上皮向间叶转化（EMT）在胰腺癌侵袭和转移过程中的发生及机制研究
摘要
背景和目的胰腺癌是一种恶性的消化系统肿瘤,具有强烈的向周围组织侵袭的倾向以及对化疗的抵抗能力,导致胰腺癌病人的预后非常差。Snail是一种抑制型的转录因子,可以赋予上皮细胞移动以及抗凋亡的能力。其表达在多种肿瘤组织中都有报道。Snail可能在胰腺癌细胞中表达并且赋予胰腺癌细胞侵袭和抵抗化疗的能力。
方法为了论证此假设,我们通过免疫组织化学的方法检测了Snail在胰腺癌组织中的表达,以及和临床病例指标的相关性。同时我们将Snail编码基因转染胰腺癌细胞系Panc-1细胞,通过Transwell侵袭小室法检测Snail对Panc-1细胞体外侵袭能力的影响;通过MTT细胞增殖试验检测转染Snail基因对Panc-1细胞增殖以及对5-氟尿嘧啶、吉西他滨等化疗药物敏感性的影响;通过裸鼠接种实验检测Snail基因对胰腺癌细胞体内生长的影响。
结果Snail在胰腺癌组织中存在着表达,在56例胰腺癌组织中发现有20例Snail的表达呈阳性,阳性率达36%。此外Snail的表达同淋巴结转移、远处转移都存在有明显的相关性。Panc-1细胞在转染了Snail基因之后发生了明显的从上皮细胞表型向间叶细胞表型的转化,同时其在体内外的侵袭能力也大大增强。另外Snail的表达还赋予了Panc-1细胞对5-氟尿嘧啶和吉西他滨的抵抗能力。
结论Snail在胰腺癌组织中存在着表达,并且可以赋予胰腺癌细胞高度的侵袭和抵抗凋亡的能力。Snail有可能作为一种预测胰腺癌恶性程度的标志,发展针对Snail的治疗措施可能为提高胰腺癌患者的预后提供新的思路。
目的探讨上皮向间叶转化(EMT)在胰腺癌组织中的发生情况,研究上皮细胞标记物E-cadherin、间叶细胞标记物vimentin在胰腺癌组织及胰腺癌细胞中的表达情况以及与胰腺癌恶性生物学行为的相关性。
方法采用免疫组织化学的方法检测56例胰腺癌组织中E-cadherin、vimentin蛋白的表达,并与临床病理资料作对照分析。同时应用Western blot和免疫荧光技术检测Snail、E-cadherin、vimentin三种标记物分子在不同胰腺癌细胞Miapaca-2、Panc-1、BxPc-3中的表达情况,通过Transwell侵袭实验检测不同细胞侵袭能力的差异。
结果56例胰腺癌组织中26例(46.4%)观察到E-cadherin表达降低,同时6例观察到vimentin表达上调。E-cadherin的表达抑制和胰腺癌的淋巴结浸润(P=0.021),远处转移(P=0.001),病理分级(P=0.049)呈显著性相关。而6例vimentin表达上调的胰腺癌组织中有3例发生了远处转移。E-cadherin表达的降低和vimentin的高表达都与Snail的表达存在着明显的相关性。在高分化的胰腺癌细胞BxPc-3中,E-cadherin呈现高表达,未发现有vimentin和Snail的表达,相对应的细胞体外侵袭能力较差。在中低分化的胰腺癌细胞Panc-1、Miapaca-2中vimentin、Snail表达逐渐增强,E-cadherin表达明显降低,相对应的细胞在体外的侵袭能力则大大增强。
结论胰腺癌的侵袭过程中存在着肿瘤细胞上皮细胞标记物的降低,同时间叶细胞标记物的增强,EMT可能参与了胰腺癌侵袭性生物学行为。Snail可能通过调控EMT从而导致了胰腺癌细胞侵袭性表型。
目的探讨缺氧微环境对胰腺癌细胞上皮向间叶转化的诱导效应以及可能机制。
方法在缺氧微环境下培养胰腺癌细胞Panc-1,Transwell侵袭小室对比检测细胞在缺氧微环境下侵袭能力的变化情况。通过Western blot、免疫荧光检测缺氧对Panc-1细胞上皮细胞标记分子E-cadherin、间叶细胞标记分子vimentin表达的影响。同时通过实时荧光定量PCR检测缺氧对Panc-1细胞Snail mRNA表达的影响。为了探讨缺氧微环境诱导胰腺癌细胞发生表型改变的机制,将编码HIF-1αsiRNA的真核表达载体pGenesil-1-HIF-1α及对照载体瞬时转染Panc-1细胞,通过缺氧处理,Western blot检测沉默HIF-1α之后对Panc-1细胞E-cadherin、vimentin表达的影响;逆转录PCR检测抑制HIF-1α对Snail mRNA表达的影响;通过Transwell侵袭小室检测对细胞体外侵袭能力的影响。
结果处于缺氧微环境下的Panc-1胰腺癌细胞在体外侵袭能力大大增强,缺氧可以抑制上皮细胞标记物E-cadherin、增强间叶细胞标记分子vimentin的表达,活化转录因子Snail的表达。缺氧微环境下通过RNA干扰技术沉默HIF-1α之后可以恢复缺氧对E-cadherin的抑制,同时降低vimentin和Snail的表达,抑制缺氧环境中细胞在体外的侵袭能力。
结论缺氧微环境可以活化HIF-1α的表达,而HIF-1α可能通过诱导Snail进而促进胰腺癌细胞发生上皮向间叶转化产生侵袭性表型。靶向HIF-1α、Snail通路的治疗措施可能为抑制胰腺癌侵袭性生物学行为提供新的方法。
Background Pancreatic cancer is a dreadful malignancy. Because of its tendency to metastasis and its resistance to chemotherapy, the prognosis remains poor. Snail is a transcriptional factor which endows epithelial cells with migratory and anti-apoptotic abilities. Its expression has been demonstrated in many tumors. We hypothesized that Snail may be expressed in pancreatic cancer, and it may confer invasive and chemoresistant properties.
Material, Methods, and results We immunohistochemically examined Snail expression in pancreatic cancer, and found that it was expressed in 20 of 56 (36%) samples of pancreatic cancer. The Snail expression had a close correlation with lymph node invasion and distant metastasis. After transfecting Snail cDNA into pancreatic cancer cell line Panc-1, we found that Snail triggered overt epithelial to mesenchymal transitions in Panc-1 cells. The tumor invasive ability in vitro was evaluated using a transwell invasive chamber. Snail dramatically promoted the invasive ability of Panc-1 cells. Chemosensitivity of Panc-1 cells to 5-fluorouracil or gemcitabine after Snail transfection was assayed by MTT cell proliferation assay. Overexpression of Snail enhanced the chemoresistance to 5-fluorouracil of gemcitabine at different dosages. Moreover, Snail transfected Panc-1 cells produced more spontaneous metastasis than parental untransfected cells after orthotopically injected into the pancreas of nude mice.
Conclusion Snail is expressed in pancreatic cancer; it confers enhanced invasive ability and chemoresistance to pancreatic cancer cells. Snail may be a marker for predicting the malignancy of pancreatic cancer. Further therapy target to Snail may be of great benefit to pancreatic cancer patients.
Objective To investigate the occurrence of EMT in pancreatic cancer and the expression of epithelial marker E-cadherin, mesenchymal marker vimentin in pancreatic cancer and its correlation with the malignant features.
Methods Snail、E-cadherin、vimentin expression were determined in 56 cases of human pancreatic carcinoma with immunohistochemistry and the results were compared with pathology. Western blot and immunofluorescence were performed to compare the expression of E-cadherin, vimentin, Snail in different pancreatic cancer cells: Miapaca-2, Panc-1 and BxPc-3. Transwell invasion assay was performed to compare the in vitro invasive abilities of different cancer cells.
Results Reduced expression of E-cadherin was found in 26 cases, vimentin, a mesenchymal marker, was found to be highly expressed in pancreatic cancer cells in 6 cases. Significant correlation was detected between the expression of Snail and the reduced expression of E-cadherin and the expression of vimentin. The expression of vimentin was high in Miapaca-2 pancreatic cancer cells and the E-cadherin was low, but the invasive ability was strong. There were no vimentin and Snail expression in BxPc-3 cells, but the E-cadherin expression was strong and the invasive ability was weak.
Conclusion Represson of epithelial marker and accquistion of mesenchymal marker may be involved in the progression of pancreatic cancer. Re-expression of Snail in pancreatic cancer may accelerate invasion through epithelial to mesenchymal transition. Epithelial to mesenchymal transition may be mechanisms for pancreatic cancer cells to acquire the invasive ability.
Objective To investigate whether hypoxia environment can induce epithelial to mesenchymal transition of pancreatic cancer cells and the potential mechanisms.
Methods The pancreatic cancer cells Panc-1 was cultured in hypoxia environment. After cultured for indicated periods, the in vitro invasive ability of Panc-1 cells was compared with normoxia group using Transwell invasion assay. The epithelial marker E-cadherin and the mesenchymal marker vimentin were assayed by Western blot. The Snail mRNA was assayed by realtime PCR. To elucidate the potential mechanisms involved in the phenotypic changes of Panc-1 cells in hypoxia environment, the plasmid pGenesil-1-HIF-1αexpressing siRNA targeting at HIF-1αgene and the control plasmid was transient tansfected into the Panc-1 cells and were cultured for indicated times. Then, Western blot was performed to detect the changes of epithelial marker E-cadherin and the mesenchymal marker vimentin. The expression of Snail mRNA was detected by RT-PCR. The invasive abilities invtro was detected by Transwell invasion assay.
Results The invasive ability was increased dramatically in hypoxia environment. Hypoxia repressed the expression of E-cadherin, and enhanced the vimentin expression. Besides, the Snail mRNA was increased in hypoxia environment. After silencing the expression of HIF-1αof Panc-1 cells in hypoxia environment, the expression of E-cadherin can be enhanced、the vimentin, Snail expression was decreased. The invasive abilities of Panc-1 cells in hpoxia environment was repressed greatly accordingly.
Conclusion Hypoxia can activate the HIF-1αexpression which can induce the Snail transcriptional factor and trigger epithelial to mesenchymal transition.
