
得结果，差异无显著性意义，P>0.05;而IH法测得结果，二者之间的差异
有显著性意义，P<0.05。统计结果同时显示，KAn/CD82的表达水平与年
龄、性别、肿瘤部位、肿瘤大小无关，P>0.05;a5的表达水平也与上述因素
无关，P>0.05。NO病例的as表达水平与Nl+NZ病例的表达水平相比
较，RT一PCR法测得结果无显著性意义，P>0 .05;而IH法测得结果有显著
性意义，P<0.05。I期病例的as表达水平与n+111+W期病例的表达水
平比较，其结果有显著性意义，P<0.05，r>0。RT一PCR法测得高分化病
例的a5表达水平比中十低分化病例高，统计学分析二者之间的差异有显
著性意义，P<0.05。而IH法测得结果无显著性意义，P>0.05。在病理分
型上，NSCLC病例组的a5表达水平与SCLC病例组的表达水平比较，二者
之间的差异无显著性意义，P>0.05。KAll/CD82与as表达水平的相关性
经统计学分析研究显示有显著性意义，r>O，P<0.05;无论是在RT一PCR
法还是在IH法，所测结果均出现很好的一致性，P<0.05。
结论
KAn/c D82作为抑癌基因，其表达水平与肺癌的淋巴结有无转移有
关，无淋巴结转移者高表达;KAll/CD82可能成为肺癌淋巴结是否转移的
预测因子。KAn/CD82的表达水平与肺癌的TNM分期有关，即与肺癌的
浸润、转移程度相关。KAll/CD82的水平低表达或阴性，预示着肺癌发展
进程加重。同时KAI 1/ CD82表达水平与分化程度有关，高分化者高表达，
低分化者呈低表达或阴性
Objective
Invasion and metastasis are very important features of malignant tumors, being the main factors that made patients die . Though diagnosis and treatments of tumors are being improved, the overall treatment effect is not satisfying. At present, five year survival rate of lung cancer is just 15% ; median survival time of untreated lung cancer patients is only 4-5 months, and one year survival rate is 10% [3] . The basic reason is that we are not able to control and block up the invasion and metastasis of tumor cells. With the development of molecular biology, the background of tumor has been being clearly identified. However, the molecular foundation of tumor cell's invasion and metastasis remains unknown, which makes invasion and metastasis of tumor cells become the hot and difficult questions of molecular biology on study. Nowadays, we have known that invasion and metastasis of tumor cells, just as its occurrence, involved not only the activation of oncogene, but the inactivation of suppressor gene, accompani
ed by the participation of cellular adhesive factors .
KAI 1/CD82 is a member of transmembrane 4 superfamily ( TM4SF) , whose structure is glycoprotein of cellular membrane. In 1995, Dong et al separated a specific metastasis suppressor gene of tumor cells from chromosome 11 of human metastatic prostatic carcinoma cell line AT6. 1. This gene was named KAI1 ( named after its Chinese meaning kang ai ) gene. The metastasis suppressor function of KAI1/CD82 gene has been widely accepted . After long years study, it has been confirmed that , in most tumor cells, the metastatic cells often involves the decrease or lack of the expression of KAI1/CD82 gene1-10'11^. Integrin is the most important cellular adhesive acceptor, which has different subunit aand, and is a membrane glycoprotein . As a member of integrin family, integrin 5 is a kind of fibronectin receptor, participating in cellular signal transmission, regulating cellular adhesion and activation[13,14,15].
It has been suggested that high expression ofct5 has a negative correlation with metastasis[16,17]. In spite of this, there are few foreign and domestic articles a-bout KAI1/CD82 ando5, with simple experiment and paradoxical conclusion. Recent study indicated that KAI1/CD82 and integrin can form into a complex, regulating adhesive function of integrin and influencing cell metastasis mediated by integrin [18,19,20]. So it is necessary to further realize the significance of KAI1/ CD82 ando5. By detecting the expression of KAI1/CD82 andct5 in human lung cancer, Our experiment explored the relation between KAI1/CD82 , 5 and clinical factors, analyzed the correlation between KAI1/CD82 ando5, and explained their effects on invasion and metastasis of lung caner cell.
