KAI1/CD82在层黏素受体介导胆管癌侵袭和转移中的作用初步探讨
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摘要
胆管癌是常见的胆道恶性肿瘤之一,其发病率有呈逐年上升的趋势,而影响其治疗和病人远期生存率的主要因素是肿瘤的局部侵袭和转移。肿瘤的侵袭和转移是多基因参与、多步骤完成的复杂过程,其中肿瘤细胞黏附、运动能力的改变,以及与细胞外基质间的相互作用是肿瘤发生侵袭转移的基础,也是肿瘤侵袭转移的关键环节。探讨影响这些环节的调控因素将有助于我们更深入的理解胆管癌侵袭和转移的机制。
层黏素受体(laminin receptor,LNR)是介导细胞与细胞外基质层黏素(laminin,LN)黏附的跨膜糖蛋白受体,在几乎所有恶性实体肿瘤中表达上调,并与肿瘤的侵袭转移密切相关。LNR与LN特异性结合能诱导肿瘤细胞或宿主细胞分泌IV型胶原酶和基质金属蛋白酶(如MMP-2、MMP-9)等蛋白水解酶,降解基底膜中的LN和IV型胶原蛋白有助于肿瘤细胞的侵袭和转移。Givant-Horwitz等研究表明高转移性肿瘤细胞LNR表达上调还可诱导一系列跨膜信号传导系统的变化,引起细胞外信号调节激酶、c-Jun N-端蛋白激酶和p38 MAPK引发信号级联反应,促进肿瘤细胞的分裂和转移。我们前期研究表明,胆管癌中LNR表达上调并在多个环节介导胆管癌侵袭和转移,而运用LNR反义寡聚核苷酸转染高转移性胆管癌细胞,则能明显抑制LNR表达上调对胆管癌侵袭能力的促进作用。但是什么原因导致LNR表达上调?其分子机制如何?这是深入研究LNR表达上调介导胆管癌侵袭和转移机制的重要环节。
KAI1/CD82是新近发现的特异性肿瘤转移抑制基因,定位于人染色体11p11.2,编码含267个氨基酸的蛋白质分子,相对分子量为29.61kD,属于跨膜4超家族(trans- membrane 4 superfamily, TM4SF)成员。KAI1/CD82在前列腺癌、肺癌、乳腺癌、消化管肿瘤、胰腺癌、膀胱癌等大多数肿瘤中表达减少或缺失,且与肿瘤侵袭转移密切相关。KAI1/CD82和其他TM4SF成员与整合素形成复合体,通过PKC、Rho GTPases、Src激酶家族等信号通道介导细胞的黏附,使肿瘤细胞不易脱离原发灶而抑制转移。Bo He等将KAI1/CD82转染前列腺癌Du145细胞后,发现细胞表面整合素α6减少,降低细胞与细胞外基质LN的黏附而抑制细胞的迁移能力。而LNR与α6共表达、交互影响,并能免疫共沉淀。由此我们推测,胆管癌中LNR表达上调可能与KAI1/CD82表达减少或缺失有关。深入研究KAI1/CD82在LNR介导胆管癌侵袭和转移中的作用,有助于我们深刻理解胆管癌侵袭和转移的调控机制,从而为寻求新的肿瘤治疗策略和方法提供理论依据。
本课题正是基于KAI1/CD82和LNR均与肿瘤侵袭转移密切相关以及KAI1/CD82表达减少或缺失可能导致LNR表达上调的设想,以临床胆管癌组织标本和胆管癌细胞系QBC939为研究对象,探讨KAI1/CD82在LNR介导胆管癌侵袭和转移中的作用。实验设计如下:首先,采用免疫组织化学方法检测KAI1/CD82在胆管癌组织标本中的表达情况,并分析其表达水平及与临床病理参数的关系;其次,采用免疫组织化学方法检测分析在不同KAI1/CD82胆管癌组织中LNR的表达差异,分析两者的关系;最后,利用基因工程技术构建含人KAI1/CD82全长基因的重组真核表达质粒pIRES2- EGFP-KAI1/CD82,并经酶切和测序鉴定证实构建成功,通过脂质体转染胆管癌QBC939细胞,免疫细胞化学、Western blot检测胆管癌QBC939细胞过表达KAI1/CD82后LNR蛋白表达的变化。
结果:
1.KAI1/CD82在胆管癌组织中的阳性表达率(31.3%,15/48)明显低于其在正常胆管组织中的表达(87.5%,7/8),两者间差异显著(χ2=6.891,P<0.01)。分化程度越高,KAI1/CD82阳性表达率越高(χ2=3.911,P<0.05),KAI1/CD82在有转移组的阳性表达率较在无转移组的低(χ2=5.765,P<0.05),而与患者的年龄、性别、肿瘤的部位和病理类型均无关(P>0.05)。这些结果表明,KAI1/CD82表达减少或缺失可能参与了胆管癌的侵袭转移,其表达下降或许可以作为胆管癌恶性程度的一个分子标志。