方法为了论证此假设,我们通过免疫组织化学的方法检测了Snail在胰腺癌组织中的表达,以及和临床病例指标的相关性。同时我们将Snail编码基因转染胰腺癌细胞系Panc-1细胞,通过Transwell侵袭小室法检测Snail对Panc-1细胞体外侵袭能力的影响;通过MTT细胞增殖试验检测转染Snail基因对Panc-1细胞增殖以及对5-氟尿嘧啶、吉西他滨等化疗药物敏感性的影响;通过裸鼠接种实验检测Snail基因对胰腺癌细胞体内生长的影响。
结果Snail在胰腺癌组织中存在着表达,在56例胰腺癌组织中发现有20例Snail的表达呈阳性,阳性率达36%。此外Snail的表达同淋巴结转移、远处转移都存在有明显的相关性。Panc-1细胞在转染了Snail基因之后发生了明显的从上皮细胞表型向间叶细胞表型的转化,同时其在体内外的侵袭能力也大大增强。另外Snail的表达还赋予了Panc-1细胞对5-氟尿嘧啶和吉西他滨的抵抗能力。
结论Snail在胰腺癌组织中存在着表达,并且可以赋予胰腺癌细胞高度的侵袭和抵抗凋亡的能力。Snail有可能作为一种预测胰腺癌恶性程度的标志,发展针对Snail的治疗措施可能为提高胰腺癌患者的预后提供新的思路。
目的探讨上皮向间叶转化(EMT)在胰腺癌组织中的发生情况,研究上皮细胞标记物E-cadherin、间叶细胞标记物vimentin在胰腺癌组织及胰腺癌细胞中的表达情况以及与胰腺癌恶性生物学行为的相关性。
方法采用免疫组织化学的方法检测56例胰腺癌组织中E-cadherin、vimentin蛋白的表达,并与临床病理资料作对照分析。同时应用Western blot和免疫荧光技术检测Snail、E-cadherin、vimentin三种标记物分子在不同胰腺癌细胞Miapaca-2、Panc-1、BxPc-3中的表达情况,通过Transwell侵袭实验检测不同细胞侵袭能力的差异。
结果56例胰腺癌组织中26例(46.4%)观察到E-cadherin表达降低,同时6例观察到vimentin表达上调。E-cadherin的表达抑制和胰腺癌的淋巴结浸润(P=0.021),远处转移(P=0.001),病理分级(P=0.049)呈显著性相关。而6例vimentin表达上调的胰腺癌组织中有3例发生了远处转移。E-cadherin表达的降低和vimentin的高表达都与Snail的表达存在着明显的相关性。在高分化的胰腺癌细胞BxPc-3中,E-cadherin呈现高表达,未发现有vimentin和Snail的表达,相对应的细胞体外侵袭能力较差。在中低分化的胰腺癌细胞Panc-1、Miapaca-2中vimentin、Snail表达逐渐增强,E-cadherin表达明显降低,相对应的细胞在体外的侵袭能力则大大增强。
结论胰腺癌的侵袭过程中存在着肿瘤细胞上皮细胞标记物的降低,同时间叶细胞标记物的增强,EMT可能参与了胰腺癌侵袭性生物学行为。Snail可能通过调控EMT从而导致了胰腺癌细胞侵袭性表型。
目的探讨缺氧微环境对胰腺癌细胞上皮向间叶转化的诱导效应以及可能机制。
方法在缺氧微环境下培养胰腺癌细胞Panc-1,Transwell侵袭小室对比检测细胞在缺氧微环境下侵袭能力的变化情况。通过Western blot、免疫荧光检测缺氧对Panc-1细胞上皮细胞标记分子E-cadherin、间叶细胞标记分子vimentin表达的影响。同时通过实时荧光定量PCR检测缺氧对Panc-1细胞Snail mRNA表达的影响。为了探讨缺氧微环境诱导胰腺癌细胞发生表型改变的机制,将编码HIF-1αsiRNA的真核表达载体pGenesil-1-HIF-1α及对照载体瞬时转染Panc-1细胞,通过缺氧处理,Western blot检测沉默HIF-1α之后对Panc-1细胞E-cadherin、vimentin表达的影响;逆转录PCR检测抑制HIF-1α对Snail mRNA表达的影响;通过Transwell侵袭小室检测对细胞体外侵袭能力的影响。
结果处于缺氧微环境下的Panc-1胰腺癌细胞在体外侵袭能力大大增强,缺氧可以抑制上皮细胞标记物E-cadherin、增强间叶细胞标记分子vimentin的表达,活化转录因子Snail的表达。缺氧微环境下通过RNA干扰技术沉默HIF-1α之后可以恢复缺氧对E-cadherin的抑制,同时降低vimentin和Snail的表达,抑制缺氧环境中细胞在体外的侵袭能力。
结论缺氧微环境可以活化HIF-1α的表达,而HIF-1α可能通过诱导Snail进而促进胰腺癌细胞发生上皮向间叶转化产生侵袭性表型。靶向HIF-1α、Snail通路的治疗措施可能为抑制胰腺癌侵袭性生物学行为提供新的方法。
Background Pancreatic cancer is a dreadful malignancy. Because of its tendency to metastasis and its resistance to chemotherapy, the prognosis remains poor. Snail is a transcriptional factor which endows epithelial cells with migratory and anti-apoptotic abilities. Its expression has been demonstrated in many tumors. We hypothesized that Snail may be expressed in pancreatic cancer, and it may confer invasive and chemoresistant properties.
Material, Methods, and results We immunohistochemically examined Snail expression in pancreatic cancer, and found that it was expressed in 20 of 56 (36%) samples of pancreatic cancer. The Snail expression had a close correlation with lymph node invasion and distant metastasis. After transfecting Snail cDNA into pancreatic cancer cell line Panc-1, we found that Snail triggered overt epithelial to mesenchymal transitions in Panc-1 cells. The tumor invasive ability in vitro was evaluated using a transwell invasive chamber. Snail dramatically promoted the invasive ability of Panc-1 cells. Chemosensitivity of Panc-1 cells to 5-fluorouracil or gemcitabine after Snail transfection was assayed by MTT cell proliferation assay. Overexpression of Snail enhanced the chemoresistance to 5-fluorouracil of gemcitabine at different dosages. Moreover, Snail transfected Panc-1 cells produced more spontaneous metastasis than parental untransfected cells after orthotopically injected into the pancreas of nude mice.
Conclusion Snail is expressed in pancreatic cancer; it confers enhanced invasive ability and chemoresistance to pancreatic cancer cells. Snail may be a marker for predicting the malignancy of pancreatic cancer. Further therapy target to Snail may be of great benefit to pancreatic cancer patients.
Objective To investigate the occurrence of EMT in pancreatic cancer and the expression of epithelial marker E-cadherin, mesenchymal marker vimentin in pancreatic cancer and its correlation with the malignant features.
Methods Snail、E-cadherin、vimentin expression were determined in 56 cases of human pancreatic carcinoma with immunohistochemistry and the results were compared with pathology. Western blot and immunofluorescence were performed to compare the expression of E-cadherin, vimentin, Snail in different pancreatic cancer cells: Miapaca-2, Panc-1 and BxPc-3. Transwell invasion assay was performed to compare the in vitro invasive abilities of different cancer cells.
Results Reduced expression of E-cadherin was found in 26 cases, vimentin, a mesenchymal marker, was found to be highly expressed in pancreatic cancer cells in 6 cases. Significant correlation was detected between the expression of Snail and the reduced expression of E-cadherin and the expression of vimentin. The expression of vimentin was high in Miapaca-2 pancreatic cancer cells and the E-cadherin was low, but the invasive ability was strong. There were no vimentin and Snail expression in BxPc-3 cells, but the E-cadherin expression was strong and the invasive ability was weak.
Conclusion Represson of epithelial marker and accquistion of mesenchymal marker may be involved in the progression of pancreatic cancer. Re-expression of Snail in pancreatic cancer may accelerate invasion through epithelial to mesenchymal transition. Epithelial to mesenchymal transition may be mechanisms for pancreatic cancer cells to acquire the invasive ability.
Objective To investigate whether hypoxia environment can induce epithelial to mesenchymal transition of pancreatic cancer cells and the potential mechanisms.
Methods The pancreatic cancer cells Panc-1 was cultured in hypoxia environment. After cultured for indicated periods, the in vitro invasive ability of Panc-1 cells was compared with normoxia group using Transwell invasion assay. The epithelial marker E-cadherin and the mesenchymal marker vimentin were assayed by Western blot. The Snail mRNA was assayed by realtime PCR. To elucidate the potential mechanisms involved in the phenotypic changes of Panc-1 cells in hypoxia environment, the plasmid pGenesil-1-HIF-1αexpressing siRNA targeting at HIF-1αgene and the control plasmid was transient tansfected into the Panc-1 cells and were cultured for indicated times. Then, Western blot was performed to detect the changes of epithelial marker E-cadherin and the mesenchymal marker vimentin. The expression of Snail mRNA was detected by RT-PCR. The invasive abilities invtro was detected by Transwell invasion assay.
Results The invasive ability was increased dramatically in hypoxia environment. Hypoxia repressed the expression of E-cadherin, and enhanced the vimentin expression. Besides, the Snail mRNA was increased in hypoxia environment. After silencing the expression of HIF-1αof Panc-1 cells in hypoxia environment, the expression of E-cadherin can be enhanced、the vimentin, Snail expression was decreased. The invasive abilities of Panc-1 cells in hpoxia environment was repressed greatly accordingly.
Conclusion Hypoxia can activate the HIF-1αexpression which can induce the Snail transcriptional factor and trigger epithelial to mesenchymal transition.
引文
1.Gunzburg WH, Salmons B. Novel clinical strategies for the treatment of pancreatic carcinoma. Trends Mol Med.2001; 7:30.
2.Ohuchida K, Mizumoto K, Murakami M, Qian LW, Sato N, Nagai E, Matsumoto K, Nakamura T, Tanaka M. Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions. Cancer Res. 2004; 64:3215.
3.Richter A, Niedergethmann M, Sturm JW, Lorenz D, Post S, Trede M. Long-term results of partial pancreaticoduodenectomy for ductal adenocarcinoma of the pancreatic head: 25-year experience. World J Surg. 2003; 27:324-9.
4.Keleg S, Buchler P, Ludwig R, Buchler MW, Friess H.Invasion and metastasis in pancreatic cancer. Mol Cancer.2003; 2:14.
5.DiMagno EP, Reber HA, Tempero MA.AGA technical review on the epidemiology, diagnosis, and treatment of pancreatic ductal adenocarcinoma. American Gastroenterological Association.Gastroenterology.1999; 117:1464.
6.Gotzmann J, Mikula M, Eger A, Schulte-Hermann R, Foisner R, Beug H, Mikulits W. Molecular aspects of epithelial cell plasticity: implications for local tumor invasion and metastasis. Mutat Res. 2004; 566:9.
7.Thiery JP. Epithelial-mesenchymal transitions in tumor progression. Nat Rev Cancer 2002, 2:442.