Method
44 lung cancer samples, including 37 cases with nsclc and 7 cases with sclc, staged according to 1997 international lung cancer TNM staging ' were detected the expression of KAI1/CD82 ando5 by RT - PCR method and immu-nohistochemistry method. All data were analyzed using SPSSIO. 0 statistics software.
Results
Among 44 lung cancer patients, 20 (45.5% ) showed positive expressions of KAI1/CD82 by RT - PCR , while by immunohistochemistry, 24 (54. 5% ). The results of this two kinds of experiments have statistical significance (p <0. 05). Among 44 lung cancer patients, 22(50. 0% ) showed positive expressions ofa5 by RT-PCR, while by immunohistochemistry, 27(61.4% ). The results of this two kinds of experiments also had statistical significance ( p < 0. 05 ). The expression of KAI 1/CD82 in NO stage compared with the one in Nl and N2 stage . The results of two groups have statistical significance (p<0. 05,r>0). The expression of KAI 1/CD82 in Patients of I stage compared with the ones of II , IH and IV stage. The results of two groups appeared statistical significance
(p < 0. 05, r > 0). The expression of KAI1/CD82 in Patients of well differentiation compared with the cases of morderate and poor. The results showed statistical significance (p <0. 05,r >0). On the pathol
浸润和转移是恶性肿瘤的重要特征，也是引起肿瘤病例死亡的主要原因。尽管肿瘤的诊断和治疗方法不断改善，但总的治疗效果并不令人满意。目前，全部肺癌患者的5年生存率只有15％；未接受治疗的转移性NSCLC的中位生存仅4～5个月，1年生存率为10％。其根本原因在于我们无法控制、阻断肿瘤的浸润和转移。随着分子生物学的深入研究，人们对肿瘤发生基础有了明确的认识。然而，对肿瘤的浸润和转移的分子基础仍了解较少，这使得肿瘤浸润和转移问题成为分子生物学研究的热点及难点。目前已知肿瘤的浸润和转移与肿瘤发生一样，不仅有促进基因的激活，还有抑制基因的失活，同时伴有细胞粘附因子的参与。
1995年，Dong等首先从转移到前列腺癌细胞系AT6.1中的人第11号染色体中分离出特异性抑制肿瘤转移的基因，命名为KAI 1(取中文抗癌Kang ai)基因。KAI1基因定位于人染色体的11p11.2，长约80Kb，DNA序列分析证明KAI1与CD82基因是相同的，其cDNA片段为2.4Kb，编码一种267个氨基酸的蛋白质，分子量为29.61KD。故并称为KAI1／CD82。KAI1／CD82属四次跨膜超家族(transmembrance 4 superfamily，TM4SF)的成员，其结构为细胞膜糖蛋白。KAI1／CD82基因在前列腺癌转移中的抑制作用已经得到公认。经过多年的研究，在多种肿瘤中均证实了转移的肿瘤往往伴随有KAI1／CD82基因的表达下降或缺失。整合素是最重要的一种细胞粘附受体，1987年Hynes等首先提出。它有不同的α亚单位和β亚单位，是一种膜镶嵌糖蛋白。其功能是多种多样的，它们通过介导细胞粘附来锚定细胞，帮助转换细胞的迁移及传导信号。作为整合素家族中的一员，整合素α5是一种纤维结合受体，其功能为参与细胞信号传导、调整细胞粘附和迁移。研究表明高表达的α5与肿瘤转移呈负相关。尽管如此，国外文献有关KAI1／CD82和α5在肺癌方面的研究报道尚少；国内缺乏相关报道；且实验方法单一，结论也有矛盾之处。最新研究发现KAI1／CD82可与整合素形成复合体，从而调节整合素的粘附功
能并影响整合素介导的细胞转移〔’8，‘，，20〕;国内目前尚无报道。因此，有必
要进一步研究，增加人们对KAll/CD82及as作用的认识。本实验研究通
过检测KAll/CD82及整合素a5在肺癌组织中的表达，探讨KAll/CD82及
as与肺癌临床特征之间的关系，并分析KAn/CD82与a5的相关性，阐述
其在肺癌浸润和转移方面的意义。
方法