2.LNR蛋白在胆管癌组织的阳性表达率为54.2%(26/48),分化程度越低,LNR阳性表达率较高(χ2=6.970,P<0.05),有转移组较无转移组明显升高(χ2 =9.952,P<0.01),而与患者性别、年龄、肿瘤部位及病理类型无关(P>0.05)。提示LNR表达上调介导了胆管癌的侵袭转移。
3.KAI1/CD82表达阳性的胆管癌组织LNR阳性表达率为20.0%(3/15),而KAI1/ CD82表达阴性的胆管癌组织LNR阳性表达率为69.7%(23/33),两者比较差异显著(χ2=10.259,P<0.01)。胆管癌组织中KAI1/CD82和LNR表达呈负相关(γ=-0.462,P<0.01)。提示KAI1/CD82表达减少或缺失可能导致LNR表达上调,进而介导胆管癌的侵袭转移。
4.经过酶切、基因测序鉴定,真核表达载体pIRES2-EGFP-KAI1/CD82含有KAI1/CD82全长基因序列,说明质粒构建成功。
5.通过脂质体分别转染pIRES2-EGFP-KAI1/CD82重组质粒及pIRES2-EGFP空载体至胆管癌QBC939细胞,免疫细胞化学和Western blot的方法检测转染后KAI1/ CD82、LNR蛋白的表达,结果显示:转染重组质粒的实验组KAI1/CD82蛋白的表达水平明显高于转染空载体的对照组(P<0.05),而LNR蛋白的表达水平较转染空载体的对照组降低(P<0.05),说明胆管癌QBC939细胞过表达KAI1/CD82可降低LNR蛋白表达。
结论:
1.胆管癌组织中KAI1/CD82表达减少或缺失。
2.胆管癌组织中KAI1/CD82表达与胆管癌分化程度、侵袭转移密切相关。
3.胆管癌组织中KAI1/CD82、LNR表达呈负相关。
4.成功构建了重组真核表达载体pIRES2-EGFP-KAI1/CD82,并经酶切和测序鉴定证实构建成功。
5.胆管癌中LNR表达上调可能与KAI1/CD82表达减少或缺失有关。
Purpose: Tumor invasion and metastasis is a multistage process, involving adherence, movement and proliferation of tumor cells, degradation of extracellular matrix (ECM) and tumor angiogenesis. Laminin receptor (LNR) is a critical cellular adhesion molecule receptor, which plays an important role in mediation of tumor cells′adhesion with ECM. Although many efforts have been made to elucidate the role of LNR in many kinds of carcinoma, there are little reports concerning the mechanism of its up-regulation in metastasis carcinoma. KAI1/CD82, as the tumor metastasis suppressor, is involved in cell migration, adhesion, and synapse formation and is decreased in various tumors. Several studies have shown that KAI1/CD82 can reduceα6 andβ1 integrin cell surface expression, leading to the attenuation of cell-ECM adhesion. Previous reports have also illustrated that there was co-regulation and interaction between LNR andα6 integrin. Therefore, we hypothesize that the overexpression of LNR in carcinoma might due to the down-regulated expression of KAI1/CD82.