8.Valdes F, Alvarez AM, Locascio A, Vega S, Herrera B, Fernandez M, Benito M, Nieto MA, Fabregat I.The epithelial mesenchymal transition confers resistance to the apoptotic effects of transforming growth factor Beta in fetal rat hepatocytes. Mol Cancer Res. 2002; 1:68.
9.Malathy PV Shekhar, Robert Pauley, Gloria Heppner. Host microenvironment in breast cancer development: Extracellular matrix–stromal cell contribution to neoplastic phenotype of epithelial cells in the breast. Breast Cancer Res. 2003; 5: 130.
10.Poser I, Dominguez D, de Herreros AG, Varnai A, Buettner R, Bosserhoff AK. Loss of E-cadherin expression in melanoma cells involves up-regulation of the transcriptional repressor Snail. J Biol Chem. 2001; 276:24661.
11.Katoh M. Epithelial-mesenchymal transition in gastric cancer Int J Oncol. 2005 Dec;27(6):1677-83.
12.del Barrio MG, Nieto MA. Overexpression of Snail family members highlights their ability to promote chick neural crest formation. Development.2002; 129:1583.
13.Carver EA, Jiang R, Lan Y, Oram KF, Gridley T. The mouse Snail gene encodes a key regulator of the epithelial-mesenchymal transition. Mol Cell Biol. 2001; 21:8184.
14.Manzanares, M., Locascio, A. and Nieto, M. A. The increasing complexity of the Snail gene superfamily in metazoan evolution. Trend Genet.2001; 17:178.
15.Duband, J. L., Monier, F., Delannet, M. and Newgreen, D. Epithelium-mesenchyme transition during neural crest development. Acta Anat (Basel).1995; 154: 63.
16.Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, Portillo F, Nieto MA.The transcription factor Snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000; 2:76.
17.Vega S, Morales AV, Ocana OH, Valdes F, Fabregat I, Nieto MA. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 2004; 18:1131.
18.Blanco MJ, Moreno-Bueno G, Sarrio D, Locascio A, Cano A, Palacios J, Nieto MA.Correlation of Snail expression with histological grade and lymph node status in breastcarcinomas.Oncogene.2002; 21:3241.
19.Roy HK, Smyrk TC, Koetsier J, Victor TA, Wali RK.The transcriptional repressor SNAIL is overexpressed in human colon cancer. Dig Dis Sci. 2005; 50:42.
20.Rosivatz E, Becker I, Specht K, Fricke E, Luber B, Busch R, Hofler H, Becker KF. Differential expression of the epithelial-mesenchymal transition regulators Snail, SIP1, and twist in gastric cancer. Am J Pathol.2002; 161:1881.
21.Poser I, Dominguez D, de Herreros AG, Varnai A, Buettner R, Bosserhoff AK. Loss of E-cadherin expression in melanoma cells involves up-regulation of the transcriptional repressor Snail. J Biol Chem. 2001; 276:24661.
22.Sobin LH, Wittekind CH. TNM classification of malignant tumors, 6th ed. New York: John Wiley & Sons. 2002.
23.Sambrook J, Fritsch EF, Maniatis T. Molecular Cloning: a laboratory manual. 2 rd ed.New York: Cold Spring Harbor Laboratory Press.1989.
24.Tsutsumi S, Yanagawa T, Shimura T, Kuwano H, Raz A.Autocrine motility factor signaling enhances pancreatic cancer metastasis. Clin Cancer Res. 2004; 10:7775.
25.Guaita S, Puig I, Franci C, Garrido M, Dominguez D, Batlle E, Sancho E, Dedhar S, De Herreros AG, Baulida J. Snail induction of epithelial to mesenchymal transition in tumor cells is accompanied by MUC1 repression and ZEB1 expression. J Biol Chem. 2002; 277:39209.
26.Yokoyama K, Kamata N, Fujimoto R, Tsutsumi S, Tomonari M, Taki M, Hosokawa H, Nagayama M. Increased invasion and matrix metalloproteinase-2 expression by Snail-induced mesenchymal transition in squamous cell carcinomas. Int J Oncol.2003; 22:891.
27.Ohkubo T, Ozawa M. The transcription factor Snail downregulates the tight junction components independently of E-cadherin downregulation. J Cell Sci. 2004;117:1675.
28.Bolos V, Peinado H, Perez-Moreno MA, Fraga MF, Esteller M, Cano A. The transcription factor Slug represses E-cadherin expression and induces epithelial tomesenchymal transitions: a comparison with Snail and E47 repressors. J Cell Sci. 2003;116:499.
29.Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, Portillo F, Nieto MA. The transcription factor Snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol.2000; 2:76.
30.Bates RC, Mercurio AM. Tumor necrosis factor-alpha stimulates the epithelial-to-mesenchymal transition of human colonic organoids. Mol Biol Cell.2003; 14:1790.
31.Behrens J, Mareel MM, Van Roy FM, Birchmeier W.Dissecting tumor cell invasion: epithelial cells acquire invasive properties after the loss of uvomorulin-mediated cell-cell adhesion. J Cell Biol.1989; 108:2435.
32.Bates RC, Goldsmith JD, Bachelder RE, Brown C, Shibuya M, Oettgen P, Mercurio AM. Flt-1-dependent survival characterizes the epithelial-mesenchymal transition of colonic organoids. Curr Biol.2003; 13:1721.
33.Vega S, Morales AV, Ocana OH, Valdes F, Fabregat I, Nieto MA.Snail blocks the cell cycle and confers resistance to cell death. Genes Dev.2004; 18:1131.
34.Kajita M, McClinic KN, Wade PA. Aberrant expression of the transcription factors Snail and slug alters the response to genotoxic stress. Mol Cell Biol. 2004; 24:7559.
35.Wey JS, Gray MJ, Fan F, Belcheva A, McCarty MF, Stoeltzing O, Somcio R, Liu W, Evans DB, Klagsbrun M, Gallick GE, Ellis LM. Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells.Br J Cancer.2005; 93:233.
36.Sugimachi K, Tanaka S, Kameyama T, Taguchi K, Aishima S, Shimada M, Sugimachi K, Tsuneyoshi M. Transcriptional repressor Snail and progression of human hepatocellular carcinoma. Clin Cancer Res. 2003; 9:2657.
37.Pignatelli M, Ansari TW, Gunter P, Liu D, Hirano S, Takeichi M, Kloppel G, Lemoine NR.Loss of membranous E-cadherin expression in pancreatic cancer: correlation withlymph node metastasis, high grade, and advanced stage. J Pathol. 1994; 174:243.
38.Yoshida R, Kimura N, Harada Y, Ohuchi N. The loss of E-cadherin, alpha- and beta-catenin expression is associated with metastasis and poor prognosis in invasive breast cancer. Int J Oncol. 2001; 18:513.
39.Cai J, Ikeguchi M, Tsujitani S, Maeta M, Liu J, Kaibara N. Significant correlation between micrometastasis in the lymph nodes and reduced expression of E-cadherin in early gastric cancer. Gastric Cancer.2001; 4:66.
40.Joo YE, Rew JS, Park CS, Kim SJ. Expression of E-cadherin, alpha- and beta-catenins in patients with pancreatic adenocarcinoma. Pancreatology.2002; 2:129.
41.Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J, Garcia De Herreros A. The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumor cells. Nat Cell Biol.2000; 2:84.
42.Gilles C, Polette M, Zahm JM, Tournier JM, Volders L, Foidart JM, Birembaut P. Vimentin contributes to human mammary epithelial cell migration J Cell Sci. 1999;112:4615.
43.Singh S, Sadacharan S, Su S, Belldegrun A, Persad S, Singh G.Overexpression of vimentin: role in the invasive phenotype in an androgen-independent model of prostate cancer. Cancer Res. 2003; 63:2306.
44.Ellenrieder V, Hendler SF, Boeck W, Seufferlein T, Menke A, Ruhland C, Adler G, Gress TM. Transforming growth factor beta1 treatment leads to an epithelial-mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-regulated kinase 2 activation. Cancer Res. 2001; 61:4222.
45.Barrallo-Gimeno A, Nieto MA. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development.2005; 132:3151.
1.Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002; 2:442–54.
2.Barrallo-Gimeno A, Nieto MA. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development. 2005 Jul;132(14):3151-61.
3.Savagner P. et al. Leaving the neighborhood: molecular mechanisms involved during epithelial-mesenchymal transition. Bioessays. 2001 Oct;23(10):912-23.
4.Gotzmann J,Mikula M,Eger A,et al.Molecular aspects of epithelial cell plasticity:implications for local invasion and metastasis. Mutat Res,2004,566:9 -20.
5.Katoh M. Epithelial-mesenchymal transition in gastric cancer Int J Oncol. 2005 Dec;27(6):1677-83.
6.Blanco MJ, Moreno-Bueno G, Sarrio D, et al. Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene, 2002, 21(20),3241-6.
7.Poser I, Dominguez D, de Herreros AG, Varnai A, Buettner R, Bosserhoff AK. Loss of E-cadherin expression in melanoma cells involves up-regulation of the transcriptional repressor Snail. J Biol Chem. 2001; 276:24661.
8.Bates RC, Mercurio AM. Tumor necrosis factor-alpha stimulates the epithelial-to-mesenchymal transition of human colonic organoids. Mol Biol Cell.2003; 14:1790.
9.Behrens J, Mareel MM, Van Roy FM, Birchmeier W.Dissecting tumor cell invasion: epithelial cells acquire invasive properties after the loss of uvomorulin-mediated cell-cell adhesion. J Cell Biol.1989; 108:2435.
10.Auersperg N, Pan J, Grove BD, Peterson T, et al. E-cadherin induces mesenchymal-to-epithelial transition in human ovarian surface epithelium. Proc Natl Acad Sci U S A. 1999 May 25;96(11):6249-54.
11.Spath GF, Weiss MC. Hepatocyte nuclear factor 4 provokes expression of epithelial marker genes, acting as a morphogen in dedifferentiated hepatoma cells, J Cell Biol, 1998, 140(4), 935-46.
12.Beavon IR. Regulation of E-cadherin: does hypoxia initiate the metastatic cascade? Mol Pathol. 1999 Aug;52(4):179-88.
13.Karayiannakis AJ, Syrigos KN, Chatzigianni E. E-cadherin expression as a differentiation marker in gastric cancer. Hepatogastroenterology, 1998, 45(24), 2437- 2442.
14.Oka H, Shiozaki H, Kobayashi K, et al. Expression of E-cadherin cell adhesion molecules in human breast cancer tissues and its relationship to metastasis. Cancer Res, 1993,53,1696-1701.
15.Gilles C, Polette Molette M, Mestdagt M,et al.Transactivation of vimentin by beta-catenin in human breast cancer cells.Cancer Res,2003,63(10):2658-2664.