44例肺癌组织标本包括NSCLC组37例和SCLC组7例，按1 997版国
际肺癌TNM分期进行分期〔川，应用RT一PcR方法和免疫组化方法(IH)分
别检测KAll/CD82及as的表达水平，同时应用SPSSIO.O版统计软件包进
行数据处理及统计分析。
结果
44例肺癌组织中，RT一PCR法测得KAn/CD82表达阳性为20例，阳
性率为45.5%。免疫组化法测得KAn/CD82表达阳性为24例，阳性率为
54.5%。统计学分析显示，两种方法的所测得结果有显著性意义，P<0.05。
44例肺癌组织中，RT一PCR法测得as表达阳性为22例，阳性率为50.
O%。免疫组化法测得as表达阳性为27例，阳性率为61.4%。统计学分
析显示，两种方法的所测得结果有显著性意义，P<0.05。两种方法检测NO
病例的KAn/CD82表达水平与Nl+NZ病例的表达水平相比较，结果有显
著性意义，P<0.05，相关系数r>0。I期病例的KAll/CD82表达水平与n
+nI+W期病例的表达水平比较，其结果有显著性意义，P<0.05，r>0。高
分化病例的KAll/CD82表达水平比中+低分化病例高，统计学分析二者之
间的差异有显著性意义，P<0.05，r>0。在病理分型上，NSCLC病例组
KAll/CD82的表达水平与 SCLc病例组的表达水平比较，RT一PCR法所测
得结果，差异无显著性意义，P>0.05;而IH法测得结果，二者之间的差异
有显著性意义，P<0.05。统计结果同时显示，KAn/CD82的表达水平与年
龄、性别、肿瘤部位、肿瘤大小无关，P>0.05;a5的表达水平也与上述因素
无关，P>0.05。NO病例的as表达水平与Nl+NZ病例的表达水平相比
较，RT一PCR法测得结果无显著性意义，P>0 .05;而IH法测得结果有显著
性意义，P<0.05。I期病例的as表达水平与n+111+W期病例的表达水
平比较，其结果有显著性意义，P<0.05，r>0。RT一PCR法测得高分化病
例的a5表达水平比中十低分化病例高，统计学分析二者之间的差异有显
著性意义，P<0.05。而IH法测得结果无显著性意义，P>0.05。在病理分
型上，NSCLC病例组的a5表达水平与SCLC病例组的表达水平比较，二者
之间的差异无显著性意义，P>0.05。KAll/CD82与as表达水平的相关性
经统计学分析研究显示有显著性意义，r>O，P<0.05;无论是在RT一PCR
法还是在IH法，所测结果均出现很好的一致性，P<0.05。
结论
KAn/c D82作为抑癌基因，其表达水平与肺癌的淋巴结有无转移有
关，无淋巴结转移者高表达;KAll/CD82可能成为肺癌淋巴结是否转移的
预测因子。KAn/CD82的表达水平与肺癌的TNM分期有关，即与肺癌的
浸润、转移程度相关。KAll/CD82的水平低表达或阴性，预示着肺癌发展
进程加重。同时KAI 1/ CD82表达水平与分化程度有关，高分化者高表达，
低分化者呈低表达或阴性
Objective
Invasion and metastasis are very important features of malignant tumors, being the main factors that made patients die . Though diagnosis and treatments of tumors are being improved, the overall treatment effect is not satisfying. At present, five year survival rate of lung cancer is just 15% ; median survival time of untreated lung cancer patients is only 4-5 months, and one year survival rate is 10% [3] . The basic reason is that we are not able to control and block up the invasion and metastasis of tumor cells. With the development of molecular biology, the background of tumor has been being clearly identified. However, the molecular foundation of tumor cell's invasion and metastasis remains unknown, which makes invasion and metastasis of tumor cells become the hot and difficult questions of molecular biology on study. Nowadays, we have known that invasion and metastasis of tumor cells, just as its occurrence, involved not only the activation of oncogene, but the inactivation of suppressor gene, accompani
ed by the participation of cellular adhesive factors .