Experimental Design: In the first part of the experiment, we examined the expression of KAI1/CD82 in surgical resection cholangiocarcinoma and normal tissues by immuno- histochemistry and assessed its correlation and clinic pathological significance. In the second part of the experiment, we examined the different expression of LNR in KAI1/CD82 cholangiocarcinoma by immunohistochemistry, and assessed the correlation of KAI1/CD82 and LNR. In the third part of the experiment, we transfected a recombinant plasmid vector containing KAI1/CD82 gene into QBC939 cell. The expression of KAI1/CD82 and LNR proteins were determined by immunocytochemistry and Western blot.
Results:
1. The positive rate of KAI1/CD82 protein in cholangiocarcinoma was 31.3%(15/48), which was lower than that of normal tissue (P<0.01). The positive rate of LNR protein in cholangiocarcinoma was 54.2%(26/48). In highly differentiated cholangiocarcinoma, the positive expression of KAI1/CD82 was high (P<0.05), while that of the LNR protein was low(P < 0.05). The positive expression of KAI1/CD82 in cholangiocarcinoma with metastasis was significantly lower than that in cholangiocarcinoma without metastasis (P<0.05), while the positive rate of LNR protein in cholangiocarcinoma with metastasis was significantly higher than that in cholangiocarcinoma without metastasis (P<0.05).
2. The expression level of KAI1/CD82 protein in cholangiocarcinoma was negatively correlated with that of LNR protein (γ=-0.462, P<0.01).
3. Eukaryotic expression plasmid vector of pIRES2-EGFP-KAI1/CD82 was designed and generated by molecular biological technology. Its quality was ensured by sequencing and identification.
4. The plasmid vectors were transfected into QBC939 cells by cation liposomes. The high expression of KAI1/CD82 protein was observed by immunocytochemistry and Western blot (P<0.05).
5. After pIRES2-EGFP-KAI1/CD82 transfected into QBC939 cell, the decreased expression of LNR protein was determined by immunocytochemistry and Western blot (P<0.05).
Conclusions: The results demonstrate that KAI1/CD82 down-expression is a critical molecular marker of cholangiocarcinoma and is strongly associated with the invasion and metastasis of this tumor. The up-regulated expression of LNR protein in cholangio- caicinoma correlates with the decreased expression of KAI1/CD82 protein. It seems that the overexpression of LNR is regulated by down-regulated KAI1/CD82 in cholangiocarcinoma.
层黏素受体(laminin receptor,LNR)是介导细胞与细胞外基质层黏素(laminin,LN)黏附的跨膜糖蛋白受体,在几乎所有恶性实体肿瘤中表达上调,并与肿瘤的侵袭转移密切相关。LNR与LN特异性结合能诱导肿瘤细胞或宿主细胞分泌IV型胶原酶和基质金属蛋白酶(如MMP-2、MMP-9)等蛋白水解酶,降解基底膜中的LN和IV型胶原蛋白有助于肿瘤细胞的侵袭和转移。Givant-Horwitz等研究表明高转移性肿瘤细胞LNR表达上调还可诱导一系列跨膜信号传导系统的变化,引起细胞外信号调节激酶、c-Jun N-端蛋白激酶和p38 MAPK引发信号级联反应,促进肿瘤细胞的分裂和转移。我们前期研究表明,胆管癌中LNR表达上调并在多个环节介导胆管癌侵袭和转移,而运用LNR反义寡聚核苷酸转染高转移性胆管癌细胞,则能明显抑制LNR表达上调对胆管癌侵袭能力的促进作用。但是什么原因导致LNR表达上调?其分子机制如何?这是深入研究LNR表达上调介导胆管癌侵袭和转移机制的重要环节。
