NF-kB与Slug在非小细胞肺癌中的表达及其在上皮间质转化中的作用
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摘要
目的：研究核因子NF-kB与锌指蛋白因子Slug在非小细胞肺癌(NSCLC)及癌旁相应正常肺组织中的表达并探讨其与肺癌上皮间质转化(EMT)的关系,为寻找非小细胞肺癌的分子治疗靶点提供理论基础。
方法：(1)采用免疫组织化学PV9000二步法测定50例NSCLC及相应20例癌旁正常肺组织中NF-kBP65、slug、E-cadherin及Vimentin蛋白表达情况。(2)采用逆转录聚合酶链反应法(RT-PCR)测定其中新鲜的25例NSCLC及10例癌旁相应正常肺组织中NF-kBP65、slug的mRNA表达。
结果：(1)免疫组织化学结果：NF-kBP65蛋白在NSCLC组织中阳性表达率78%(39/50)及阳性强度分别明显高于癌旁正常肺组织中的阳性表达率20%(4/20)及阳性强度(χ2=20.28,P<0.01；Z=-2.370,P<0.05)；Slug蛋白在NSCLC组织中阳性表达率82%(41/50)及阳性强度亦分别明显高于癌旁相应正常肺组织的阳性表达率30%(6/20)及阳性强度(χ2=17.51,P<0.01；Z=-4.443,P<0.01)；50例NSCLC组织中,NF-kBP65阳性癌组织中E-cadherin蛋白阳性表达率(17/39,43.6%)明显低于NF-kBP65阴性癌组织中E-cadherin蛋白阳性表达率(9/11,81.8%),差异有统计学意义(Z=5.024,P<0.05)；50例NSCLC组织中,NF-kBP65阳性癌组织中Vimentin蛋白阳性表达率(25/39,64.1%)明显高于NF-kBP65阴性癌组织Vimentin蛋白阳性表达率(3/11,27.3%),差异有统计学意义(Z=4.723,P<0.05)。NSCLC组织中,Slug性癌组织中E-cadherin蛋白阳性表达率(18/41,43.9%)明显低于Slug阴性癌组织中E-cadherin蛋白阳性表达率(8/9,88.9%),差异有统计学意义(χ=5.984,P<0.05)；Slug阳性癌组织中Vimentin蛋白阳性表达率(26/41,63.4%)明显高于Slug阴性癌组织中Vimentin阳性表达率(2/9,22.2%),差异有统计学意义(#=5.028,P<0.05)。另外,NSCLC组织中,NF-kB在高中分化组的阳性表达率明显低于低分化组的阳性表达率(χ2=5.024,P<0.05),在淋巴结无转移组的阳性表达率明显低于淋巴结有转移组的阳性表达率()c2=7.933,P<0.01),在Ⅰ-Ⅱ期阳性表达率明显低于Ⅲ-Ⅳ期阳性表达率(χ2=5.614,P<0.05),NF-kB与性别、年龄、组织类型均无明显相关性(P>0.05)；Slug在淋巴结无转移组的阳性表达率明显低于淋巴结有转移组的阳性表达率(χ2=6.174,P<0.05),在Ⅰ-Ⅱ期阳性表达率明显低于Ⅲ-Ⅳ期阳性表达率(χ2=7.317,P<0.01),Slug与性别、年龄、组织类型、分化程度均无明显相关性(P>0.05)。NF-kBP65蛋白与Slug蛋白呈极显著正相关性(r=0.443,P<0.01)。(2)RT-PCR
结果：NF-kBP65mRNA及SlugmRNA在NSCLC组织中的表达量均明显高于癌旁相应正常肺组织(t=4.967,6.483；P<0.01)；两者表达量亦呈显著正相关性(r=0.439,P<0.05)。
结论：NF-kB及Slug可能均与NSCLC的发生、进展及转移关系密切；NF-kB阳性癌组织中E-cadherin表达降低,Vimentin表达升高,说明NF-kB能够抑制E-cadherin的表达,促进Vimentin的表达,在NSCLC的EMT中发挥重要作用；Slug阳性癌组织中E-cadherin表达降低,Vimentin表达升高,提示Slug同样能够抑制E-cadherin的表达,促进Vimentin的表达,在NSCLC的EMT中发挥重要作用；NF-kB与Slug在基因及蛋白水平表达均呈显著正相关性,提示NF-kB和Slug可能协同促进NSCLC的发生,协同抑制E-cadherin的表达、促进Vimentin的表达,共同诱使NSCLC的EMT发生,从而为进一步研究NSCLC的EMT提供理论依据。
Objective:To investigate the expression of NF-kB and Slug in NSCLC, adjacent normal lung tissue, and their effects on EMT, and to provide theoretical basis for searching molecular therapy targets of NSCLC.