KAI 1/CD82 is a member of transmembrane 4 superfamily ( TM4SF) , whose structure is glycoprotein of cellular membrane. In 1995, Dong et al separated a specific metastasis suppressor gene of tumor cells from chromosome 11 of human metastatic prostatic carcinoma cell line AT6. 1. This gene was named KAI1 ( named after its Chinese meaning kang ai ) gene. The metastasis suppressor function of KAI1/CD82 gene has been widely accepted . After long years study, it has been confirmed that , in most tumor cells, the metastatic cells often involves the decrease or lack of the expression of KAI1/CD82 gene1-10'11^. Integrin is the most important cellular adhesive acceptor, which has different subunit aand, and is a membrane glycoprotein . As a member of integrin family, integrin 5 is a kind of fibronectin receptor, participating in cellular signal transmission, regulating cellular adhesion and activation[13,14,15].
It has been suggested that high expression ofct5 has a negative correlation with metastasis[16,17]. In spite of this, there are few foreign and domestic articles a-bout KAI1/CD82 ando5, with simple experiment and paradoxical conclusion. Recent study indicated that KAI1/CD82 and integrin can form into a complex, regulating adhesive function of integrin and influencing cell metastasis mediated by integrin [18,19,20]. So it is necessary to further realize the significance of KAI1/ CD82 ando5. By detecting the expression of KAI1/CD82 andct5 in human lung cancer, Our experiment explored the relation between KAI1/CD82 , 5 and clinical factors, analyzed the correlation between KAI1/CD82 ando5, and explained their effects on invasion and metastasis of lung caner cell.
Method
44 lung cancer samples, including 37 cases with nsclc and 7 cases with sclc, staged according to 1997 international lung cancer TNM staging ' were detected the expression of KAI1/CD82 ando5 by RT - PCR method and immu-nohistochemistry method. All data were analyzed using SPSSIO. 0 statistics software.
Results
Among 44 lung cancer patients, 20 (45.5% ) showed positive expressions of KAI1/CD82 by RT - PCR , while by immunohistochemistry, 24 (54. 5% ). The results of this two kinds of experiments have statistical significance (p <0. 05). Among 44 lung cancer patients, 22(50. 0% ) showed positive expressions ofa5 by RT-PCR, while by immunohistochemistry, 27(61.4% ). The results of this two kinds of experiments also had statistical significance ( p < 0. 05 ). The expression of KAI 1/CD82 in NO stage compared with the one in Nl and N2 stage . The results of two groups have statistical significance (p<0. 05,r>0). The expression of KAI 1/CD82 in Patients of I stage compared with the ones of II , IH and IV stage. The results of two groups appeared statistical significance
(p < 0. 05, r > 0). The expression of KAI1/CD82 in Patients of well differentiation compared with the cases of morderate and poor. The results showed statistical significance (p <0. 05,r >0). On the pathol
引文
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13. Hynes, R. O. Integrins : Versatility, modulation, and signaling in cell adhesion. Cell, 1992,69:11-25.
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16. Blystone, S. D., Graham, I. L., Lindberg, F. P., and Brow, E. J. Integrin ανβ3 differentially regulates adhesive and phagocytic functions of the fibronectin receptor α5 β1. J. Cell Biol. , 1994,127:1129-1137.