16.Gilles C., Polette M., Zahm J. M., Tournier J. M., Volders L., Foidart J. M., Birembaut P. Vimentin contributes to human mammary epithelial cell migration. J. Cell Sci., 112 (Pt 24):4615-4625, 1999.
17.Hendrix M. J., Seftor E. A., Seftor R. E., Trevor K. T. Experimental co-expression of vimentin and keratin intermediate filaments in human breast cancer cells results in phenotypic interconversion and increased invasive behavior. Am. J. Pathol., 150: 483-495, 1997.
18.Eckes B., Dogic D., Colucci-Guyon E., et al. Impaired mechanical stability, migration and contractile capacity in vimentin-deficient fibroblasts. J. Cell Sci., 111 (Pt 13): 1897-1907, 1998.
19.Eckes B., Colucci-Guyon E., Smola H., Nodder S., Babinet C., Krieg T., Martin P. Impaired wound healing in embryonic and adult mice lacking vimentin. J. Cell Sci., 113: 2455-2462, 2000
20.Korsching E, Packeisen J, Liedtke C,et al. The origin of vimentin expression in invasive breast cancer: epithelial-mesenchymal transition, myoepithelial histogenesis or histogenesis from progenitor cells with bilinear differentiation potential? J Pathol. 2005; 206(4):451-7.
21.Gotzmann J, Mikula M, Eger A. Molecular aspects of epithelial cell plasticity: implications for local tumor invasion and metastasis. Mutat Res, 2004, 566(1), 9-20.
1.Rofstad EK. Microenvironment-induced cancer metastasis. Int J Radiat Biol. 2000 May;76(5):589-605.
2. Subarsky P, Hill RP. The hypoxic tumour microenvironment and metastatic progression.Clin Exp Metastasis. 2003;20(3):237-50.
3. Beavon IR. Regulation of E-cadherin: does hypoxia initiate the metastatic cascade? Mol Pathol. 1999 Aug;52(4):179-88.
4. Gotzmann J,Mikula M,Eger A,et al. Molecular aspects of epithelial cell plasticity:implications for local invasion and metastasis.Mutat Res,2004,566:9 -20.
5. Duffy JP, Eibl G, Reber HA, et al. Influence of hypoxia and neoangiogenesis on the growth of pancreatic cancer. Mol Cancer. 2003 Jan 22;2:12.
6. Yassa, N. A., Yang, J., Stein, S., Johnson, M., and Ralls, P. Gray-scale and color flow sonography of pancreatic ductal adenocarcinoma. J. Clin. Ultrasound, 25: 473–480,1997.
7. Wei H, Wang C, Chen L. Proliferating cell nuclear antigen, survivin, and CD34expression in pancreatic cancer and their correlation with hypoxia-inducible factor 1alpha. Pancreas. 2006 Mar 32(2):159-63.
8. Duffy JP, Eibl G, Reber HA, et al. Influence of hypoxia and neoangiogenesis on the growth of pancreatic cancer. Mol Cancer. 2003 Jan 22;2:12.
9. Buchler P, Reber HA, Buchler M, et al. Hypoxia-inducible factor 1 regulates vascular endothelial growth factor expression in human pancreatic cancer. Pancreas. 2003 Jan;26(1):56-64.
10. Pouyssegur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce tumour regression.Nature. 2006 May 25;441(7092):437-43.
11. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002; 2:442–54.
12. Bates RC, Mercurio AM. Tumor necrosis factor-alpha stimulates the epithelial-to-mesenchymal transition of human colonic organoids. Mol Biol Cell.2003; 14:1790.
13. Behrens J, Mareel MM, Van Roy FM, Birchmeier W.Dissecting tumor cell invasion: epithelial cells acquire invasive properties after the loss of uvomorulin-mediated cell-cell adhesion. J Cell Biol.1989; 108:2435.
14. Auersperg N, Pan J, Grove BD, Peterson T, et al. E-cadherin induces mesenchymal-to-epithelial transition in human ovarian surface epithelium. Proc Natl Acad Sci U S A. 1999 May 25;96(11):6249-54.
15. Li YJ, Ji XR. Relationship between expression of E-cadherin-catenin complex and clinicopathologic characteristics of pancreatic cancer. World J Gastroenterol 2003 Feb 15;9(2):368-372
16. Bremnes RM, Veve R, Hirsch FR, et al. The E-cadherin cell-cell adhesion complex and lung cancer invasion, metastasis, and prognosis. Lung Cancer. 2002 May;36(2):115-24.
17. Beavon IR. The E-cadherin-catenin complex in tumour metastasis: structure, function and regulation. Eur J Cancer. 2000 Aug;36(13 Spec No):1607-20.
18. Gilles C., Polette M., Zahm J. M., Tournier J. M., Volders L., Foidart J. M., Birembaut P. Vimentin contributes to human mammary epithelial cell migration. J. Cell Sci., 112 (Pt 24): 4615-4625, 1999.
19. Hendrix M. J., Seftor E. A., Seftor R. E., Trevor K. T. Experimental co-expression of vimentin and keratin intermediate filaments in human breast cancer cells results in phenotypic interconversion and increased invasive behavior. Am. J. Pathol., 150: 483-495, 1997.
20. Barrallo-Gimeno A, Nieto MA.The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development. 2005 Jul;132(14):3151-61.
21. Kurrey NK, K A, Bapat SA. Snail and Slug are major determinants of ovarian cancer invasiveness at the transcription level. Gynecol Oncol. 2005 Apr;97(1):155-65.
22. Zhang Q, Wang SY, Nottke AC, et al. Redox sensor CtBP mediates hypoxia-induced tumor cell migration. Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9029-33.
23. Ryan HE, Poloni M, McNulty W.Hypoxia-inducible factor-1alpha is a positive factor in solid tumor growth. Cancer Res. 2000 Aug 1;60(15):4010-5.
24. Vukovic V, Haugland HK, Nicklee T, Morrison AJ, Hedley DW: Hypoxia-inducible factor-1alpha is an intrinsic marker for hypoxia in cervical cancer xenografts. Cancer Res 2001, 61:7394–7398
25. Vukovic V, Haugland HK, Nicklee T, Morrison AJ, Hedley DW: Hypoxia-inducible factor-1alpha is an intrinsic marker for hypoxia in cervical cancer xenografts. Cancer Res 2001, 61:7394–7398
26. Swinson DE, O'Byrne KJ. Interactions between hypoxia and epidermal growth factor receptor in non-small-cell lung. Clin Lung Cancer. 2006 Jan;7(4):250-6.
27. Brizel DM, Sibley GS, Prosnitz LR, Scher RL, Dewhirst MW: Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 1997, 38:285–289.
28. Kitada T, Seki S, Sakaguchi H, et al. Clinicopathological significance ofhypoxia-inducible factor-1alpha expression in human pancreatic carcinoma. Histopathology. 2003 Dec;43(6):550-5.
29. Imai T, Horiuchi A, Wang C, et al. Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells. Am J Pathol. 2003 Oct;163(4):1437-47.
30. Tsutsumi S, Yanagawa T, Shimura T, Kuwano H, Raz A.Autocrine motility factor signaling enhances pancreatic cancer metastasis. Clin Cancer Res. 2004; 10:7775.
1. Newgreen, D.F., and S.J. McKeown. Neural crest cells migration. In Rise and Fall of Epithelial Phenotype: Concepts of Epithelial-Mesenchymal Transition. P. Savagner, editor. Landes Bioscience, Texas.2005, 29–39.
2. Huang, X., and J.P. Saint-Jeannet. Induction of the neural crest and the opportuniti- es of life on the edge. Dev. Biol,2004,275:1–11.
3. Auersperg N, Pan J, Grove BD, et al. E-cadherin induces mesenchymal-to- epithelial transition in human ovarian surface epithelium. Proc Natl Acad Sci U S A. 1999 May 25; 96(11):6249-54.
4. Thiery JP: Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 2003, 15:740-746.
5. Barrallo-Gimeno A, Nieto MA. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development,2005 Jul; 132(14):3151-61.
6. Moody, S.E., D. Perez, T.C. Pan, C.J. et al. The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell.2005,8:197–209.
7. Willipinski-Stapelfeldt, B., S. Riethdorf, V. et al. Changes in cytoskeletal protein composition indicative of an epithelial-mesenchymal transition in human micrometas- tatic and primary breast carcinoma cells. Clin. Cancer Res.2005,11:8006–8014.
8. Brabletz T, Hlubek F, Spaderna S, et al. Invasion and metastasis in colorectal cancer: epithelial-mesenchymal transition, mesenchymal-epithelial transition, stem cells and beta-catenin. Cells Tissues Organs. 2005;179(1-2):56-65.
9. Thiery JP: Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer 2002, 2:442-454.
10. Xue C, Plieth D, Venkov C, Xu C, Neilson EG: The gatekeeper effect of epithelial -mesenchymal transition regulates the frequency of breast cancer metastasis. Cancer Res 2003,63:3386-3394.
11. Petersen OW, Nielsen HL, Gudjonsson T, Villadsen R,et al: Epithelial- to- mesenchymal transition in human breast cancer can provide a nonmalignant stroma. Am J Pathol 2003, 162:391-402.
12. Eitner F, Floege J: Novel insights into renal fibrosis. Curr Opin Nephrol Hypertens 2003, 12:227-232.
13. Neilson, E.G. Setting a trap for tissue fi brosis. Nat. Med.2005,11:373–374.
14. Iwano, M., D. Plieth, T.M. Danoff, C. et al. Evidence that fi broblasts derive from epithelium during tissue fibrosis. J. Clin. Invest.2002,110:341–350.
15. Nishitani, Y., M. Iwano, Y. Yamaguchi, K. et al. 2005. Fibroblast-specifi c protein 1 is a specifi c prognostic marker for renal survival in patients with IgAN. Kidney Int. 68:1078–1085.
16. Lan HY: Tubular epithelial-myofibroblast transdifferentiation mechanisms in proximal tubule cells. Curr Opin Nephrol Hypertens 2003, 12:25-29.
17. Yanez-Mo M, Lara-Pezzi E, Selgas R, Ramirez-Huesca M, et al.: Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells. N Engl J Med 2003, 348:403-413.
18. Saika S, Miyamoto T, Tanaka S, Tanaka T, et al.: Response of lens epithelial cells to injury: role of lumican in epithelial–mesenchymal transition. Invest Ophthalmol Vis Sci 2003,44:2094-2102.
19. Zavadil J, Bottinger EP. TGF-beta and epithelial-to-mesenchymal transitions. Oncogene. 2005 Aug 29;24(37):5764-74.
20. Janda E, Lehmann K, Killisch I, et al: Ras and TGFb cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol 2002, 156:299-313.