Methods:(1) The expression of NF-kBP65, Slug, E-cadherin and Vimentin protein was detected immunohistochemically in50cases NSCLC tissue and20cases corresponding adjacent normal lung tissue with PV9000two-step method.(2) RT-PCR was performed to determine the expression of NF-kBP65mRNA and SlugmRNA in25cases fresh NSCLC tissues and10cases fresh adjacent normal lung tissue.
Results:(1)Immunohistochemical Results:In NSCLC tissue, NF-kBP65protein expressive rate78%(39/50) and expressive intensity were both higher than that in adjacent normal lung tissue20%(4/20)(χ2=20.28, P<0.01; Z=-2.370,P<0.05); Slug protein expressive rate82%(41/50) and expressive intensity were also both higher than that in adjacent normal lung tissue30%(6/20)(χ2=17.51, P<0.01; Z=-4.443,P<0.01); In50cases NSCLC tissue, E-cadherin protein expressive rate (17/39,43.6%) in NF-kBP65positive tissue was lower than that in NF-kBP65negative tissue (9/11,81.8%)(χ2=5.024,P<0.05).Vimentin protein expressive rate (25/39,64.1%) in NF-kBP65positive tissue was higher than that in NF-kBP65negative tissue (3/11,27.3%)(χ2=4.723,P<0.05). E-cadherin protein expressive rate (18/41,43.9%) in Slug positive tissues was lower than that in Slug negative tissue (8/9,88.9%)(χ2=5.984,P<0.05) Vimentin protein expressive rate (26/41,63.4%) in Slug positive tissues was higher than that in Slug negative tissue (2/9,22.2%)(χ2=5.028,P<0.05). The expression of NF-kB protein in high-moderate differentiation group was lower than that in poor differentiation group (χ2=5.024,P<0.05), in negative lymph node group was lower than that in positive group (χ2=7.933,P<0.01), and in stage Ⅰ-Ⅱ was lower than that in stage Ⅲ-Ⅳ (χ2=5.614,P<0.05), but had no relation to gender, age and histological types (P>0.05). The expression of Slug protein in negative lymph node group was lower than that in positive group (χ2=6.174,P<0.05), and in stage Ⅰ-Ⅱ was lower than that in stage Ⅲ-Ⅳ (χ2=7.317,P<0.01), but not related to gender, age, histological types and differentiation (P>0.05). NF-kBP65protein was significant positively correlated with Slug protein (r=0.443,P<0.01).
(2) RT-PCR results:The expression of NF-kBP65and Slug mRNA was both significantly higher than that in adjacent normal lung tissues (t=4.967,6.483,P<0.01 respectively).
NF-kBP65mRNA expression was positively correlated with Slug mRNA (r=0.439,P <0.05).
Conclusion:The increased expression of NF-kB and Slug in NSCLC may be related to the occurrence, development and metastasis of NSCLC; In NF-kB positive NSCLC tissues, E-cadherin expression is decreased while vimentin expression increased. It implies that NF-kB may suppress E-cadherin expression and promote vimentin expression, and may be important to EMT of NSCLC. In Slug positive NSCLC tissues, E-cadherin expression is decreased and Vimentin expression increased. It also implies that Slug may suppress expression of E-cadherin and promote expression of vimentin, and may also be important to EMT of NSCLC. Both in protein and mRNA level, NF-kB are positively correlated with Slug. It implies that NF-kB and Slug may synergistically inhibit E-cadherin expression, promote Vimentin expression, and induce EMT of NSCLC. It provides further theoretical basis to the researches on EMT of NSCLC.