17. Wang, D., Zhou, G., Birkenmeier, T. M., Gong, J., Sun, L., and Brattain, M. G. Autocrine transforming growth factor β1 modulates the expression of integrinα5 β1 in human colon carcinoma FET cells. J. Biol. Chem. , 1995,270:14154-14159.
18. Hemler ME, Mannion BA; Berditchevski F. Association of TM4SF proteins with integrins: relevance to cancer. Biochim Biophys Acta, 1996,1287:67.
19. Berditchevski F, Zutter MM, Hemler ME. Characterization of novel complexes on the cell surface between integrins and proteins with 4 transmembrane domains. Mol Biol Cell, 1996,7:193.
20. Berditchevski F, Odintsova E. Characterization of integrin -tetraspanin adhesion complexes: role of tetraspanins in integrin signaling [J]. J Cell Biol, 1999,146(2):477-492.
21. Clifton, F. , and Mountain, M. D. Revisions in the international system for staging lung cancer. Chest, 1997,111:1710-1717.
22. Adachi M, Taki T, Ieki Y, et al. Correlation of KAI1/CD82 gene expression with good prognosis in patients with non - small cell lung cancer. Cancer Res, 1996;56:1751-1755.
23. Adachi M, Taki T, Konishi T, et al. Novel staging protocol for non - small -cell lung cancers according to MRP- 1/CD9 and KAI1/CD82 gene expression. J Clin Oncol, 1998,16:1397-1406.
24. Higashiyama M, Kodama K, Yokouchi H, et al. KAI1/CD82 expression in nonsmall cell lung carcinoma is a novel, favorable prognostic factor: an immunohistochemical analysis. Cancer, 1998, 83:466-474.
25．李珊珊，方伟岗，任秀花，等．不同转移潜能人肺癌细胞系KAI1基因的表达．河南医科大学学报，2000；35(2)：98-100．
26. Tagawa K, Arihiro K, Takeshima Y, et al. Down-regulation of KAI1 messenger RNA expression is not associated with Ioss of heterozygosity of the KAI1 gene region in lung adenocarcinoma. Jpn J Cancer RES, 1999, 90:970-976.
27. Ginsberg, M. H., Du, X., and Plow, E. F. Inside- out integrin signaling. Curr. Opin. Cell Biol., 1992, 4:766-771.
28. Akiyama, S. K., Yamada, S. S., Chen,W. T., and Yamada, K. M. Analysis of fibronectin receptor function with monoclonal antibodies: roles in cell adhesion, migration, matrix assembly, and cytoskeletal organization. J. Cell Biol., 1989 109:863-875.
29. Werb, Z., Tremble, P. M., Behrendsten, O., Crowley, E., and Damsky, C. H. Signal transduction through the fibronectin receptor induces collagenase and stromelysin gene expression. J. Cell Biol., 1989,109:877-889.
30. Giancotti, F. G., and Rouslahti, E. Elevated levels of theoα5 β1 fibronectin receptor suppress the transformed phenotype of Chinese hamster ovary cells. Cell, 1990,60:849-859.
31. Dedhar, S., Argraves. W. S., Suzuki, S., Ruoslahti, E., and Pierschbacher, M. D. Human osteosarcoma cells resistant to detachment by an Arg-Gly-Asp-containing peptide overproduce the fibronectin receptor. J. Cell Biol., 19871,05:1175-1182.
32. Plantefaber, L. C., and Hynes, R. O. Changes in integrin receptors on oncogenically transformed cells. Cell, 1989,56:281-290.
33. Tennenbaum. T., Yuspa. S. H., Grover, A., Castmovo, C., Sobel, M. E., Yamada, Y., and De Luca, L. M. Extracellular matrix receptors and mouse skin carcinogenesis: altered expression linked to appearance of early
markers of tumor progression. Cancer Res., 52:2966-2976,1992.