KAI1/CD82是新近发现的特异性肿瘤转移抑制基因,定位于人染色体11p11.2,编码含267个氨基酸的蛋白质分子,相对分子量为29.61kD,属于跨膜4超家族(trans- membrane 4 superfamily, TM4SF)成员。KAI1/CD82在前列腺癌、肺癌、乳腺癌、消化管肿瘤、胰腺癌、膀胱癌等大多数肿瘤中表达减少或缺失,且与肿瘤侵袭转移密切相关。KAI1/CD82和其他TM4SF成员与整合素形成复合体,通过PKC、Rho GTPases、Src激酶家族等信号通道介导细胞的黏附,使肿瘤细胞不易脱离原发灶而抑制转移。Bo He等将KAI1/CD82转染前列腺癌Du145细胞后,发现细胞表面整合素α6减少,降低细胞与细胞外基质LN的黏附而抑制细胞的迁移能力。而LNR与α6共表达、交互影响,并能免疫共沉淀。由此我们推测,胆管癌中LNR表达上调可能与KAI1/CD82表达减少或缺失有关。深入研究KAI1/CD82在LNR介导胆管癌侵袭和转移中的作用,有助于我们深刻理解胆管癌侵袭和转移的调控机制,从而为寻求新的肿瘤治疗策略和方法提供理论依据。
本课题正是基于KAI1/CD82和LNR均与肿瘤侵袭转移密切相关以及KAI1/CD82表达减少或缺失可能导致LNR表达上调的设想,以临床胆管癌组织标本和胆管癌细胞系QBC939为研究对象,探讨KAI1/CD82在LNR介导胆管癌侵袭和转移中的作用。实验设计如下:首先,采用免疫组织化学方法检测KAI1/CD82在胆管癌组织标本中的表达情况,并分析其表达水平及与临床病理参数的关系;其次,采用免疫组织化学方法检测分析在不同KAI1/CD82胆管癌组织中LNR的表达差异,分析两者的关系;最后,利用基因工程技术构建含人KAI1/CD82全长基因的重组真核表达质粒pIRES2- EGFP-KAI1/CD82,并经酶切和测序鉴定证实构建成功,通过脂质体转染胆管癌QBC939细胞,免疫细胞化学、Western blot检测胆管癌QBC939细胞过表达KAI1/CD82后LNR蛋白表达的变化。
结果:
1.KAI1/CD82在胆管癌组织中的阳性表达率(31.3%,15/48)明显低于其在正常胆管组织中的表达(87.5%,7/8),两者间差异显著(χ2=6.891,P<0.01)。分化程度越高,KAI1/CD82阳性表达率越高(χ2=3.911,P<0.05),KAI1/CD82在有转移组的阳性表达率较在无转移组的低(χ2=5.765,P<0.05),而与患者的年龄、性别、肿瘤的部位和病理类型均无关(P>0.05)。这些结果表明,KAI1/CD82表达减少或缺失可能参与了胆管癌的侵袭转移,其表达下降或许可以作为胆管癌恶性程度的一个分子标志。
2.LNR蛋白在胆管癌组织的阳性表达率为54.2%(26/48),分化程度越低,LNR阳性表达率较高(χ2=6.970,P<0.05),有转移组较无转移组明显升高(χ2 =9.952,P<0.01),而与患者性别、年龄、肿瘤部位及病理类型无关(P>0.05)。提示LNR表达上调介导了胆管癌的侵袭转移。
3.KAI1/CD82表达阳性的胆管癌组织LNR阳性表达率为20.0%(3/15),而KAI1/ CD82表达阴性的胆管癌组织LNR阳性表达率为69.7%(23/33),两者比较差异显著(χ2=10.259,P<0.01)。胆管癌组织中KAI1/CD82和LNR表达呈负相关(γ=-0.462,P<0.01)。提示KAI1/CD82表达减少或缺失可能导致LNR表达上调,进而介导胆管癌的侵袭转移。
4.经过酶切、基因测序鉴定,真核表达载体pIRES2-EGFP-KAI1/CD82含有KAI1/CD82全长基因序列,说明质粒构建成功。
5.通过脂质体分别转染pIRES2-EGFP-KAI1/CD82重组质粒及pIRES2-EGFP空载体至胆管癌QBC939细胞,免疫细胞化学和Western blot的方法检测转染后KAI1/ CD82、LNR蛋白的表达,结果显示:转染重组质粒的实验组KAI1/CD82蛋白的表达水平明显高于转染空载体的对照组(P<0.05),而LNR蛋白的表达水平较转染空载体的对照组降低(P<0.05),说明胆管癌QBC939细胞过表达KAI1/CD82可降低LNR蛋白表达。
结论:
1.胆管癌组织中KAI1/CD82表达减少或缺失。
2.胆管癌组织中KAI1/CD82表达与胆管癌分化程度、侵袭转移密切相关。
3.胆管癌组织中KAI1/CD82、LNR表达呈负相关。
4.成功构建了重组真核表达载体pIRES2-EGFP-KAI1/CD82,并经酶切和测序鉴定证实构建成功。
5.胆管癌中LNR表达上调可能与KAI1/CD82表达减少或缺失有关。
Purpose: Tumor invasion and metastasis is a multistage process, involving adherence, movement and proliferation of tumor cells, degradation of extracellular matrix (ECM) and tumor angiogenesis. Laminin receptor (LNR) is a critical cellular adhesion molecule receptor, which plays an important role in mediation of tumor cells′adhesion with ECM. Although many efforts have been made to elucidate the role of LNR in many kinds of carcinoma, there are little reports concerning the mechanism of its up-regulation in metastasis carcinoma. KAI1/CD82, as the tumor metastasis suppressor, is involved in cell migration, adhesion, and synapse formation and is decreased in various tumors. Several studies have shown that KAI1/CD82 can reduceα6 andβ1 integrin cell surface expression, leading to the attenuation of cell-ECM adhesion. Previous reports have also illustrated that there was co-regulation and interaction between LNR andα6 integrin. Therefore, we hypothesize that the overexpression of LNR in carcinoma might due to the down-regulated expression of KAI1/CD82.