方法：(1)采用免疫组织化学PV9000二步法测定50例NSCLC及相应20例癌旁正常肺组织中NF-kBP65、slug、E-cadherin及Vimentin蛋白表达情况。(2)采用逆转录聚合酶链反应法(RT-PCR)测定其中新鲜的25例NSCLC及10例癌旁相应正常肺组织中NF-kBP65、slug的mRNA表达。
结果：(1)免疫组织化学结果：NF-kBP65蛋白在NSCLC组织中阳性表达率78%(39/50)及阳性强度分别明显高于癌旁正常肺组织中的阳性表达率20%(4/20)及阳性强度(χ2=20.28,P<0.01；Z=-2.370,P<0.05)；Slug蛋白在NSCLC组织中阳性表达率82%(41/50)及阳性强度亦分别明显高于癌旁相应正常肺组织的阳性表达率30%(6/20)及阳性强度(χ2=17.51,P<0.01；Z=-4.443,P<0.01)；50例NSCLC组织中,NF-kBP65阳性癌组织中E-cadherin蛋白阳性表达率(17/39,43.6%)明显低于NF-kBP65阴性癌组织中E-cadherin蛋白阳性表达率(9/11,81.8%),差异有统计学意义(Z=5.024,P<0.05)；50例NSCLC组织中,NF-kBP65阳性癌组织中Vimentin蛋白阳性表达率(25/39,64.1%)明显高于NF-kBP65阴性癌组织Vimentin蛋白阳性表达率(3/11,27.3%),差异有统计学意义(Z=4.723,P<0.05)。NSCLC组织中,Slug性癌组织中E-cadherin蛋白阳性表达率(18/41,43.9%)明显低于Slug阴性癌组织中E-cadherin蛋白阳性表达率(8/9,88.9%),差异有统计学意义(χ=5.984,P<0.05)；Slug阳性癌组织中Vimentin蛋白阳性表达率(26/41,63.4%)明显高于Slug阴性癌组织中Vimentin阳性表达率(2/9,22.2%),差异有统计学意义(#=5.028,P<0.05)。另外,NSCLC组织中,NF-kB在高中分化组的阳性表达率明显低于低分化组的阳性表达率(χ2=5.024,P<0.05),在淋巴结无转移组的阳性表达率明显低于淋巴结有转移组的阳性表达率()c2=7.933,P<0.01),在Ⅰ-Ⅱ期阳性表达率明显低于Ⅲ-Ⅳ期阳性表达率(χ2=5.614,P<0.05),NF-kB与性别、年龄、组织类型均无明显相关性(P>0.05)；Slug在淋巴结无转移组的阳性表达率明显低于淋巴结有转移组的阳性表达率(χ2=6.174,P<0.05),在Ⅰ-Ⅱ期阳性表达率明显低于Ⅲ-Ⅳ期阳性表达率(χ2=7.317,P<0.01),Slug与性别、年龄、组织类型、分化程度均无明显相关性(P>0.05)。NF-kBP65蛋白与Slug蛋白呈极显著正相关性(r=0.443,P<0.01)。(2)RT-PCR
结果：NF-kBP65mRNA及SlugmRNA在NSCLC组织中的表达量均明显高于癌旁相应正常肺组织(t=4.967,6.483；P<0.01)；两者表达量亦呈显著正相关性(r=0.439,P<0.05)。
结论：NF-kB及Slug可能均与NSCLC的发生、进展及转移关系密切；NF-kB阳性癌组织中E-cadherin表达降低,Vimentin表达升高,说明NF-kB能够抑制E-cadherin的表达,促进Vimentin的表达,在NSCLC的EMT中发挥重要作用；Slug阳性癌组织中E-cadherin表达降低,Vimentin表达升高,提示Slug同样能够抑制E-cadherin的表达,促进Vimentin的表达,在NSCLC的EMT中发挥重要作用；NF-kB与Slug在基因及蛋白水平表达均呈显著正相关性,提示NF-kB和Slug可能协同促进NSCLC的发生,协同抑制E-cadherin的表达、促进Vimentin的表达,共同诱使NSCLC的EMT发生,从而为进一步研究NSCLC的EMT提供理论依据。
Objective:To investigate the expression of NF-kB and Slug in NSCLC, adjacent normal lung tissue, and their effects on EMT, and to provide theoretical basis for searching molecular therapy targets of NSCLC.
Methods:(1) The expression of NF-kBP65, Slug, E-cadherin and Vimentin protein was detected immunohistochemically in50cases NSCLC tissue and20cases corresponding adjacent normal lung tissue with PV9000two-step method.(2) RT-PCR was performed to determine the expression of NF-kBP65mRNA and SlugmRNA in25cases fresh NSCLC tissues and10cases fresh adjacent normal lung tissue.