21. Peinado, H., Quintanilla, M., and Cano, A. Transforming growth factor beta-1 induces Snail transcription factor in epithelial cell lines: implications for epithelial mesenchymal transitions. Oncogene ,2003,23, 21113-21123.
22. Yi, J.Y., Shin, I., and Artega, C.L. Type I transforming growth factor beta receptor binds to and activates phosphatidylinositol 3-kinase. J. Biol. Chem.2005,280, 10870-10876.
23. Janda, E., Lehmann, K., Killisch, I., et al. Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J. Cell Biol. 2002,156, 299-313.
24. Ozdamar, B., Bose, R., Barrios-Rodiles, M., et al. Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science.2005,307, 1603-1609.
25. Nicolas FJ, Lehmann K, Warne PH, et al. Epithelial-to-mesenchymal transition in Madin- Darby canine kidney cells is accompanied by down-regulation of Smad3 expression, leading to resistance to transforming growthfactor-β-induced growth arrest. J Biol Chem 2003, 278: 3251- 3256.
26. Kim JT, Joo CK: Involvement of cell–cell interactions in the rapid stimulation of Cas tyrosine phosphorylation and Src kinase activity by transforming growth factor b1. J BiolChem 2002,277:31938-31948.
27. Shimizu Y, Yamamichi N, Saitoh K, et al.: Kinetics of v-src-induced epithelial- mesenchymal transition in developing glandular stomach. Oncogene 2003, 22:884- 893.
28 Gotzmann J, Fischer AN, Zojer M, et al. A crucial function of PDGF in TGF-beta- mediated cancer progression of hepatocytes. Oncogene. 2006 May 25;25(22):3170-85
29. Edme N, Downward J, Thiery JP, Boyer B: Involvement of MAPK and Rac in epithelial cell scattering, J Cell Sci 2002, 115.
30. Janda E, Lehmann K, Killisch I, et al: Ras and TGFb cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol 2002, 156:299-313.
31. Grille SJ, Bellacosa A, Upson J, et al: The protein kinase akt induces epithelial– mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res 2003, 63:2172-2178.
32. Lamorte L, Royal I, Naujokas M, Park M: Crk adapter proteins promote an epithelial-mesenchymal-like transition and are required for HGF-mediated cell spreading and breakdown of epithelial adherens junctions. Mol Biol Cell 2002, 13:1449-1461.
33. Sahai E, Marshall CJ: ROCK and Dia have opposing effects on adherens junctions downstream of Rho. Nat Cell Biol 2002, 4:408-415.
34. Psichari E, Balmain A, Plows D, et al: High activity of serum response factor in the mesenchymal transition of epithelial tumor cells is regulated by RhoA signaling. J Biol Chem 2002, 277: 29490-29495.
35. Benitah SA, Valeron PF, Rui H, Lacal JC: STAT5a activation mediates the epithelial-to- mesenchymal transition induced by incogenic RhoA. Mol Biol Cell 2003, 14:40-53.
36. Thiery JP: Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 2003, 15:740-746.
37 Kim, K., Lu, Z., and Hay, E.D. Direct evidence for a role of beta-catenin/LEF-1 signalling pathway in the induction of EMT. Cell Biol. Int. 2002,26, 463-476.
38 Liebner S, Cattelino A, Gallini R, et al.β-catenin is required for endothelial- mesenchymal transformation during heart cushion development in the mouse. J Cell Biol 2004, 166:359-367.
39. Pasca di Magliano M, Hebrok M: Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer 2003, 3:903-911.
40. Karhadkar SS, Bova GS, Abdallah N, et al: Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 2004, 431:707-712.
41. Louro ID, Bailey EC, Li X, et al.: Comparative gene expression profile analysis of GLI and c-MYC in an epithelial model of malignant transformation. Cancer Res 2002, 62:5867-5873.
42. Xie L, Law BK, Chytil AM, Brown KA, et al: Activation of the Erk pathway is required for TGF-β-1-induced EMT in vitro. Neoplasia 2004, 6:603-610.
43. Mullor JL, Dahmane N, Sun T, Ruiz i Altaba A: Wnt signals are targets and mediators of Gli function. Curr Biol 2001,11:769-773.
44. Radtke F, Raj K: The role of Notch in tumorigenesis: oncogene or tumour supper- ssor? Nat Rev Cancer 2003, 3:756-767.
45. Timmerman LA, Grego-Bessa J, Raya A, et al.: Notch promotes epithelialmesenc- hymal transition during cardiac development and oncogenic transformation. Genes Dev 2004, 18:99-115.
46. Grego-Bessa J, Diez J, Timmerman L, de la Pompa JL: Notch and epithelial- mesenchyme transition in development and tumor progression: another turn of the screw. Cell Cycle 2004, 3:718-721.
47. Nieto MA: The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol 2002, 3:155-166.
48. Bolos V, Peinado H, Perez-Moreno MA, et al: The transcription factor Slug represses E-cadherin expression and induces epithelial-to-mesenchymal transitions: a comparison with Snail and E47 repressors. J Cell Sci 2003, 116:499-511.
49. Peinado H, Quintanilla M, Cano A: Transforming growth factorβ-1 induces snail transcription factor in epithelial cell lines:mechanisms for epithelial mesenchymal transitions. J Biol Chem 2003, 278:21113-21123.
50. Guaita S, Puig I, Franci C, et al: Snail induction of epithelial-to-mesenchymal transition in tumor cells is accompanied by MUC1 repression and ZEB1 expression. J Biol Chem 2002, 277:39209-39216.
51. Fujita N, Jaye DL, Kajita M, et al: MTA3, a Mi-2/NuRD complex subunit, regulates an invasive growth pathway in breast cancer. Cell 2003, 113:207-219.
52. Louro ID, Bailey EC, Li X, et al.: Comparative gene expression profile analysis of GLI and c-MYC in an epithelial model of malignant transformation. Cancer Res 2002, 62:5867-5873.
53. Gschwind A, Fischer OM, Ullrich A: The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer2004, 4:361-370.
54. Yingling JM, Blanchard KL, Sawyer JS: Development of TGF-βsignalling inhibitors for cancer therapy. Nat Rev Drug Discov 2004, 3:1011-1022.
55. Pasca di Magliano M, Hebrok M: Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer 2003, 3:903-911.
56. Downward J: Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 2003, 3:11-22.
57. Karin M, Yamamoto Y, Wang QM: The IKK NF-kB system: a treasure trove for drug development. Nat Rev Drug Discov 2004, 3:17-26
1. Nakayama H, Scott IC, Cross JC. The transition to endoreduplication in trophoblast giant cells is regulated by the mRNA zinc finger transcription factor. Dev Biol, 1998,199: 150-163
2. Fuse, N., Hirose, S. and Hayashi, S. Diploidy of Drosophila imaginal cells is maintained by a transcriptional repressor encoded by escargot. Genes Dev,1994,8, 2270-2281.
3. H. L. Grimes, T. O. Chan, Patrick A. et al. The Gfi-1 proto-oncoprotein contains a novel transcriptional repressor domain, SNAG, and inhibits G1 arrest induced by IL-2 withdrawal. Molecular and Cellular Biology 1996 16(11):6263-6272.
4. Y. Nibu, H. Zhang, E. Bajor, S. Barolo, S. Small, and M. Levine dCtBP mediates transcriptional repression by Knirps, Kruppel and Snail in the Drosophila embryo EMBO J., December 1, 1998; 17(23): 7009– 7020
5. Tateno M, Fukunishi Y, Komatsu S, Okazaki Y, et al. Identification of a novel member of the snail/Gri-1 repressor family, mlt 1, which is methylated and silenced in liver tumors of SV40 T antigen transgenic mice. Cancer Res, 2001; 61: 1144-1153
6. Thiery JP. Epithelial-mesenchymal transitions in tumor progression. Nat Rev Cancer 2002, 2:442.
7. Cano, A., Pérez-Moreno, M. A., Rodrigo, I., Locascio, A., et al. The transcription factor Snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat. Cell Biol. 2000,2,76 -83.
8. Elloul, S., Bukholt Elstrand, M., Nesland, J., et al. Snail, Slug, and Smad-interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma. Cancer 2005,103,1631 -1643
9. Rosivatz, E., Becker, I., Specht, K., Fricke, et al. Differential expression of the epithelial-mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. Am. J. Pathol.,2002,61,1881 -1891.
10. Sugimachi, K., Tanaka, S., Kameyama, T., et al. Transcriptional repressor Snail and progression of human hepatocellular carcinoma. Clin. Cancer Res. 2003,9,2657 -2664.
11. Palmer, H. G., Larriba, M. J., Garcia, J. M.. et al. The transcription factor SNAIL represses vitamin D receptor expression and responsiveness in human colon cancer. Nat. Med. 2004,10,917 -919
12. Saito, T., Oda, Y., Kawaguchi, K., Sugimachi, K., et al. E-cadherin mutation and Snail overexpression as alternative mechanisms of E-cadherin inactivation in synovial sarcoma. Oncogene,2004,23,8629 -8638
13. Nieto, M. A. The snail superfamily of zinc-finger transcription factors. Nat. Rev. Mol. Cell. Biol. 2002.3,155 -166.
14. Thiery, J. P. Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2002.2, 442-454.
15. Miyoshi, A., Kitajima, Y., Kido, S., et al.Snail accelerates cancer invasion by upregulating MMP expression and is associated with poor prognosis of hepatocellular carcinoma. Br. J. Cancer.
16. De Craene B, Gilbert B, Stove C, Bruyneel E, et al. The transcription factor snail induces tumor cell invasion through modulation of the epithelial cell differentiation program.Cancer Res. 2005,65(14):6237-44.
17. Miyoshi A,Kitajima Y,Sumi K,Sato K,Hagiwara A,Koga Y,Miyazaki K.Snail and SIP1 increase cancer invasion by upregulating MMP family in hepatocellular carcinoma cells.Br J Cancer 2004; 90:1265-1273.
18. Palmer, H. G., Larriba, M. J., Garcia, J. M., et al. The transcription factor SNAIL represses vitamin D receptor expression and responsiveness in human colon cancer. Nat. Med. 2004,10,917 -919.
19. Kallay, E., Bareis, P., Bajna, E., et al. Vitamin D receptor activity and prevention of colonic hyperproliferation and oxidative stress. Food Chem. Toxicol. 2002,40,1191 -1196.
20. Yamashita, S., Miyagi, C., Fukada, T., Kagara, N., et al. Zinc transporter LIVI controls epithelial-mesenchymal transition in zebrafish gastrula organizer. Nature,2004,429,298 -302.
21. Savagner, P., Kusewitt, D., Carver, E., Magnino, F., et al. Developmental transcription factor Slug is required for effective re-epithelialization by adult keratinocytes. J. Cell. Physiol.2005, 202,858 -866.
