E-cadherin表达下调激活Notch信号通路增强前列腺癌化疗耐药的机制研究
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摘要
背景与目的前列腺癌(prostate cancer,PCa)化疗耐药与其侵袭性和转移性密切相关。最新研究显示上皮细胞–间充质转化(epithelial-to-mesenchymal transition,EMT)可能在前列腺癌化疗耐药和转移中发挥重要作用。因此,作为EMT的标志物,E-cadherin被认为有可能与肿瘤化疗耐药有重要关系。然而,PCa化疗耐药的分子机制尚不清楚。本研究旨在探讨EMT与PCa化疗耐药的关系,以及E-cadherin表达变化是否影响PCa化疗耐药。方法以亲代PC3和DU145细胞及其化疗耐药PC3-TxR和DU145-TxR细胞作为研究对象。用E-cadherin过表达的慢病毒感染PC3-TxR和DU145-TxR细胞,使E-cadherin过表达;同时,用小干扰RNA转染PC3和DU145细胞,使E-cadherin表达沉默。采用蛋白免疫印迹和实时定量聚合酶链反应分析EMT相关标志物及信号通路的变化。分别通过划痕、transwell和克隆形成实验检测肿瘤细胞的迁移、侵袭和克隆形成能力。采用MTS法检测细胞对紫杉醇的药物敏感性。结果与亲代PC3和DU145细胞相比,化疗耐药PC3-TxR和DU145-TxR细胞表现出EMT相关的标志物表达改变,包括E-cadherin表达下调和Vimentin、Snail与N-cadherin表达上调。当E-cadherin在PC3-TxR和DU-145-TxR细胞中过表达时,Vimentin和Caldun-1表达下调,肿瘤细胞的迁移和侵袭受到抑制。特别是E-cadherin过表达以后,PC3-TxR和DU145-TxR细胞对紫杉醇的敏感性被重新激活。并且,在亲代PC3和DU145细胞中沉默E-cadherin表达后,Vimentin和Snail表达上调,对紫杉醇的敏感性降低。有趣的是,与亲代PC3和DU145细胞相比,PC3-TxR和DU145-TxR细胞中Notch-1表达上调,而E-cadherin在这些细胞中的表达下调。我们的研究还显示,Notch信号通路抑制剂γ-分泌酶抑制剂可显著增加化疗耐药细胞对紫杉醇的敏感性。结论 E-cadherin下调可以激活Notch信号通路,从而增强PCa化疗耐药,抑制Notch信号通路可能逆转PCa化疗耐药。
引文
1.Siegel R,Naishadham D,Jemal A.Cancer statistics,2013CA Cancer J Clin.2013;63(1):11-30.doi:10.3322/caac.21166.
2.Siegel R,Ma J,Zou Z,Jemal A.Cancer statistics,2014.CACancer J Clin.2014;64(1):9-29.doi:10.3322/caac.21208.
3.Chen W,Zheng R,Zeng H,Zhang S.The updated incidences and mortalities of major cancers in China2011.Chin J Cancer.2015;34(11):502-7.doi:10.1186/s40880-015-0042-6.
4.Gleave ME,Goldenberg SL,Chin JL,Warner J,Saad FKlotz LH,et al.Randomized comparative study of 3 versus8-month neoadjuvant hormonal therapy before radica prostatectomy:biochemical and pathological effects.J Urol2001;166(2):500-6.
5.Shiota M,Song Y,Takeuchi A,Yokomizo A,Kashiwagi EKuroiwa K,et al.Antioxidant therapy alleviates oxidative stress by androgen deprivation and prevents conversion from androgen dependent to castration resistant prostate cancer.J Urol.2012;187(2):707-14.doi:10.1016/j juro.2011.09.147.
6.Gaztanaga M,Crook J.Androgen deprivation therapy:minimizing exposure and mitigating side effects.J Nat Compr Cancer Netw.2012;10(9):1088-95.
7.Rolfo C,Passiglia F,Castiglia M,Raez LE,Germonpre PGil-Bazo I,et al.ALK and crizotinib:after the honeymoon…what else?Resistance mechanisms and new therapies to overcome it.Transl Lung Cancer Res.2014;3(4):250-61doi:10.3978/j.issn.2218-6751.2014.03.01.
8.Szakacs G,Paterson JK,Ludwig JA,Booth-Genthe CGottesman MM.Targeting multidrug resistance in cancer Nat Rev Drug Discov.2006;5(3):219-34.doi:10.1038/nrd1984.