Results:(1)Immunohistochemical Results:In NSCLC tissue, NF-kBP65protein expressive rate78%(39/50) and expressive intensity were both higher than that in adjacent normal lung tissue20%(4/20)(χ2=20.28, P<0.01; Z=-2.370,P<0.05); Slug protein expressive rate82%(41/50) and expressive intensity were also both higher than that in adjacent normal lung tissue30%(6/20)(χ2=17.51, P<0.01; Z=-4.443,P<0.01); In50cases NSCLC tissue, E-cadherin protein expressive rate (17/39,43.6%) in NF-kBP65positive tissue was lower than that in NF-kBP65negative tissue (9/11,81.8%)(χ2=5.024,P<0.05).Vimentin protein expressive rate (25/39,64.1%) in NF-kBP65positive tissue was higher than that in NF-kBP65negative tissue (3/11,27.3%)(χ2=4.723,P<0.05). E-cadherin protein expressive rate (18/41,43.9%) in Slug positive tissues was lower than that in Slug negative tissue (8/9,88.9%)(χ2=5.984,P<0.05) Vimentin protein expressive rate (26/41,63.4%) in Slug positive tissues was higher than that in Slug negative tissue (2/9,22.2%)(χ2=5.028,P<0.05). The expression of NF-kB protein in high-moderate differentiation group was lower than that in poor differentiation group (χ2=5.024,P<0.05), in negative lymph node group was lower than that in positive group (χ2=7.933,P<0.01), and in stage Ⅰ-Ⅱ was lower than that in stage Ⅲ-Ⅳ (χ2=5.614,P<0.05), but had no relation to gender, age and histological types (P>0.05). The expression of Slug protein in negative lymph node group was lower than that in positive group (χ2=6.174,P<0.05), and in stage Ⅰ-Ⅱ was lower than that in stage Ⅲ-Ⅳ (χ2=7.317,P<0.01), but not related to gender, age, histological types and differentiation (P>0.05). NF-kBP65protein was significant positively correlated with Slug protein (r=0.443,P<0.01).
(2) RT-PCR results:The expression of NF-kBP65and Slug mRNA was both significantly higher than that in adjacent normal lung tissues (t=4.967,6.483,P<0.01 respectively).
NF-kBP65mRNA expression was positively correlated with Slug mRNA (r=0.439,P <0.05).
Conclusion:The increased expression of NF-kB and Slug in NSCLC may be related to the occurrence, development and metastasis of NSCLC; In NF-kB positive NSCLC tissues, E-cadherin expression is decreased while vimentin expression increased. It implies that NF-kB may suppress E-cadherin expression and promote vimentin expression, and may be important to EMT of NSCLC. In Slug positive NSCLC tissues, E-cadherin expression is decreased and Vimentin expression increased. It also implies that Slug may suppress expression of E-cadherin and promote expression of vimentin, and may also be important to EMT of NSCLC. Both in protein and mRNA level, NF-kB are positively correlated with Slug. It implies that NF-kB and Slug may synergistically inhibit E-cadherin expression, promote Vimentin expression, and induce EMT of NSCLC. It provides further theoretical basis to the researches on EMT of NSCLC.
引文
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[44]Gianluca S,Pasquale S,Sara M,et al. TNFalpha up-regulates SLUG via the NF-kappaB/HIFl alpha axis,which imparts breast cancer cells with a stem cell-like phenotype[J].J Cell Physiol,2010,225(3):682-691
[45]Yadi W,Jiong D,Piotr G,et al. Stabilization of Snail by NF-κB Is Required for Inflammation-Induced Cell Migration and Invasion[J].Cancer Cell,2009,15(5):416-428.
[46]Wu Y,Deng J,Rychahou PG,Ever BM,et al.Stabilization of snail by NF-kB is required for inflammation-induced cell migration and invasion[J].Cancer Cell,2009;15(5):416-428.
[1]Guarino M. Epithelial-mesenehymal transition and tumour invasion[J]. Int J Biochem Cell Biol, 2007,39(12):2153-2160.
[2]Singh H,Sen R,Baltimore D,Sharp PA.A nuclear factor that binds to a conserved sequence motif in transcriptional control elements of immunoglobulin genes[J].Nature,1986,319(6049):154-158.
[3]Greenburg G,Hay ED.Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells[J].J Cell Biol,1982,95(1):333-339.