22. Ohkubo T, Ozawa M. The transcription factor Snail downregulates the tight junction components independently of E-cadherin downregulation. J Cell Sci. 2004;117:1675.
23 Moody SE, Perez D, Pan TC, Sarkisian CJ, et al.The transcriptional repressor Snail promotes mammary tumor recurrence.Cancer Cell. 2005 Sep;8(3):197-209.
24. Guaita S,Puig I,Franci C,et al.Snail induction of epithelial to mesenchymal transition intumor cells is accompanied by MUC1 repression and ZEB1 expression.J Biol Chem,2002,277 (42):39209-39216.
25. Vega, S., Morales, A. V., Ocana, O. H., Valdes, F., Fabregat, I. and Nieto, M. A. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 2004,18,1131 -1143
26. Tribulo, C., Aybar, M. J., Sanchez, S. S. and Mayor, R. A balance between the anti-apoptotic activity of Slug and the apoptotic activity of msx1 is required for the proper development of the neural crest. Dev. Biol. 2004,275,325 -342.
27. Roy, H. K., Iversen, P., Hart, J., Liu, Y., et al.Down-regulation of SNAIL suppresses MIN mouse tumorigenesis: modulation of apoptosis, proliferation, and fractal dimension. Mol. Cancer Ther. 3,2004,1159 -1165.
28. Inukai, T., Inoue, A., Kurosawa, H.,et al. Slug, a ces-1-related zinc finger transcription factor gene with antiapoptotic activity is a downstream target of the E2A-HLF oncoprotein. Mol. Cell 1999,4,343 -352.
29. Inoue, A., Seidel, M. G., Wu, W., Kamizono, S., et al. Slug, a highly conserved zinc finger transcriptional repressor, protects hematopoietic progenitor cells from radiation-induced apoptosis in vivo. Cancer Cell,2002,2, 279-288.
30. Kajita, M., McClinic, K. N. and Wade, P. A. Aberrant expression of the transcription factors Snail and Slug alters the response to genotoxic stress. Mol. Cell. Biol. 2004, 24,7559 -7566.
31. Vega, S., Morales, A. V., Ocana, O. H., Valdes, F., et al. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 2004, 18, 1131 -1143.
32. Spagnoli, F. M., Cicchini, C., Tripodi, M. et al. Inhibition of MMH (Met murine hepatocyte) cell differentiation by TGF-? is abrogated by pretreatment with the inheritable differentiation factor FGF1. J. Cell Sci.2000,113,3639 -3647
33. Tribulo, C., Aybar, M. J., Sanchez, S. S. and Mayor, R. A balance between the anti-apoptotic activity of Slug and the apoptotic activity of msx1 is required for the proper development of the neural crest. Dev. Biol. 2004, 275,325 -342.
34. Martinez-Alvarez, C., Blanco, M. J., Perez, R., et al. Snail family members and cell survival in physiological and pathological cleft palates. Dev. Biol. 2004, 265,207 -218
35. Inoue A, Seidel MG, Wu W, Kamizono S,et al.Slug, a highly conserved zinc finger transcriptional repressor, protects hematopoietic progenitor cells from radiation-induced apoptosis in vivo. Cancer Cell. 2002 Oct;2(4):279-88.
36. Perez-Losada J, Sanchez-Martin M, Perez-Caro M et al. The radioresistance biological function of the SCF/kit signaling pathway is mediated by the zinc-finger transcription factor Slug. Oncogene. 2003 Jul 3;22(27):4205-11.
37. M Peinado, H., Quintanilla, M. and Cano, A. Transforming Growth Factor {beta}-1 induces Snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transitions. J. Biol. Chem. 2003,278,21113 -21123.
38. Vega, S., Morales, A. V., Ocana, O. H., Valdes, F., et al. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 2004,18,1131 -1143.
39. Burstyn-Cohen, T. and Kalcheim, C. Association between cell cycle and neural crest delamination through specific regulation of G1/S transition. Dev. Cell ,2002.3, 383-395
40. Foe, V. E. Mitotic domains reveals early commitment of cells in Drosophila embryos. Development 107,1989,1 -22.
41. Jung, A., Schrauder, M., Oswald, U., Knoll, C., et al. The invasion front of human colorectal adenocarcinomas shows co-localization of nuclear ?-catenin, cyclin D1, and p16INK4A and is a region of low proliferation. Am. J. Pathol. 159,2001,1613 -1617.
42. Jamora, C., Lee, P., Kocieniewski, P., Azhar, M., et al.. A signaling pathway involving TGF-?2 and Snail in hair follicle morphogenesis. PLoS Biol. 2005,3,e11 .
43. Dominguez, D., Montserrat-Sentis, B., Virgos-Soler, A.,et al, Phosphorylation regulates the subcellular location and activity of the snail transcriptional repressor. Mol. Cell. Biol. 2003,23,5078 -5089.
44. Zhou, B., Deng, J., Xia, W., et al, Dual regulation of Snail by GSK-3?-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat. Cell Biol. 2004, 6,931-940.
45. Yook, J. I., Li, X.-Y., Ota, I., et al, Wnt-dependent regulation of the E-cadherin repressor snail. J. Biol. Chem. 2005,280,11740 -11748.
46. Bachelder, R. E., Yoon, S.-O., Franci, C., et al, Glycogen synthase kinase-3 is an endogenous inhibitor of Snail transcription: implications for the epithelial-mesenchymal transition. J. Cell Biol. 2005,168, 29-33.
47. Yang, Z., Rayala, S., Nguyen, D., et al.. Pak1 phosphorylation of Snail, a master regulator of epithelial-to-mesenchyme transition, modulates Snail's subcellular localization and functions. Cancer Res. 2005,65,3179 -3184
48. Kim, K., Lu, Z. and Hay, E. (2002). Direct evidence for a role of beta-catenin/LEF-1 signaling pathway in induction of EMT. Cell Biol. Int. 2002,26,463 -476.
49. Liebner, S., Cattelino, A., Gallini, R., Rudini, N., Iurlaro, M., Piccolo, S. and Dejana, E.. ?-Catenin is required for endothelial-mesenchymal transformation during heart cushion development in the mouse. J. Cell Biol. 2004,166,359 -367.
50. Bastidas, F., De Calisto, J. and Mayor, R. (2004). Identification of neural crest competence territory: role of Wnt signaling. Dev. Dyn. 229,109 -117
51. Meulemans, D. and Bronner-Fraser, M. (2004). Gene-regulatory interactions in neural crest evolution and development. Dev. Cell 7,291 -299.
52. Yamashita, S., Miyagi, C., Fukada, T., Kagara, N., et al. (2004). Zinc transporter LIVI controls epithelial-mesenchymal transition in zebrafish gastrula organizer. Nature 429,298 -302.
53. P. Savagner, K. M. Yamada, and J. P. Thiery. The Zinc-Finger Protein Slug Causes Desmosome Dissociation, an Initial and Necessary Step for Growth Factor-induced Epithelial-Mesenchymal Transition.J. Cell Biol., June 16, 1997; 137(6): 1403 - 1419.
54. Shah, O. J., Ghosh, S., and Hunter, T. 2003. Mitotic regulation of ribosomal S6 kinase 1 involves Ser/Thr,Pro phosphorylation of consensus and non-consensus sites by Cdc2. J. Biol. Chem.278:16433-16442.
55. A. Isaac, M.J. Cohn, P. Ashby, P. Ataliotis, D.B. Spicer, J. Cooke, C. Tickle. FGF and genes encoding transcription factors in early limb specification. Mech. Dev.2000.93: 41-48.
56. Valdes, A. M. Alvarez, A. Locascio, S. et al. The Epithelial Mesenchymal Transition Confers Resistance to the Apoptotic Effects of Transforming Growth Factor {beta} in Fetal Rat Hepatocytes. Mol. Cancer Res., November 1, 2002; 1(1): 68 - 78.
57. Spagnoli, C Cicchini, M Tripodi, and MC Weiss. Inhibition of MMH (Met murine hepatocyte) cell differentiation by TGF(beta) is abrogated by pre-treatment with the heritable differentiation effector FGF1. J Cell Sci 2000 113: 3639-3647.
58. J. Gotzmann, H. Huber, C. Thallinger, M. Wolschek, et al. Hepatocytes convert to a fibroblastoid phenotype through the cooperation of TGF-{beta}1 and Ha-Ras: steps towards invasiveness. J. Cell Sci., March 15, 2002; 115(6): 1189 - 1202.
59. Bolos V, Peinado H, Perez-Moreno MA. The transcription factor Slug represses E-cadherin expression and induces epithelial-to-mesenchymal transitions: a comparison with Snail and E47 repressors. J Cell Sci, 2003, 499-511.
60. Grille SJ,Bellacosa A,Upson J,Klein-Szanto AJ,van Roy F,Lee-Kwon W,Donowitz M,Tsichlis PN,Larue L.The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res 2003; 63:2172-2178.
61. Saika S,Kono-Saika S,Ohnishi Y,Sato M,Muragaki Y,Ooshima A,Flanders KC,Yoo J,Anzano M,Liu CY,Kao WWY,Roberts AB,Smad3 signaling is required for epithelial mesenchymal transition of lens epithelium postinjury.Am J Pathol,2004 ;164:651-663.
62.Tan C, Costello P, Sanghera J, et al.: Inhibition of integrin linked kinase (ILK) suppresses beta-catenin-Lef/Tcf-dependent transcription and expression of the E-cadherin repressor, snail, in APC-/- human colon carcinoma cells. Oncogene,2001,20:133–140.
63. Wali RK, L. KJ, Bissonnette M, et al.: Polyethylene glycol (PEG) suppresses transcriptional factor SNAIL in azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) and human colon cancer cell line HCT-116. Gastroenterology,2003,124:A-604.
64. Wali RK, Khare S, Tretiakova M, et al.: Ursodeoxycholic acid and F(6)-D(3) inhibit aberrant crypt proliferation in the rat azoxymethane model of colon cancer: Roles of cyclin D1 and E-cadherin. Cancer Epidemiol Biomarkers Prev ,2002, 11:1653–1662.
65. Olmeda D, Jorda M, Peinado H, Fabra A, et al. Snail silencing effectively suppresses tumour growth and invasiveness. Oncogene. 2007 Mar 22;26(13):1862-74.
2.Ohuchida K, Mizumoto K, Murakami M, Qian LW, Sato N, Nagai E, Matsumoto K, Nakamura T, Tanaka M. Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions. Cancer Res. 2004; 64:3215.
3.Richter A, Niedergethmann M, Sturm JW, Lorenz D, Post S, Trede M. Long-term results of partial pancreaticoduodenectomy for ductal adenocarcinoma of the pancreatic head: 25-year experience. World J Surg. 2003; 27:324-9.