9.Yang Y,Ma Y,Sheng J,Huang Y,Zhao Y,Fang W,et al A multicenter,retrospective epidemiologic sur vey of the clinical features and management of bone metastatic disease in China.Chin J Cancer.2016;35:40.doi:10.1186/s40880-016-0102-6.
10.Nakamura M,Tokura Y.Epithelial-mesenchymal transition in the skin.J Dermatol Sci.2011;61(1):7-13.doi:10.1016/j.jdermsci.2010.11.015.
11.Sanchez-Tillo E,Lazaro A,Torrent R,Cuatrecasas MVaquero EC,Castells A,et al.ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SN Fchromatin-remode lingprote in BRG 1.Oncogene2010;29(24):3490-500.doi:10.1038/onc.2010.102.
12.Du C,Zhang C,Hassan S,Bis was MH,Balaji KCProtein kinase D1 suppresses epithelial-to-mesenchymal transition through phosphory lation of snai l.Cancer R es.2010;70(20):7810-9.doi:10.1158/0008-5472can-09-4481.
13.Putzke AP,Ventura AP,Bailey AM,Akture C,Opoku-Ansah J,Celiktas M,et al.Metastatic progression of prostate cancer and e-cadherin regulation by zeb1 and SRC family kinases.Am J Pathol.2011;179(1):400-10.doi:10.1016/j.ajpath.2011.03.028.
14.Veveris-Lowe TL,Law rence MG,Col lard RL,Bui LHerington AC,Nicol DL,et al.Kallikrein 4(hK4)and prostate-specific antigen(PSA)are associated with the loss of E-cadherin and an epithelial-mesenchymal transition(EMT)-like effect in prostate cancer cells.Endocr Relat Cancer.2005;12(3):631-43.doi:10.1677/erc.1.00958.
15.Bougen NM,Amiry N,Yuan Y,Kong XJ,Pandey V,Vidal LJ,et al.Trefoil factor 1 suppression of E-CADHERINen hances prostate carcinomacel linvasiveness and metastasis.Cancer Lett.2013;332(1):19-29.doi:10.1016/j.canlet.2012.12.012.
16.Fan L,Wang H,Xia X,R ao Y,Ma X,Ma D,et al.Loss of E-cadherin promotes prostate cancer metastasis via upregulation of metastasisassociated gene 1 expression Oncol Lett.2012;4(6):1225-33.doi:10.3892/ol.2012.934
17.Li F,Mahato RI.MicroRNAs and drug resistance in prostate cancers.Mol Pharm.2014;11(8):2539-52.doi:10.1021/mp500099g.
18.Marin-Aguilera M,Codony-Ser vat J,Reig O,Lozano J J,Fernandez PL,Pereira MV,et al.Epithelial-tomesenchymal transition mediates docetaxel resistance and high risk of relapse in prostate cancer.Mol Cancer Ther.2014;13(5):1270-84.doi:10.1158/1535-7163mct-13-0775.
19.Duran GE,Wang YC,Francisco EB,Rose JC,Martinez F J,Coller J,et al.Mechanisms of resistance to cabazita xel.Mol Cancer Ther.2015;14(1):193-201doi:10.1158/1535-7163.mct-14-0155.
20.Puhr M,Hoefer J,Schafer G,Erb HH,Oh SJ,Klocker H,et al.Epithelial-tomesenchymal transition leads to docetaxel resistance in prostate cancer and is mediated by reduced expression of miR-200c and miR-205.Am J Pathol2012;181(6):2188-201.doi:10.1016/j.ajpath.2012.08.011.
21.Ni J,Cozzi P,Hao J,Beretov J,Chang L,Duan W,et al Epithelial cell adhesion molecule(EpCAM)is associated with prostate cancer metastasis and chemo/radioresistance via the PI3K/Akt/mTORsignaling path way.In t JBiochem Cell Biol.2013;45(12):2736-48.doi:10.1016/j.biocel.2013.09.008.
22.Zhao JH,Luo Y,Jiang YG,He DL,Wu CT.Knockdown of beta-Catenin through shRNA cause a reversal of EMTand metastat ic phenot y pes induced by H I F-1alpha Cancer Invest.2011;29(6):377-82.doi:10.3109/07357907.2010.512595.
23.Liu J,Chen Y,Shuai S,Ding D,Li R,Luo R.TRPM8promotes aggressiveness of breast cancer cells by regulating EMT via activating AKT/GSK-3beta pathway Tumour Bio l.2014;35(9):8969-77.doi:10.1007/s13277-014-2077-8.