[4]Boyer Brigitte, Valls Ana Maria, Edme Natacha. Induction and regulation of epithelia mesenchymal transitions[J]. Biochemical Pharmacology,2000,60(8):1091-1099.
[5]Grunert S,Jechlinger M,Beug H.Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis[J],Nat Rev Mol Cell Boil,2003,4(8):657-665.
[6]Birchmeiev W. Cadherin expression in carcinomas:role of the formation of cell junction and the prevetion of invasiveness [J].BBA,1994,1198:11
[7]Hirohashis. Inactivation of the E-cadherin-mediated cell adhesion system in humancancers[J]. Am J Pathol,1998,153(2):333-339.
[8]Coulombe PA,Wong P.Cytoplasmic intermediate filamments revealed as dynamic and multipurpose scaffolds[J].Nat Cell Biol,2004,6(8):699-706.
[9]Thompson E W, Newgreen D F, Tarin D. Carcinoma invasion and metastasis:a role for epithelial-mesenchymal transition [J]. Cancer Res,2005,65 (14):5991—5995
[10]Savagner P. Leaving the neighborhood:molecular mechanisms involved during epithelial-mesenchymal transition [J]. BioEssays,2001,23 (10):912—923.
[11]Boyer B,Valles AM,Edme N.Induction and regulation of epithelial mesenchymal transitions. Biochem Pharmacol,2000,60:1091-1099.
[12]Kerosuo L,Bronner-Fraser M. What is bad in cancer is good in the embryo:Importance of EMT in neural crest development[J].Semin Cell Dev Biol,2012:[Epub ahead of print].
[13]Demayo F,Minoo P,Plopper CG,et al.Mesenchymal-epithelial interactions in lung development and repair:are modeling and remodeling the same process[J].Am J Physiol Lung Cell Mol Physiol,2002,283(3):510-517.
[14]Valdes F,Alvarez AM,Locascio A,et al. The epithelial mesenchymal transition confers resistance to the apoptotic effects of transforming growth factor beta in fetal rat hepatocytes[J].Mol Cancer Res,2002,1(1):68-78.
[15]Barasch J,Yang J,Ware CB,et al.Mesenchymal to epithelial conversion in rat metanephros is induced bu LIF[J].Cell,1999,99(4):377-386.
[16]Potten CS,Booth C.Keratinocyte stem cells:a commentary[J]. Invest Dermatol,2002,119(4):888-999.
[17]Geiger TR,Peeper DS.Metastasis mechanisms[J].Biochim Biochim Biophys Acta,2009,1796(2):293-308.
[18]Thiery JP,Acloque H,Huang RY,et al.Epithelial-mesenchymal transitions in development and disease[J].Cell,2009,139(5):871-890.
[19]Gos M, Miloszewska J, Przybyszewska M.Epithelial- mesenchymal transition in cancer progression [J].Posteby Biochemi,2009,55(2):121-128.
[20]Huber MA, Kraut N, Beug Ho Molecular requirements for epithelial-mesenchymal transition during tumor progression[J].Curr Opin Cell Biol,2005,17(5):548-558.
[21]Hotta K,Oyama T,Akamatsu T,et al.A comparison of outcomes of endoscopic submucosal dissection(ESD) for early gastric neoplasms between high-volume and low-volume centers:multicenter retrospective questionnaire study conducted by the Nagano ESD Study Group. Iy.tern Med,2010,49(4):253-259.
[22]Kim JH,Kim MA,Lee HS,et al.Comparative analysis of protein expression in primary and metastatic gastriccacinomas[J].Hum Pathol,2009,40(3):314-322.
[23]Katoh M.Epithelial-mesenchymal transition in gastric cancer[J]. International Journal of Oncology,2005,27,(6):1677-1683.
[24]Czyzewska J,Guzinska-Ustymowicz K,Ustymowicz M,et al.The expression of E-cadherin-catenin complex in patients with advanced gastric cancer:role in formation of metastasis[J].Folia Histochem Cytobiol,2010,48(1):37-45.
[25]吴功侃,赵荣宇.试论我国乳腺癌的诊治现状与改革对策[J]医师进修杂志.2000,23(11)：59-62.
[26]徐杨荣,梁庆模.乳腺癌转移基因的研究进展[J].医学综述,2007,13(2)：100-103
[27]Takeichi M.Biochem[J].1990,59:237.