34. Danen, E. H. J., Ten Berge, P. J. M., Van Muijen,G. N. P,Vant Hof-Grootenboer, A. E., Broker, E. B., and Reiter, D. J. Emergence of ot5β1 fibronectin-and αvβ3 vitronectin-receptor expression in melanocytic tumor progression. Histopathology, 1994,24:249-256.
35. Natali, P. G., Nicotra. M. R., Di Filippo, F., and Bigotti, A. Expression of fibronectin, flbronectin isoforms and integrin receptors melanocytic lesions. Br. J. Cancer, 1995,71:1243-1247.
36. Gomez, M., and Cano, A. Expression of β1 integrin receptors in transformed mouse epidermal keratinocytes: Upregulation of α5β1 in spindle carcinoma cells. Mol. Carcinog., 1995,12:153-165.
37. Libert, M., Washington, R., Stein, J., Wedemeyer, G., and Grossman, H. B. Expression of the VLA 131 integrin family in bladder cancer. Am. J. Pathol., 1994,144:1016-1022.
38. Lessey, B. A., Alblelda, S., Buck, C. A., Castelbaum, A. J., Yeh, L., Kohler, M., and Berchuck, A. Distribution of integrin cell adhesion molecules in endometrial cancer. Am. J. Pathol., 1995,146:717-726.
39. Schiller, J. H., and Bittner, G. Loss of the tumorigenic phenotype with in vitro, but not in vivo, passaging of a novel series of human bronchial epithelial cell lines: possible role of an α5/β1-integrin-fi-bronectin interaction. Cancer Res., 1995,55:6215-6221.
40. Suzuki, S., Takahashi, T., Nakamura, S., Koike, K., Ariyoshi, Y., Takahashi, T., and Ueda, R. Alterations of integrin expression in human lung cancer. Jpn. J. Cancer Res., 1993,84:168-174.
41. Albelda, S. M. Role of integrins and other cell adhesion molecules in tumor progression and metastasis. Lab. Invest., 1993, 68:4-17.
42. Varner, J. A., Emerson, D. A., and Juliano, R. L. Integrin α5β1 expression negatively regulates cell geowth: reversal by attachment to fibronectin. Mol. Biol. Cell, 1995,6:725-740.
43. Zhang, Z., Vuori, K., Reed, J. C., and Ruoslahti, E. The α5β1 integrin supports survival of cells on fibronectin and up-regulates Bcl-2 ex-
pression. Proc. Nail. Acad. Sci., USA, 1995,92:6161-6165.
44. Mannion,B. A., F Berditchevski, S. K Kraeft,et al. TM4SF protein CD81 (TAPA-1), CD82, CD63 and CD53 specifically association with α4β1 integrin. 1996,J. Immunol. 157:2039-2047.
45. Fedor Berditchevski and Elena Odintsova. Characterization of Integrin-Tetraspanin Adhesion Complexes: Role of Tetraspanins in Integrin Signaling.The Journal of Cell Biology 1999,146:477-492
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6. Dong JT, Suzuki H, Pin SS, et al. Down -regulation of the KAI1 metastasis suppressor gene during the progression of human prostatic cancer infrequently involves gene mutation or allelie loss. Cancer Res, 1996, 56:4387-4390.
7. Dong JT, Isaacs WB, Barrett JC, et al. Genomic organization of the human KAI1 metastasis - suppressor gene. Genomics, 1997,41:25-32.
8. Ward JM, Konishi N, Ohshima M, et al. Expression of KAI1 in paraffinembedded normal, hyperplastic and neoplastic prostate and prostate carcinoma cell lines. Pathol Int, 1998,48:87-92.
9. Ueda T, Ichikawa T, Tamaru J, et al. Expression of the KAI1 protein in benign prostatic hyperplasia and prostate cater. Am J Pathol, 1996,149:1435-1440.
10. Takaoka A, Hinoda Y, Sato S, et al. Reduced invasive and metastatic potentials of KAI1 -transfected melanoma cells. Jpn J Cancer Res, 1998, 89:397-404.