Experimental Design: In the first part of the experiment, we examined the expression of KAI1/CD82 in surgical resection cholangiocarcinoma and normal tissues by immuno- histochemistry and assessed its correlation and clinic pathological significance. In the second part of the experiment, we examined the different expression of LNR in KAI1/CD82 cholangiocarcinoma by immunohistochemistry, and assessed the correlation of KAI1/CD82 and LNR. In the third part of the experiment, we transfected a recombinant plasmid vector containing KAI1/CD82 gene into QBC939 cell. The expression of KAI1/CD82 and LNR proteins were determined by immunocytochemistry and Western blot.
Results:
1. The positive rate of KAI1/CD82 protein in cholangiocarcinoma was 31.3%(15/48), which was lower than that of normal tissue (P<0.01). The positive rate of LNR protein in cholangiocarcinoma was 54.2%(26/48). In highly differentiated cholangiocarcinoma, the positive expression of KAI1/CD82 was high (P<0.05), while that of the LNR protein was low(P < 0.05). The positive expression of KAI1/CD82 in cholangiocarcinoma with metastasis was significantly lower than that in cholangiocarcinoma without metastasis (P<0.05), while the positive rate of LNR protein in cholangiocarcinoma with metastasis was significantly higher than that in cholangiocarcinoma without metastasis (P<0.05).
2. The expression level of KAI1/CD82 protein in cholangiocarcinoma was negatively correlated with that of LNR protein (γ=-0.462, P<0.01).
3. Eukaryotic expression plasmid vector of pIRES2-EGFP-KAI1/CD82 was designed and generated by molecular biological technology. Its quality was ensured by sequencing and identification.
4. The plasmid vectors were transfected into QBC939 cells by cation liposomes. The high expression of KAI1/CD82 protein was observed by immunocytochemistry and Western blot (P<0.05).
5. After pIRES2-EGFP-KAI1/CD82 transfected into QBC939 cell, the decreased expression of LNR protein was determined by immunocytochemistry and Western blot (P<0.05).
Conclusions: The results demonstrate that KAI1/CD82 down-expression is a critical molecular marker of cholangiocarcinoma and is strongly associated with the invasion and metastasis of this tumor. The up-regulated expression of LNR protein in cholangio- caicinoma correlates with the decreased expression of KAI1/CD82 protein. It seems that the overexpression of LNR is regulated by down-regulated KAI1/CD82 in cholangiocarcinoma.