[28]Siitonen SM, Kononen JT,Helin HJ,et al.Reduced E-cadherin expression is associated with in vasiveness and unfavorable prognosis in breast cancer. Am J Clin Pathol,1996,105(4):394-402.
[29]Maguire TM,Shering SG,Mc Dermott EW et al.Assay of E-Cadherin by ELISA in human breast cancer.Eur J Cancer,1997,33(3):404-408
[30]英德水,闫明霞,刘蕾,等.人肺癌高转移细胞转移特性的初步研究[C],华东地区第十届实验动物科学学术交流会论文集,2008：204-208.
[31]Lee MY, Chou CY, Tang MJ and Shen MR. Epithelial-mesenchymal transition in cervical cancer: correlation with tumor progression, epidermal growth factor receptor overexpression, and snail up-regulation[J].Clin Cancer Res,2008,14:4743-4750.
[32]Putz E.Phenotypic charateristics of cell lines derieved from disseminated cancer cells in bone marrow of patients with solid epithelial tumor:Establishment of working models for human micrometastases[J].Exp Gerentol.2002,31:188-196.
[33]Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell,2002,109 (Supp 1) 81-96.
[34]Charles K,Steren MR,Craig AR.Selection of optical kB\Rel DNA-binding Motifs:interaction of both subunits of NF-kB with DNA is required for transcriptional activation[J].Mol Cell Biol,1992,12(10):4412-4419.
[35]Bharti AC, Aggarwal BB. Nuclear factor-kappa B and cancer:its role in prevention and therapy[J].Biochem Pharmacol,2002,64(5-6):883-888.
[36]Huber MA, Krant N, Beng H.Molecular requriments for epithelial-mesenchymal transition during tumor progression[J],Curr Opin Cell Biol,2005,17(5):548-558.
[37]Huber MA,Azoitei N. NF-kB is essential for epithelial-mesenchymal transition and metastasis in a modal of breast cancer progression[J].J Clin Invest,2004,114(4):569-581.
[38]Sovak MA,Bellas RE,Kim DW,et al.Aberrant nuclear factor-kB\Rel expression and pathogenesis of breast cancer[J].J Clin Invest,1997,100(12):2952-2960.
[39]Guttridge DC,Albanese C,Reuther JY,et al.NF-kappa B controls cell growth and differentiation through transcriptional regulation of cyclin D1[J].Mol Cell Biol,1999,19(8):5785-5799.
[40]石磊,王世明,贺杰峰.核转录因子-kB在胰腺癌中的表达及其与上皮细胞间质转化的关系[J].肿瘤研究与临床,2011,23(3)：191-193
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[56]Hotz B, Arndt M, Dullat S, et al. Epithelial to mesenchymal transition:expression of the regulators snail, Slug, and twist in pancreatic cancer [J]. Clin Cancer Res,2007,13(16):4769-4776.
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[1]Guarino M. Epithelial-mesenehymal transition and tumour invasion[J]. Int J Biochem Cell Biol, 2007,39(12):2153-2160.
[2]Singh H,Sen R,Baltimore D,Sharp PA.A nuclear factor that binds to a conserved sequence motif in transcriptional control elements of immunoglobulin genes[J].Nature,1986,319(6049):154-158.
[3]Greenburg G,Hay ED.Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells[J].J Cell Biol,1982,95(1):333-339.
[4]Boyer Brigitte, Valls Ana Maria, Edme Natacha. Induction and regulation of epithelia mesenchymal transitions[J]. Biochemical Pharmacology,2000,60(8):1091-1099.
[5]Grunert S,Jechlinger M,Beug H.Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis[J],Nat Rev Mol Cell Boil,2003,4(8):657-665.
[6]Birchmeiev W. Cadherin expression in carcinomas:role of the formation of cell junction and the prevetion of invasiveness [J].BBA,1994,1198:11
[7]Hirohashis. Inactivation of the E-cadherin-mediated cell adhesion system in humancancers[J]. Am J Pathol,1998,153(2):333-339.
[8]Coulombe PA,Wong P.Cytoplasmic intermediate filamments revealed as dynamic and multipurpose scaffolds[J].Nat Cell Biol,2004,6(8):699-706.
[9]Thompson E W, Newgreen D F, Tarin D. Carcinoma invasion and metastasis:a role for epithelial-mesenchymal transition [J]. Cancer Res,2005,65 (14):5991—5995
[10]Savagner P. Leaving the neighborhood:molecular mechanisms involved during epithelial-mesenchymal transition [J]. BioEssays,2001,23 (10):912—923.