24.Wang Z,Li Y,Kong D,Banerjee S,Ahmad A,Azmi ASet al.Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway Cancer Res.2009;69(6):2400-7.doi:10.1158/0008-5472can-08-4312.
25.Noseda M,McLean G,Niessen K,Chang L,Pollet IMontpetit R,et al.Notch activation results in phenotypic and functional changes consistent with endothelial-tomesenchymal transformation.Circ Res.2004;94(7):910-7doi:10.1161/01.res.0000124300.76171.c9.
26.Niimi H,PardaliK,Vanlandewijck M,Held in CHMoustakas A.Notch signaling is necessary for epithelial growth arrest by TGF-beta.J Cell Biol.2007;176(5):695-707.doi:10.1083/jcb.200612129.
27.Becker KF,Rosivatz E,Blechschmidt K,Kremmer E,Sarbia M,Hofler H.Analysis of the E-cadherin repressor Snail in primary human cancers.Cells Tissues Organs.2007;185(1-3):204-12.doi:10.1159/000101321.
28.Niessen K,Fu Y,Chang L,Hood less PA,McFadden D,Karsan A.Slug is a direct Notch target required for initiation of cardiac cushion cellularization.J Cell Biol2008;182(2):315-25.doi:10.1083/jcb.200710067.
29.Martz CA,Ottina KA,Singleton KR,Jasper JS,Wardel SE,Peraza-Penton A,et al.Systematic identification of signaling pathways with potential to confer anticancer drug resistance.Sci Signal.2014;7(357):ra121.doi:10.1126/scisignal.aaa1877.
30.Meng RD,Shelton CC,Li YM,Qin LX,Notterman D,Paty PB,et al.gamma-Secretase inhibitors abrogate oxaliplatininduced activation of the Notch-1 signaling pathway in colon cancer cells resulting in enhanced chemosensitivity Cancer Res.2009;69(2):573-82.doi:10.1158/0008-5472can-08-2088.
31.Euhus DM,Hudd C,LaRegina MC,Johnson FE.Tumor measurement in the nude mouse.J Surg Oncol1986;31(4):229-34.
32.Lu Y,Cai Z,Galson DL,Xiao G,Liu Y,George DE,et al.Monocyte chemotactic protein-1(MCP-1)acts as a paracrine and autocrine factor for prostate cancer growth and invasion.Prostate.2006;66(12):1311-8.doi:10.1002/pros.20464.
33.Lu Y,Cai Z,Xiao G,Liu Y,Keller ET,Yao Z,et al.CCR2expression correlates with prostate cancer progression J Cel l Biochem.2007;101(3):676-85.doi:10.1002/jcb.21220.
34.Lu Y,Xiao G,Galson DL,Nishio Y,Mizokami AKeller ET,et al.PTHrPinduced MCP-1 production by human bone marrow endothelial cells and osteoblasts promotes osteoclast differentiation and prostate cancer cell proliferation and invasion in v itro.Int J Cancer2007;121(4):724-33.doi:10.1002/ijc.22704.
35.Wallace TA,Prueitt RL,Yi M,Howe TM,Gillespie JWYfantis HG,et al.Tumor immunobiological differences in prostate cancer between African-American and European-A meicanmen.Cancer Res.2008;68(3):927-36doi:10.1158/0008-5472.can-07-2608.
36.Vogelzang NJ,Fizazi K,Burke JM,De Wit R,Bellmunt JHutson TE,et al.Circulating tumor cells in a phase 3 study of docetaxel and prednisone with or without lenalidomide in metastatic castration-resistant prostate cancer.Eur Urol2016.doi:10.1016/j.eururo.2016.07.051.
37.Lu L,Tang D,Wang L,Huang LQ,Jiang GS,Xiao XY,et al.Gambogic acid inhibits TNF-alpha-induced invasion of human prostate cancer PC3 cells in vitro through PI3K/Akt and NF-kappaB signaling pathways.Acta Pharmacol Sin2012;33(4):531-41.doi:10.1038/aps.2011.180.
38.Yu Y,Wang L,Tang W,Zhang D,Shang T.RNA interferencemediated knockdown of Notch-1 inhibits migration and invasion,down-regulates matrix metalloproteinases and suppresses NF-kappaB signaling pathway in trophoblast cells.Acta Histochem.2014;116(5):911-9.doi:10.1016/j acthis.2014.03.003.