4.Keleg S, Buchler P, Ludwig R, Buchler MW, Friess H.Invasion and metastasis in pancreatic cancer. Mol Cancer.2003; 2:14.
5.DiMagno EP, Reber HA, Tempero MA.AGA technical review on the epidemiology, diagnosis, and treatment of pancreatic ductal adenocarcinoma. American Gastroenterological Association.Gastroenterology.1999; 117:1464.
6.Gotzmann J, Mikula M, Eger A, Schulte-Hermann R, Foisner R, Beug H, Mikulits W. Molecular aspects of epithelial cell plasticity: implications for local tumor invasion and metastasis. Mutat Res. 2004; 566:9.
7.Thiery JP. Epithelial-mesenchymal transitions in tumor progression. Nat Rev Cancer 2002, 2:442.
8.Valdes F, Alvarez AM, Locascio A, Vega S, Herrera B, Fernandez M, Benito M, Nieto MA, Fabregat I.The epithelial mesenchymal transition confers resistance to the apoptotic effects of transforming growth factor Beta in fetal rat hepatocytes. Mol Cancer Res. 2002; 1:68.
9.Malathy PV Shekhar, Robert Pauley, Gloria Heppner. Host microenvironment in breast cancer development: Extracellular matrix–stromal cell contribution to neoplastic phenotype of epithelial cells in the breast. Breast Cancer Res. 2003; 5: 130.
10.Poser I, Dominguez D, de Herreros AG, Varnai A, Buettner R, Bosserhoff AK. Loss of E-cadherin expression in melanoma cells involves up-regulation of the transcriptional repressor Snail. J Biol Chem. 2001; 276:24661.
11.Katoh M. Epithelial-mesenchymal transition in gastric cancer Int J Oncol. 2005 Dec;27(6):1677-83.
12.del Barrio MG, Nieto MA. Overexpression of Snail family members highlights their ability to promote chick neural crest formation. Development.2002; 129:1583.
13.Carver EA, Jiang R, Lan Y, Oram KF, Gridley T. The mouse Snail gene encodes a key regulator of the epithelial-mesenchymal transition. Mol Cell Biol. 2001; 21:8184.
14.Manzanares, M., Locascio, A. and Nieto, M. A. The increasing complexity of the Snail gene superfamily in metazoan evolution. Trend Genet.2001; 17:178.
15.Duband, J. L., Monier, F., Delannet, M. and Newgreen, D. Epithelium-mesenchyme transition during neural crest development. Acta Anat (Basel).1995; 154: 63.
16.Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, Portillo F, Nieto MA.The transcription factor Snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000; 2:76.
17.Vega S, Morales AV, Ocana OH, Valdes F, Fabregat I, Nieto MA. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 2004; 18:1131.
18.Blanco MJ, Moreno-Bueno G, Sarrio D, Locascio A, Cano A, Palacios J, Nieto MA.Correlation of Snail expression with histological grade and lymph node status in breastcarcinomas.Oncogene.2002; 21:3241.
19.Roy HK, Smyrk TC, Koetsier J, Victor TA, Wali RK.The transcriptional repressor SNAIL is overexpressed in human colon cancer. Dig Dis Sci. 2005; 50:42.
20.Rosivatz E, Becker I, Specht K, Fricke E, Luber B, Busch R, Hofler H, Becker KF. Differential expression of the epithelial-mesenchymal transition regulators Snail, SIP1, and twist in gastric cancer. Am J Pathol.2002; 161:1881.
21.Poser I, Dominguez D, de Herreros AG, Varnai A, Buettner R, Bosserhoff AK. Loss of E-cadherin expression in melanoma cells involves up-regulation of the transcriptional repressor Snail. J Biol Chem. 2001; 276:24661.
22.Sobin LH, Wittekind CH. TNM classification of malignant tumors, 6th ed. New York: John Wiley & Sons. 2002.
23.Sambrook J, Fritsch EF, Maniatis T. Molecular Cloning: a laboratory manual. 2 rd ed.New York: Cold Spring Harbor Laboratory Press.1989.
24.Tsutsumi S, Yanagawa T, Shimura T, Kuwano H, Raz A.Autocrine motility factor signaling enhances pancreatic cancer metastasis. Clin Cancer Res. 2004; 10:7775.
25.Guaita S, Puig I, Franci C, Garrido M, Dominguez D, Batlle E, Sancho E, Dedhar S, De Herreros AG, Baulida J. Snail induction of epithelial to mesenchymal transition in tumor cells is accompanied by MUC1 repression and ZEB1 expression. J Biol Chem. 2002; 277:39209.
26.Yokoyama K, Kamata N, Fujimoto R, Tsutsumi S, Tomonari M, Taki M, Hosokawa H, Nagayama M. Increased invasion and matrix metalloproteinase-2 expression by Snail-induced mesenchymal transition in squamous cell carcinomas. Int J Oncol.2003; 22:891.
27.Ohkubo T, Ozawa M. The transcription factor Snail downregulates the tight junction components independently of E-cadherin downregulation. J Cell Sci. 2004;117:1675.
28.Bolos V, Peinado H, Perez-Moreno MA, Fraga MF, Esteller M, Cano A. The transcription factor Slug represses E-cadherin expression and induces epithelial tomesenchymal transitions: a comparison with Snail and E47 repressors. J Cell Sci. 2003;116:499.
29.Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, Portillo F, Nieto MA. The transcription factor Snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol.2000; 2:76.
30.Bates RC, Mercurio AM. Tumor necrosis factor-alpha stimulates the epithelial-to-mesenchymal transition of human colonic organoids. Mol Biol Cell.2003; 14:1790.
31.Behrens J, Mareel MM, Van Roy FM, Birchmeier W.Dissecting tumor cell invasion: epithelial cells acquire invasive properties after the loss of uvomorulin-mediated cell-cell adhesion. J Cell Biol.1989; 108:2435.
32.Bates RC, Goldsmith JD, Bachelder RE, Brown C, Shibuya M, Oettgen P, Mercurio AM. Flt-1-dependent survival characterizes the epithelial-mesenchymal transition of colonic organoids. Curr Biol.2003; 13:1721.
33.Vega S, Morales AV, Ocana OH, Valdes F, Fabregat I, Nieto MA.Snail blocks the cell cycle and confers resistance to cell death. Genes Dev.2004; 18:1131.
34.Kajita M, McClinic KN, Wade PA. Aberrant expression of the transcription factors Snail and slug alters the response to genotoxic stress. Mol Cell Biol. 2004; 24:7559.
35.Wey JS, Gray MJ, Fan F, Belcheva A, McCarty MF, Stoeltzing O, Somcio R, Liu W, Evans DB, Klagsbrun M, Gallick GE, Ellis LM. Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells.Br J Cancer.2005; 93:233.
36.Sugimachi K, Tanaka S, Kameyama T, Taguchi K, Aishima S, Shimada M, Sugimachi K, Tsuneyoshi M. Transcriptional repressor Snail and progression of human hepatocellular carcinoma. Clin Cancer Res. 2003; 9:2657.
37.Pignatelli M, Ansari TW, Gunter P, Liu D, Hirano S, Takeichi M, Kloppel G, Lemoine NR.Loss of membranous E-cadherin expression in pancreatic cancer: correlation withlymph node metastasis, high grade, and advanced stage. J Pathol. 1994; 174:243.
38.Yoshida R, Kimura N, Harada Y, Ohuchi N. The loss of E-cadherin, alpha- and beta-catenin expression is associated with metastasis and poor prognosis in invasive breast cancer. Int J Oncol. 2001; 18:513.
39.Cai J, Ikeguchi M, Tsujitani S, Maeta M, Liu J, Kaibara N. Significant correlation between micrometastasis in the lymph nodes and reduced expression of E-cadherin in early gastric cancer. Gastric Cancer.2001; 4:66.
40.Joo YE, Rew JS, Park CS, Kim SJ. Expression of E-cadherin, alpha- and beta-catenins in patients with pancreatic adenocarcinoma. Pancreatology.2002; 2:129.
41.Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J, Garcia De Herreros A. The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumor cells. Nat Cell Biol.2000; 2:84.
42.Gilles C, Polette M, Zahm JM, Tournier JM, Volders L, Foidart JM, Birembaut P. Vimentin contributes to human mammary epithelial cell migration J Cell Sci. 1999;112:4615.
43.Singh S, Sadacharan S, Su S, Belldegrun A, Persad S, Singh G.Overexpression of vimentin: role in the invasive phenotype in an androgen-independent model of prostate cancer. Cancer Res. 2003; 63:2306.
44.Ellenrieder V, Hendler SF, Boeck W, Seufferlein T, Menke A, Ruhland C, Adler G, Gress TM. Transforming growth factor beta1 treatment leads to an epithelial-mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-regulated kinase 2 activation. Cancer Res. 2001; 61:4222.
45.Barrallo-Gimeno A, Nieto MA. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development.2005; 132:3151.
1.Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002; 2:442–54.
2.Barrallo-Gimeno A, Nieto MA. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development. 2005 Jul;132(14):3151-61.
3.Savagner P. et al. Leaving the neighborhood: molecular mechanisms involved during epithelial-mesenchymal transition. Bioessays. 2001 Oct;23(10):912-23.
4.Gotzmann J,Mikula M,Eger A,et al.Molecular aspects of epithelial cell plasticity:implications for local invasion and metastasis. Mutat Res,2004,566:9 -20.
5.Katoh M. Epithelial-mesenchymal transition in gastric cancer Int J Oncol. 2005 Dec;27(6):1677-83.
6.Blanco MJ, Moreno-Bueno G, Sarrio D, et al. Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene, 2002, 21(20),3241-6.
7.Poser I, Dominguez D, de Herreros AG, Varnai A, Buettner R, Bosserhoff AK. Loss of E-cadherin expression in melanoma cells involves up-regulation of the transcriptional repressor Snail. J Biol Chem. 2001; 276:24661.
8.Bates RC, Mercurio AM. Tumor necrosis factor-alpha stimulates the epithelial-to-mesenchymal transition of human colonic organoids. Mol Biol Cell.2003; 14:1790.
9.Behrens J, Mareel MM, Van Roy FM, Birchmeier W.Dissecting tumor cell invasion: epithelial cells acquire invasive properties after the loss of uvomorulin-mediated cell-cell adhesion. J Cell Biol.1989; 108:2435.
10.Auersperg N, Pan J, Grove BD, Peterson T, et al. E-cadherin induces mesenchymal-to-epithelial transition in human ovarian surface epithelium. Proc Natl Acad Sci U S A. 1999 May 25;96(11):6249-54.