11. Yang X, Welch DR, Phillips KK, et al. KAI1, a putative marker for metastatic potential in human breast cancer. Cancer Lett, 1997,119:149-155.
12. Hynes, R. O. Integrins : a family of cell surface receptors. Cell, 1987,48:549-554.
13. Hynes, R. O. Integrins : Versatility, modulation, and signaling in cell adhesion. Cell, 1992,69:11-25.
14．曾益新．肿瘤学．北京：人民卫生出版社 1999：55-195
15. Ruoslahti, E., and Giancotti, F. G. Integrins and tumor cell dissemination. Cancer Cells, 1989,1:119-126.
16. Blystone, S. D., Graham, I. L., Lindberg, F. P., and Brow, E. J. Integrin ανβ3 differentially regulates adhesive and phagocytic functions of the fibronectin receptor α5 β1. J. Cell Biol. , 1994,127:1129-1137.
17. Wang, D., Zhou, G., Birkenmeier, T. M., Gong, J., Sun, L., and Brattain, M. G. Autocrine transforming growth factor β1 modulates the expression of integrinα5 β1 in human colon carcinoma FET cells. J. Biol. Chem. , 1995,270:14154-14159.
18. Hemler ME, Mannion BA; Berditchevski F. Association of TM4SF proteins with integrins: relevance to cancer. Biochim Biophys Acta, 1996,1287:67.
19. Berditchevski F, Zutter MM, Hemler ME. Characterization of novel complexes on the cell surface between integrins and proteins with 4 transmembrane domains. Mol Biol Cell, 1996,7:193.
20. Berditchevski F, Odintsova E. Characterization of integrin -tetraspanin adhesion complexes: role of tetraspanins in integrin signaling [J]. J Cell Biol, 1999,146(2):477-492.
21. Clifton, F. , and Mountain, M. D. Revisions in the international system for staging lung cancer. Chest, 1997,111:1710-1717.
22. Adachi M, Taki T, Ieki Y, et al. Correlation of KAI1/CD82 gene expression with good prognosis in patients with non - small cell lung cancer. Cancer Res, 1996;56:1751-1755.
23. Adachi M, Taki T, Konishi T, et al. Novel staging protocol for non - small -cell lung cancers according to MRP- 1/CD9 and KAI1/CD82 gene expression. J Clin Oncol, 1998,16:1397-1406.
24. Higashiyama M, Kodama K, Yokouchi H, et al. KAI1/CD82 expression in nonsmall cell lung carcinoma is a novel, favorable prognostic factor: an immunohistochemical analysis. Cancer, 1998, 83:466-474.
25．李珊珊，方伟岗，任秀花，等．不同转移潜能人肺癌细胞系KAI1基因的表达．河南医科大学学报，2000；35(2)：98-100．
26. Tagawa K, Arihiro K, Takeshima Y, et al. Down-regulation of KAI1 messenger RNA expression is not associated with Ioss of heterozygosity of the KAI1 gene region in lung adenocarcinoma. Jpn J Cancer RES, 1999, 90:970-976.
27. Ginsberg, M. H., Du, X., and Plow, E. F. Inside- out integrin signaling. Curr. Opin. Cell Biol., 1992, 4:766-771.
28. Akiyama, S. K., Yamada, S. S., Chen,W. T., and Yamada, K. M. Analysis of fibronectin receptor function with monoclonal antibodies: roles in cell adhesion, migration, matrix assembly, and cytoskeletal organization. J. Cell Biol., 1989 109:863-875.
29. Werb, Z., Tremble, P. M., Behrendsten, O., Crowley, E., and Damsky, C. H. Signal transduction through the fibronectin receptor induces collagenase and stromelysin gene expression. J. Cell Biol., 1989,109:877-889.