引文
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8. Dong J T, Lamb PW, Rinker Schaeffer CW, et al. KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2. Science, 1995, 268(5212): 884-886.
9. Liu WM, Zhang XA.KAI1/CD82, a tumor metastasis suppressor. Cancer Lett, 2006 (240): 183-194.
10. Jee B, Jin K, Hahu JH, et al. Metastasis-suppressor KAI1/CD82 induces homotypic aggregation of human prostate cancer cells through Src-dependent pathway. Exp Mol Med, 2003, 35(1): 30-37.
11. He B, Liu L, Cook GA, et al. Tetraspanin CD82 attenuates cellular morphogenesis through down-regulating integrinα6-mediated cell adhesion. J Biol Chem, 2005, 280(5): 3346-3354.
12. BoKeun J, JooYong L, Young L, et al. Effect of KAI1/CD82 on theβ1 integrin maturation in highly migratory carcinoma cells. Biochemical and Biophysical Research Communications, 2007, 359(5): 703-708.
13. Ardini E, Tagliabue E, Magnifico A, et al. Co-regulation and physical association of the 67kDa monomeric laminin receptor and theα6β4 integrin. J Biol Chem, 1997, 272(4): 2342-2345.
14. Lee HS, Lee HK, Kim HS, et al. Tumor suppressor gene expression correlates with gastric cancer prognosis. J Pathol, 2003, 200(4): 39-46.
15. Dong JT, Isaacs WB, Barret JC, et al. Genomic organization of the human KAI1 metastasis-suppressor gene. Genomics, 1997, 41(1): 25-32.
16. Nagira M, Imai T, Ishikawa I, et al. Mouse homologue of C33 antigen (CD82), a member of the transmembrane 4 superfamily: complementary DNA, genomic structure, and expression. Cell Immunol, 1994, 157(1): 144-157.
17. Hemler ME. Specific tetraspanin functions. J Cell Biol. 2001, 155(7): 1103-1108.
18. Stipp CS, Kolesnikova TV, Hemler ME. Functional domains in tetraspanin proteins. Trends Biochem Sci, 2003, 28(1):106-112.
19. Zoller M. Gastrointestinal tumors: metastasis and tetraspanins. Gastroenterology, 2006, 44(7): 573-586.
20. Yang X, Wei L, Tang C, et al. Overexpression of KAI1 suppresses in vitro invasiveness and in vivo metastasis in breast cancer cells. Cancer Res, 2001, 61(13): 5284-5288.
21. Ai X, Zhang X, Wu Z, et al. Expression of KAI1/CD82 and MRP-1/CD9 in transitional cell carcinoma of bladder. J Hua zhong Univ Sci Technol Med Sci, 2007, 27(1): 79-82.
22. Takeda T, Hattorin, Tokuhara T, et al. Adenoviral transduction of MRP-1/CD9 and KAI1/ CD82 inhibits lymph node metastasis in orthotopic lung cancer model. Cancer Res, 2007, 67(4): 1744-1749.
23. Ow K, Delprodo W, Fisher R, et al. Relationship between expression of the KAI1 metastasis suppressor and other markers of advanced bladder cancer. J Pathol, 2000, 191(l): 39-47.
24. Mehrdad N, Mehdi N, Manuel F, et al. Laminin receptor in lymph node negative breast carcinoma. Cancer, 1999, 85(2): 432-436.
25. Tanaka M, Narumi K, Isemura M, et al. Expression of the 37–kDa 1aminin binding protein in murine 1ung tumor cell corre1ates with tumor angiogenesis.Cancer Lett, 2000, 153(1): 161-168.
26. Ardini E, Sporchia B, Pollegioni L, et al. Identification of a nove1 function for 67 kDa lamlnin receptor: increase inlaninin degradation rate and release of motility frag Inents. Cancer Res, 2002, 62(5): 1321-1325.
27. Givant-Horwitz V, Davidson B, Reich R. Laminin-induced signaling in tumor cells: the role of the M(r)67,000 laminin receptor. Cancer Res, 2004, 64(10): 3572-3579.