39.Blanco D,Vicent S,Elizegi E,Pino I,Fraga MF,Esteller M,et al.Altered expression of adhesion molecules and epithelial-mesenchymal transition in silica-induced rat lung carcinogenesis.Lab Invest.2004;84(8):999-1012doi:10.1038/labinvest.3700129.
40.Shou J,Ross S,Koeppen H,de Sauvage FJ,Gao WQ.Dynamics of notchexpression during murine prostate development and tumorigenesis.Cancer Res2001;61(19):7291-7.
41.Bao B,Wang Z,Ali S,Kong D,Li Y,Ahmad A,et al.Notch-1induces epithelial-mesenchymal transition consistent w ith cancer stem cell phenoty pe in pancreatic cancer cells.Cancer Lett.2011;307(1):26-36.doi:10.1016/j canlet.2011.03.012.
42.Vauclair S,Nicolas M,Barrandon Y,R adtke F.Notch1is essential for postnatal hair follicle development and homeostasi s.Dev Biol.2005;284(1):184-93.do i:10.1016/j.ydbio.2005.05.018.
43.Andersson ER,Lendahl U.Therapeutic modulation of Notch signalling-are we there yet?Nat Rev Drug Discov2014;13(5):357-78.doi:10.1038/nrd4252.
2.Siegel R,Ma J,Zou Z,Jemal A.Cancer statistics,2014.CACancer J Clin.2014;64(1):9-29.doi:10.3322/caac.21208.
3.Chen W,Zheng R,Zeng H,Zhang S.The updated incidences and mortalities of major cancers in China2011.Chin J Cancer.2015;34(11):502-7.doi:10.1186/s40880-015-0042-6.
4.Gleave ME,Goldenberg SL,Chin JL,Warner J,Saad FKlotz LH,et al.Randomized comparative study of 3 versus8-month neoadjuvant hormonal therapy before radica prostatectomy:biochemical and pathological effects.J Urol2001;166(2):500-6.
5.Shiota M,Song Y,Takeuchi A,Yokomizo A,Kashiwagi EKuroiwa K,et al.Antioxidant therapy alleviates oxidative stress by androgen deprivation and prevents conversion from androgen dependent to castration resistant prostate cancer.J Urol.2012;187(2):707-14.doi:10.1016/j juro.2011.09.147.
6.Gaztanaga M,Crook J.Androgen deprivation therapy:minimizing exposure and mitigating side effects.J Nat Compr Cancer Netw.2012;10(9):1088-95.
7.Rolfo C,Passiglia F,Castiglia M,Raez LE,Germonpre PGil-Bazo I,et al.ALK and crizotinib:after the honeymoon…what else?Resistance mechanisms and new therapies to overcome it.Transl Lung Cancer Res.2014;3(4):250-61doi:10.3978/j.issn.2218-6751.2014.03.01.
8.Szakacs G,Paterson JK,Ludwig JA,Booth-Genthe CGottesman MM.Targeting multidrug resistance in cancer Nat Rev Drug Discov.2006;5(3):219-34.doi:10.1038/nrd1984.
9.Yang Y,Ma Y,Sheng J,Huang Y,Zhao Y,Fang W,et al A multicenter,retrospective epidemiologic sur vey of the clinical features and management of bone metastatic disease in China.Chin J Cancer.2016;35:40.doi:10.1186/s40880-016-0102-6.
10.Nakamura M,Tokura Y.Epithelial-mesenchymal transition in the skin.J Dermatol Sci.2011;61(1):7-13.doi:10.1016/j.jdermsci.2010.11.015.
11.Sanchez-Tillo E,Lazaro A,Torrent R,Cuatrecasas MVaquero EC,Castells A,et al.ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SN Fchromatin-remode lingprote in BRG 1.Oncogene2010;29(24):3490-500.doi:10.1038/onc.2010.102.
12.Du C,Zhang C,Hassan S,Bis was MH,Balaji KCProtein kinase D1 suppresses epithelial-to-mesenchymal transition through phosphory lation of snai l.Cancer R es.2010;70(20):7810-9.doi:10.1158/0008-5472can-09-4481.
13.Putzke AP,Ventura AP,Bailey AM,Akture C,Opoku-Ansah J,Celiktas M,et al.Metastatic progression of prostate cancer and e-cadherin regulation by zeb1 and SRC family kinases.Am J Pathol.2011;179(1):400-10.doi:10.1016/j.ajpath.2011.03.028.