[11]Boyer B,Valles AM,Edme N.Induction and regulation of epithelial mesenchymal transitions. Biochem Pharmacol,2000,60:1091-1099.
[12]Kerosuo L,Bronner-Fraser M. What is bad in cancer is good in the embryo:Importance of EMT in neural crest development[J].Semin Cell Dev Biol,2012:[Epub ahead of print].
[13]Demayo F,Minoo P,Plopper CG,et al.Mesenchymal-epithelial interactions in lung development and repair:are modeling and remodeling the same process[J].Am J Physiol Lung Cell Mol Physiol,2002,283(3):510-517.
[14]Valdes F,Alvarez AM,Locascio A,et al. The epithelial mesenchymal transition confers resistance to the apoptotic effects of transforming growth factor beta in fetal rat hepatocytes[J].Mol Cancer Res,2002,1(1):68-78.
[15]Barasch J,Yang J,Ware CB,et al.Mesenchymal to epithelial conversion in rat metanephros is induced bu LIF[J].Cell,1999,99(4):377-386.
[16]Potten CS,Booth C.Keratinocyte stem cells:a commentary[J]. Invest Dermatol,2002,119(4):888-999.
[17]Geiger TR,Peeper DS.Metastasis mechanisms[J].Biochim Biochim Biophys Acta,2009,1796(2):293-308.
[18]Thiery JP,Acloque H,Huang RY,et al.Epithelial-mesenchymal transitions in development and disease[J].Cell,2009,139(5):871-890.
[19]Gos M, Miloszewska J, Przybyszewska M.Epithelial- mesenchymal transition in cancer progression [J].Posteby Biochemi,2009,55(2):121-128.
[20]Huber MA, Kraut N, Beug Ho Molecular requirements for epithelial-mesenchymal transition during tumor progression[J].Curr Opin Cell Biol,2005,17(5):548-558.
[21]Hotta K,Oyama T,Akamatsu T,et al.A comparison of outcomes of endoscopic submucosal dissection(ESD) for early gastric neoplasms between high-volume and low-volume centers:multicenter retrospective questionnaire study conducted by the Nagano ESD Study Group. Iy.tern Med,2010,49(4):253-259.
[22]Kim JH,Kim MA,Lee HS,et al.Comparative analysis of protein expression in primary and metastatic gastriccacinomas[J].Hum Pathol,2009,40(3):314-322.
[23]Katoh M.Epithelial-mesenchymal transition in gastric cancer[J]. International Journal of Oncology,2005,27,(6):1677-1683.
[24]Czyzewska J,Guzinska-Ustymowicz K,Ustymowicz M,et al.The expression of E-cadherin-catenin complex in patients with advanced gastric cancer:role in formation of metastasis[J].Folia Histochem Cytobiol,2010,48(1):37-45.
[25]吴功侃,赵荣宇.试论我国乳腺癌的诊治现状与改革对策[J]医师进修杂志.2000,23(11)：59-62.
[26]徐杨荣,梁庆模.乳腺癌转移基因的研究进展[J].医学综述,2007,13(2)：100-103
[27]Takeichi M.Biochem[J].1990,59:237.
[28]Siitonen SM, Kononen JT,Helin HJ,et al.Reduced E-cadherin expression is associated with in vasiveness and unfavorable prognosis in breast cancer. Am J Clin Pathol,1996,105(4):394-402.
[29]Maguire TM,Shering SG,Mc Dermott EW et al.Assay of E-Cadherin by ELISA in human breast cancer.Eur J Cancer,1997,33(3):404-408
[30]英德水,闫明霞,刘蕾,等.人肺癌高转移细胞转移特性的初步研究[C],华东地区第十届实验动物科学学术交流会论文集,2008：204-208.
[31]Lee MY, Chou CY, Tang MJ and Shen MR. Epithelial-mesenchymal transition in cervical cancer: correlation with tumor progression, epidermal growth factor receptor overexpression, and snail up-regulation[J].Clin Cancer Res,2008,14:4743-4750.
[32]Putz E.Phenotypic charateristics of cell lines derieved from disseminated cancer cells in bone marrow of patients with solid epithelial tumor:Establishment of working models for human micrometastases[J].Exp Gerentol.2002,31:188-196.
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