28.王曙光,韩本立,段恒春,等.肝外胆管癌细胞系的建立.中华实验外科杂志. 1997, 14(2): 67-69.
29. Iwata S, Kobayashi H, Miyake-Nishijima R, et al. Distinctive signaling pathways through CD82 and beta1 integrins in human T cells. Eur J Immunol, 2002, 32(5): 1328- 1337.
30. Zhang XA, He B, Zhou B, et al. Requirement of the p130CAS-Crk coupling for metastasis suppressor KAI1/CD82-mediated inhibition of cell migration. J Biol Chem, 2003, (29): 27319-27328.
31. Odintsova E, Voortman J, Gilbert E, et al. Tetraspanin CD82 regulates compartmental- isation and ligand-induced dimerization of EGFR. J Cell Sci, 2003, 116(22): 4557-4566.
32. Bass R, Werner F, Odintsova E, et al. Regulation of urokinase receptor proteolytic function by the tetraspanin CD82. J Biol Chem, 2005, 280(15): 14811-14818.
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4. Takeda T, Hattorin, Tokuhara T, et al. Adenoviral transduction of MRP-1/CD9 and KAI1/CD82 inhibits lymph node metastasis in orthotopic lung cancer model. Cancer Res, 2007, 67(4): 1744-1749.
5. Hemler ME. Specific tetraspanin functions. J Cell Biol. 2001, 155(7): 1103-1108.
6. Stipp CS, Kolesnikova TV, Hemler ME. Functional domains in tetraspanin proteins. Trends Biochem Sci, 2003, 28(1): 106-112.
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4. Nelson J, McFerran NV, Pivato G, et al. The 67 kDa laminin receptor: structure, function and role in disease. Biosci Rep. 2008, 28(1): 33-48.
5.李大江,陈健,陈长宏,等.胆管癌组织中层粘连蛋白及67KDa层粘连蛋白受体的表达及临床意义.中国组织化学与细胞化学杂志, 2007, 16(1): 110-114.
6.李大江,陈健,陈长宏,等.层粘素受体下调对蛋白水解酶MMP-2, MMP-9, u-PA蛋白表达的影响.中华消化外科杂志, 2006, 5(6): 455-458.
7.王曙光,陈长宏,李大江,等.胆管癌细胞层粘连蛋白受体表达下调对蛋白水解酶尿激酶型纤维蛋白溶解酶原激酶mRNA表达的影响.中华医学杂志, 2004, 84: 1642-1644.
8. Dong J T, Lamb PW, Rinker Schaeffer CW, et al. KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2. Science, 1995, 268(5212): 884-886.
9. Liu WM, Zhang XA.KAI1/CD82, a tumor metastasis suppressor. Cancer Lett, 2006 (240): 183-194.
10. Jee B, Jin K, Hahu JH, et al. Metastasis-suppressor KAI1/CD82 induces homotypic aggregation of human prostate cancer cells through Src-dependent pathway. Exp Mol Med, 2003, 35(1): 30-37.
11. He B, Liu L, Cook GA, et al. Tetraspanin CD82 attenuates cellular morphogenesis through down-regulating integrinα6-mediated cell adhesion. J Biol Chem, 2005, 280(5): 3346-3354.
12. BoKeun J, JooYong L, Young L, et al. Effect of KAI1/CD82 on theβ1 integrin maturation in highly migratory carcinoma cells. Biochemical and Biophysical Research Communications, 2007, 359(5): 703-708.
13. Ardini E, Tagliabue E, Magnifico A, et al. Co-regulation and physical association of the 67kDa monomeric laminin receptor and theα6β4 integrin. J Biol Chem, 1997, 272(4): 2342-2345.
14. Lee HS, Lee HK, Kim HS, et al. Tumor suppressor gene expression correlates with gastric cancer prognosis. J Pathol, 2003, 200(4): 39-46.
15. Dong JT, Isaacs WB, Barret JC, et al. Genomic organization of the human KAI1 metastasis-suppressor gene. Genomics, 1997, 41(1): 25-32.