14.Veveris-Lowe TL,Law rence MG,Col lard RL,Bui LHerington AC,Nicol DL,et al.Kallikrein 4(hK4)and prostate-specific antigen(PSA)are associated with the loss of E-cadherin and an epithelial-mesenchymal transition(EMT)-like effect in prostate cancer cells.Endocr Relat Cancer.2005;12(3):631-43.doi:10.1677/erc.1.00958.
15.Bougen NM,Amiry N,Yuan Y,Kong XJ,Pandey V,Vidal LJ,et al.Trefoil factor 1 suppression of E-CADHERINen hances prostate carcinomacel linvasiveness and metastasis.Cancer Lett.2013;332(1):19-29.doi:10.1016/j.canlet.2012.12.012.
16.Fan L,Wang H,Xia X,R ao Y,Ma X,Ma D,et al.Loss of E-cadherin promotes prostate cancer metastasis via upregulation of metastasisassociated gene 1 expression Oncol Lett.2012;4(6):1225-33.doi:10.3892/ol.2012.934
17.Li F,Mahato RI.MicroRNAs and drug resistance in prostate cancers.Mol Pharm.2014;11(8):2539-52.doi:10.1021/mp500099g.
18.Marin-Aguilera M,Codony-Ser vat J,Reig O,Lozano J J,Fernandez PL,Pereira MV,et al.Epithelial-tomesenchymal transition mediates docetaxel resistance and high risk of relapse in prostate cancer.Mol Cancer Ther.2014;13(5):1270-84.doi:10.1158/1535-7163mct-13-0775.
19.Duran GE,Wang YC,Francisco EB,Rose JC,Martinez F J,Coller J,et al.Mechanisms of resistance to cabazita xel.Mol Cancer Ther.2015;14(1):193-201doi:10.1158/1535-7163.mct-14-0155.
20.Puhr M,Hoefer J,Schafer G,Erb HH,Oh SJ,Klocker H,et al.Epithelial-tomesenchymal transition leads to docetaxel resistance in prostate cancer and is mediated by reduced expression of miR-200c and miR-205.Am J Pathol2012;181(6):2188-201.doi:10.1016/j.ajpath.2012.08.011.
21.Ni J,Cozzi P,Hao J,Beretov J,Chang L,Duan W,et al Epithelial cell adhesion molecule(EpCAM)is associated with prostate cancer metastasis and chemo/radioresistance via the PI3K/Akt/mTORsignaling path way.In t JBiochem Cell Biol.2013;45(12):2736-48.doi:10.1016/j.biocel.2013.09.008.
22.Zhao JH,Luo Y,Jiang YG,He DL,Wu CT.Knockdown of beta-Catenin through shRNA cause a reversal of EMTand metastat ic phenot y pes induced by H I F-1alpha Cancer Invest.2011;29(6):377-82.doi:10.3109/07357907.2010.512595.
23.Liu J,Chen Y,Shuai S,Ding D,Li R,Luo R.TRPM8promotes aggressiveness of breast cancer cells by regulating EMT via activating AKT/GSK-3beta pathway Tumour Bio l.2014;35(9):8969-77.doi:10.1007/s13277-014-2077-8.
24.Wang Z,Li Y,Kong D,Banerjee S,Ahmad A,Azmi ASet al.Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway Cancer Res.2009;69(6):2400-7.doi:10.1158/0008-5472can-08-4312.
25.Noseda M,McLean G,Niessen K,Chang L,Pollet IMontpetit R,et al.Notch activation results in phenotypic and functional changes consistent with endothelial-tomesenchymal transformation.Circ Res.2004;94(7):910-7doi:10.1161/01.res.0000124300.76171.c9.
26.Niimi H,PardaliK,Vanlandewijck M,Held in CHMoustakas A.Notch signaling is necessary for epithelial growth arrest by TGF-beta.J Cell Biol.2007;176(5):695-707.doi:10.1083/jcb.200612129.
27.Becker KF,Rosivatz E,Blechschmidt K,Kremmer E,Sarbia M,Hofler H.Analysis of the E-cadherin repressor Snail in primary human cancers.Cells Tissues Organs.2007;185(1-3):204-12.doi:10.1159/000101321.
28.Niessen K,Fu Y,Chang L,Hood less PA,McFadden D,Karsan A.Slug is a direct Notch target required for initiation of cardiac cushion cellularization.J Cell Biol2008;182(2):315-25.doi:10.1083/jcb.200710067.