30. Giancotti, F. G., and Rouslahti, E. Elevated levels of theoα5 β1 fibronectin receptor suppress the transformed phenotype of Chinese hamster ovary cells. Cell, 1990,60:849-859.
31. Dedhar, S., Argraves. W. S., Suzuki, S., Ruoslahti, E., and Pierschbacher, M. D. Human osteosarcoma cells resistant to detachment by an Arg-Gly-Asp-containing peptide overproduce the fibronectin receptor. J. Cell Biol., 19871,05:1175-1182.
32. Plantefaber, L. C., and Hynes, R. O. Changes in integrin receptors on oncogenically transformed cells. Cell, 1989,56:281-290.
33. Tennenbaum. T., Yuspa. S. H., Grover, A., Castmovo, C., Sobel, M. E., Yamada, Y., and De Luca, L. M. Extracellular matrix receptors and mouse skin carcinogenesis: altered expression linked to appearance of early
markers of tumor progression. Cancer Res., 52:2966-2976,1992.
34. Danen, E. H. J., Ten Berge, P. J. M., Van Muijen,G. N. P,Vant Hof-Grootenboer, A. E., Broker, E. B., and Reiter, D. J. Emergence of ot5β1 fibronectin-and αvβ3 vitronectin-receptor expression in melanocytic tumor progression. Histopathology, 1994,24:249-256.
35. Natali, P. G., Nicotra. M. R., Di Filippo, F., and Bigotti, A. Expression of fibronectin, flbronectin isoforms and integrin receptors melanocytic lesions. Br. J. Cancer, 1995,71:1243-1247.
36. Gomez, M., and Cano, A. Expression of β1 integrin receptors in transformed mouse epidermal keratinocytes: Upregulation of α5β1 in spindle carcinoma cells. Mol. Carcinog., 1995,12:153-165.
37. Libert, M., Washington, R., Stein, J., Wedemeyer, G., and Grossman, H. B. Expression of the VLA 131 integrin family in bladder cancer. Am. J. Pathol., 1994,144:1016-1022.
38. Lessey, B. A., Alblelda, S., Buck, C. A., Castelbaum, A. J., Yeh, L., Kohler, M., and Berchuck, A. Distribution of integrin cell adhesion molecules in endometrial cancer. Am. J. Pathol., 1995,146:717-726.
39. Schiller, J. H., and Bittner, G. Loss of the tumorigenic phenotype with in vitro, but not in vivo, passaging of a novel series of human bronchial epithelial cell lines: possible role of an α5/β1-integrin-fi-bronectin interaction. Cancer Res., 1995,55:6215-6221.
40. Suzuki, S., Takahashi, T., Nakamura, S., Koike, K., Ariyoshi, Y., Takahashi, T., and Ueda, R. Alterations of integrin expression in human lung cancer. Jpn. J. Cancer Res., 1993,84:168-174.
41. Albelda, S. M. Role of integrins and other cell adhesion molecules in tumor progression and metastasis. Lab. Invest., 1993, 68:4-17.
42. Varner, J. A., Emerson, D. A., and Juliano, R. L. Integrin α5β1 expression negatively regulates cell geowth: reversal by attachment to fibronectin. Mol. Biol. Cell, 1995,6:725-740.
43. Zhang, Z., Vuori, K., Reed, J. C., and Ruoslahti, E. The α5β1 integrin supports survival of cells on fibronectin and up-regulates Bcl-2 ex-
pression. Proc. Nail. Acad. Sci., USA, 1995,92:6161-6165.
44. Mannion,B. A., F Berditchevski, S. K Kraeft,et al. TM4SF protein CD81 (TAPA-1), CD82, CD63 and CD53 specifically association with α4β1 integrin. 1996,J. Immunol. 157:2039-2047.
45. Fedor Berditchevski and Elena Odintsova. Characterization of Integrin-Tetraspanin Adhesion Complexes: Role of Tetraspanins in Integrin Signaling.The Journal of Cell Biology 1999,146:477-492