16. Nagira M, Imai T, Ishikawa I, et al. Mouse homologue of C33 antigen (CD82), a member of the transmembrane 4 superfamily: complementary DNA, genomic structure, and expression. Cell Immunol, 1994, 157(1): 144-157.
17. Hemler ME. Specific tetraspanin functions. J Cell Biol. 2001, 155(7): 1103-1108.
18. Stipp CS, Kolesnikova TV, Hemler ME. Functional domains in tetraspanin proteins. Trends Biochem Sci, 2003, 28(1):106-112.
19. Zoller M. Gastrointestinal tumors: metastasis and tetraspanins. Gastroenterology, 2006, 44(7): 573-586.
20. Yang X, Wei L, Tang C, et al. Overexpression of KAI1 suppresses in vitro invasiveness and in vivo metastasis in breast cancer cells. Cancer Res, 2001, 61(13): 5284-5288.
21. Ai X, Zhang X, Wu Z, et al. Expression of KAI1/CD82 and MRP-1/CD9 in transitional cell carcinoma of bladder. J Hua zhong Univ Sci Technol Med Sci, 2007, 27(1): 79-82.
22. Takeda T, Hattorin, Tokuhara T, et al. Adenoviral transduction of MRP-1/CD9 and KAI1/ CD82 inhibits lymph node metastasis in orthotopic lung cancer model. Cancer Res, 2007, 67(4): 1744-1749.
23. Ow K, Delprodo W, Fisher R, et al. Relationship between expression of the KAI1 metastasis suppressor and other markers of advanced bladder cancer. J Pathol, 2000, 191(l): 39-47.
24. Mehrdad N, Mehdi N, Manuel F, et al. Laminin receptor in lymph node negative breast carcinoma. Cancer, 1999, 85(2): 432-436.
25. Tanaka M, Narumi K, Isemura M, et al. Expression of the 37–kDa 1aminin binding protein in murine 1ung tumor cell corre1ates with tumor angiogenesis.Cancer Lett, 2000, 153(1): 161-168.
26. Ardini E, Sporchia B, Pollegioni L, et al. Identification of a nove1 function for 67 kDa lamlnin receptor: increase inlaninin degradation rate and release of motility frag Inents. Cancer Res, 2002, 62(5): 1321-1325.
27. Givant-Horwitz V, Davidson B, Reich R. Laminin-induced signaling in tumor cells: the role of the M(r)67,000 laminin receptor. Cancer Res, 2004, 64(10): 3572-3579.
28.王曙光,韩本立,段恒春,等.肝外胆管癌细胞系的建立.中华实验外科杂志. 1997, 14(2): 67-69.
29. Iwata S, Kobayashi H, Miyake-Nishijima R, et al. Distinctive signaling pathways through CD82 and beta1 integrins in human T cells. Eur J Immunol, 2002, 32(5): 1328- 1337.
30. Zhang XA, He B, Zhou B, et al. Requirement of the p130CAS-Crk coupling for metastasis suppressor KAI1/CD82-mediated inhibition of cell migration. J Biol Chem, 2003, (29): 27319-27328.
31. Odintsova E, Voortman J, Gilbert E, et al. Tetraspanin CD82 regulates compartmental- isation and ligand-induced dimerization of EGFR. J Cell Sci, 2003, 116(22): 4557-4566.
32. Bass R, Werner F, Odintsova E, et al. Regulation of urokinase receptor proteolytic function by the tetraspanin CD82. J Biol Chem, 2005, 280(15): 14811-14818.
1. Menard S, Castronovo V, Tagliabue E, et al. New insights into the metastasis- associated 67 kD laminin receptor. Ce11 Biochem, 1997, 67(1): 155–165.
2. Hipfel R, Schittek B, Bodingbauer Y, et al. Specifically regulated genes in malignant melanoma tissues identified by subtractive hybridization. Br J Cancer, 2000, 82(6): 1149-1157.
3. Buto S, Tagliabue E, Ardini E, et al. Formation of the 67-kDa laminin receptor by acylation of the precursor. Cell Biochem, 1998, 69(3): 244-251.
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