29.Martz CA,Ottina KA,Singleton KR,Jasper JS,Wardel SE,Peraza-Penton A,et al.Systematic identification of signaling pathways with potential to confer anticancer drug resistance.Sci Signal.2014;7(357):ra121.doi:10.1126/scisignal.aaa1877.
30.Meng RD,Shelton CC,Li YM,Qin LX,Notterman D,Paty PB,et al.gamma-Secretase inhibitors abrogate oxaliplatininduced activation of the Notch-1 signaling pathway in colon cancer cells resulting in enhanced chemosensitivity Cancer Res.2009;69(2):573-82.doi:10.1158/0008-5472can-08-2088.
31.Euhus DM,Hudd C,LaRegina MC,Johnson FE.Tumor measurement in the nude mouse.J Surg Oncol1986;31(4):229-34.
32.Lu Y,Cai Z,Galson DL,Xiao G,Liu Y,George DE,et al.Monocyte chemotactic protein-1(MCP-1)acts as a paracrine and autocrine factor for prostate cancer growth and invasion.Prostate.2006;66(12):1311-8.doi:10.1002/pros.20464.
33.Lu Y,Cai Z,Xiao G,Liu Y,Keller ET,Yao Z,et al.CCR2expression correlates with prostate cancer progression J Cel l Biochem.2007;101(3):676-85.doi:10.1002/jcb.21220.
34.Lu Y,Xiao G,Galson DL,Nishio Y,Mizokami AKeller ET,et al.PTHrPinduced MCP-1 production by human bone marrow endothelial cells and osteoblasts promotes osteoclast differentiation and prostate cancer cell proliferation and invasion in v itro.Int J Cancer2007;121(4):724-33.doi:10.1002/ijc.22704.
35.Wallace TA,Prueitt RL,Yi M,Howe TM,Gillespie JWYfantis HG,et al.Tumor immunobiological differences in prostate cancer between African-American and European-A meicanmen.Cancer Res.2008;68(3):927-36doi:10.1158/0008-5472.can-07-2608.
36.Vogelzang NJ,Fizazi K,Burke JM,De Wit R,Bellmunt JHutson TE,et al.Circulating tumor cells in a phase 3 study of docetaxel and prednisone with or without lenalidomide in metastatic castration-resistant prostate cancer.Eur Urol2016.doi:10.1016/j.eururo.2016.07.051.
37.Lu L,Tang D,Wang L,Huang LQ,Jiang GS,Xiao XY,et al.Gambogic acid inhibits TNF-alpha-induced invasion of human prostate cancer PC3 cells in vitro through PI3K/Akt and NF-kappaB signaling pathways.Acta Pharmacol Sin2012;33(4):531-41.doi:10.1038/aps.2011.180.
38.Yu Y,Wang L,Tang W,Zhang D,Shang T.RNA interferencemediated knockdown of Notch-1 inhibits migration and invasion,down-regulates matrix metalloproteinases and suppresses NF-kappaB signaling pathway in trophoblast cells.Acta Histochem.2014;116(5):911-9.doi:10.1016/j acthis.2014.03.003.
39.Blanco D,Vicent S,Elizegi E,Pino I,Fraga MF,Esteller M,et al.Altered expression of adhesion molecules and epithelial-mesenchymal transition in silica-induced rat lung carcinogenesis.Lab Invest.2004;84(8):999-1012doi:10.1038/labinvest.3700129.
40.Shou J,Ross S,Koeppen H,de Sauvage FJ,Gao WQ.Dynamics of notchexpression during murine prostate development and tumorigenesis.Cancer Res2001;61(19):7291-7.
41.Bao B,Wang Z,Ali S,Kong D,Li Y,Ahmad A,et al.Notch-1induces epithelial-mesenchymal transition consistent w ith cancer stem cell phenoty pe in pancreatic cancer cells.Cancer Lett.2011;307(1):26-36.doi:10.1016/j canlet.2011.03.012.
42.Vauclair S,Nicolas M,Barrandon Y,R adtke F.Notch1is essential for postnatal hair follicle development and homeostasi s.Dev Biol.2005;284(1):184-93.do i:10.1016/j.ydbio.2005.05.018.
43.Andersson ER,Lendahl U.Therapeutic modulation of Notch signalling-are we there yet?Nat Rev Drug Discov2014;13(5):357-78.doi:10.1038/nrd4252.