11.Spath GF, Weiss MC. Hepatocyte nuclear factor 4 provokes expression of epithelial marker genes, acting as a morphogen in dedifferentiated hepatoma cells, J Cell Biol, 1998, 140(4), 935-46.
12.Beavon IR. Regulation of E-cadherin: does hypoxia initiate the metastatic cascade? Mol Pathol. 1999 Aug;52(4):179-88.
13.Karayiannakis AJ, Syrigos KN, Chatzigianni E. E-cadherin expression as a differentiation marker in gastric cancer. Hepatogastroenterology, 1998, 45(24), 2437- 2442.
14.Oka H, Shiozaki H, Kobayashi K, et al. Expression of E-cadherin cell adhesion molecules in human breast cancer tissues and its relationship to metastasis. Cancer Res, 1993,53,1696-1701.
15.Gilles C, Polette Molette M, Mestdagt M,et al.Transactivation of vimentin by beta-catenin in human breast cancer cells.Cancer Res,2003,63(10):2658-2664.
16.Gilles C., Polette M., Zahm J. M., Tournier J. M., Volders L., Foidart J. M., Birembaut P. Vimentin contributes to human mammary epithelial cell migration. J. Cell Sci., 112 (Pt 24):4615-4625, 1999.
17.Hendrix M. J., Seftor E. A., Seftor R. E., Trevor K. T. Experimental co-expression of vimentin and keratin intermediate filaments in human breast cancer cells results in phenotypic interconversion and increased invasive behavior. Am. J. Pathol., 150: 483-495, 1997.
18.Eckes B., Dogic D., Colucci-Guyon E., et al. Impaired mechanical stability, migration and contractile capacity in vimentin-deficient fibroblasts. J. Cell Sci., 111 (Pt 13): 1897-1907, 1998.
19.Eckes B., Colucci-Guyon E., Smola H., Nodder S., Babinet C., Krieg T., Martin P. Impaired wound healing in embryonic and adult mice lacking vimentin. J. Cell Sci., 113: 2455-2462, 2000
20.Korsching E, Packeisen J, Liedtke C,et al. The origin of vimentin expression in invasive breast cancer: epithelial-mesenchymal transition, myoepithelial histogenesis or histogenesis from progenitor cells with bilinear differentiation potential? J Pathol. 2005; 206(4):451-7.
21.Gotzmann J, Mikula M, Eger A. Molecular aspects of epithelial cell plasticity: implications for local tumor invasion and metastasis. Mutat Res, 2004, 566(1), 9-20.
1.Rofstad EK. Microenvironment-induced cancer metastasis. Int J Radiat Biol. 2000 May;76(5):589-605.
2. Subarsky P, Hill RP. The hypoxic tumour microenvironment and metastatic progression.Clin Exp Metastasis. 2003;20(3):237-50.
3. Beavon IR. Regulation of E-cadherin: does hypoxia initiate the metastatic cascade? Mol Pathol. 1999 Aug;52(4):179-88.
4. Gotzmann J,Mikula M,Eger A,et al. Molecular aspects of epithelial cell plasticity:implications for local invasion and metastasis.Mutat Res,2004,566:9 -20.
5. Duffy JP, Eibl G, Reber HA, et al. Influence of hypoxia and neoangiogenesis on the growth of pancreatic cancer. Mol Cancer. 2003 Jan 22;2:12.
6. Yassa, N. A., Yang, J., Stein, S., Johnson, M., and Ralls, P. Gray-scale and color flow sonography of pancreatic ductal adenocarcinoma. J. Clin. Ultrasound, 25: 473–480,1997.
7. Wei H, Wang C, Chen L. Proliferating cell nuclear antigen, survivin, and CD34expression in pancreatic cancer and their correlation with hypoxia-inducible factor 1alpha. Pancreas. 2006 Mar 32(2):159-63.
8. Duffy JP, Eibl G, Reber HA, et al. Influence of hypoxia and neoangiogenesis on the growth of pancreatic cancer. Mol Cancer. 2003 Jan 22;2:12.
9. Buchler P, Reber HA, Buchler M, et al. Hypoxia-inducible factor 1 regulates vascular endothelial growth factor expression in human pancreatic cancer. Pancreas. 2003 Jan;26(1):56-64.
10. Pouyssegur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce tumour regression.Nature. 2006 May 25;441(7092):437-43.
11. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002; 2:442–54.
12. Bates RC, Mercurio AM. Tumor necrosis factor-alpha stimulates the epithelial-to-mesenchymal transition of human colonic organoids. Mol Biol Cell.2003; 14:1790.
13. Behrens J, Mareel MM, Van Roy FM, Birchmeier W.Dissecting tumor cell invasion: epithelial cells acquire invasive properties after the loss of uvomorulin-mediated cell-cell adhesion. J Cell Biol.1989; 108:2435.
14. Auersperg N, Pan J, Grove BD, Peterson T, et al. E-cadherin induces mesenchymal-to-epithelial transition in human ovarian surface epithelium. Proc Natl Acad Sci U S A. 1999 May 25;96(11):6249-54.
15. Li YJ, Ji XR. Relationship between expression of E-cadherin-catenin complex and clinicopathologic characteristics of pancreatic cancer. World J Gastroenterol 2003 Feb 15;9(2):368-372
16. Bremnes RM, Veve R, Hirsch FR, et al. The E-cadherin cell-cell adhesion complex and lung cancer invasion, metastasis, and prognosis. Lung Cancer. 2002 May;36(2):115-24.
17. Beavon IR. The E-cadherin-catenin complex in tumour metastasis: structure, function and regulation. Eur J Cancer. 2000 Aug;36(13 Spec No):1607-20.
18. Gilles C., Polette M., Zahm J. M., Tournier J. M., Volders L., Foidart J. M., Birembaut P. Vimentin contributes to human mammary epithelial cell migration. J. Cell Sci., 112 (Pt 24): 4615-4625, 1999.
19. Hendrix M. J., Seftor E. A., Seftor R. E., Trevor K. T. Experimental co-expression of vimentin and keratin intermediate filaments in human breast cancer cells results in phenotypic interconversion and increased invasive behavior. Am. J. Pathol., 150: 483-495, 1997.
20. Barrallo-Gimeno A, Nieto MA.The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development. 2005 Jul;132(14):3151-61.
21. Kurrey NK, K A, Bapat SA. Snail and Slug are major determinants of ovarian cancer invasiveness at the transcription level. Gynecol Oncol. 2005 Apr;97(1):155-65.
22. Zhang Q, Wang SY, Nottke AC, et al. Redox sensor CtBP mediates hypoxia-induced tumor cell migration. Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9029-33.
23. Ryan HE, Poloni M, McNulty W.Hypoxia-inducible factor-1alpha is a positive factor in solid tumor growth. Cancer Res. 2000 Aug 1;60(15):4010-5.
24. Vukovic V, Haugland HK, Nicklee T, Morrison AJ, Hedley DW: Hypoxia-inducible factor-1alpha is an intrinsic marker for hypoxia in cervical cancer xenografts. Cancer Res 2001, 61:7394–7398
25. Vukovic V, Haugland HK, Nicklee T, Morrison AJ, Hedley DW: Hypoxia-inducible factor-1alpha is an intrinsic marker for hypoxia in cervical cancer xenografts. Cancer Res 2001, 61:7394–7398
26. Swinson DE, O'Byrne KJ. Interactions between hypoxia and epidermal growth factor receptor in non-small-cell lung. Clin Lung Cancer. 2006 Jan;7(4):250-6.
27. Brizel DM, Sibley GS, Prosnitz LR, Scher RL, Dewhirst MW: Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 1997, 38:285–289.
28. Kitada T, Seki S, Sakaguchi H, et al. Clinicopathological significance ofhypoxia-inducible factor-1alpha expression in human pancreatic carcinoma. Histopathology. 2003 Dec;43(6):550-5.
29. Imai T, Horiuchi A, Wang C, et al. Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells. Am J Pathol. 2003 Oct;163(4):1437-47.
30. Tsutsumi S, Yanagawa T, Shimura T, Kuwano H, Raz A.Autocrine motility factor signaling enhances pancreatic cancer metastasis. Clin Cancer Res. 2004; 10:7775.
1. Newgreen, D.F., and S.J. McKeown. Neural crest cells migration. In Rise and Fall of Epithelial Phenotype: Concepts of Epithelial-Mesenchymal Transition. P. Savagner, editor. Landes Bioscience, Texas.2005, 29–39.
2. Huang, X., and J.P. Saint-Jeannet. Induction of the neural crest and the opportuniti- es of life on the edge. Dev. Biol,2004,275:1–11.
3. Auersperg N, Pan J, Grove BD, et al. E-cadherin induces mesenchymal-to- epithelial transition in human ovarian surface epithelium. Proc Natl Acad Sci U S A. 1999 May 25; 96(11):6249-54.
4. Thiery JP: Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 2003, 15:740-746.
5. Barrallo-Gimeno A, Nieto MA. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development,2005 Jul; 132(14):3151-61.
6. Moody, S.E., D. Perez, T.C. Pan, C.J. et al. The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell.2005,8:197–209.
7. Willipinski-Stapelfeldt, B., S. Riethdorf, V. et al. Changes in cytoskeletal protein composition indicative of an epithelial-mesenchymal transition in human micrometas- tatic and primary breast carcinoma cells. Clin. Cancer Res.2005,11:8006–8014.
8. Brabletz T, Hlubek F, Spaderna S, et al. Invasion and metastasis in colorectal cancer: epithelial-mesenchymal transition, mesenchymal-epithelial transition, stem cells and beta-catenin. Cells Tissues Organs. 2005;179(1-2):56-65.
9. Thiery JP: Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer 2002, 2:442-454.
10. Xue C, Plieth D, Venkov C, Xu C, Neilson EG: The gatekeeper effect of epithelial -mesenchymal transition regulates the frequency of breast cancer metastasis. Cancer Res 2003,63:3386-3394.
11. Petersen OW, Nielsen HL, Gudjonsson T, Villadsen R,et al: Epithelial- to- mesenchymal transition in human breast cancer can provide a nonmalignant stroma. Am J Pathol 2003, 162:391-402.
12. Eitner F, Floege J: Novel insights into renal fibrosis. Curr Opin Nephrol Hypertens 2003, 12:227-232.
13. Neilson, E.G. Setting a trap for tissue fi brosis. Nat. Med.2005,11:373–374.
14. Iwano, M., D. Plieth, T.M. Danoff, C. et al. Evidence that fi broblasts derive from epithelium during tissue fibrosis. J. Clin. Invest.2002,110:341–350.
15. Nishitani, Y., M. Iwano, Y. Yamaguchi, K. et al. 2005. Fibroblast-specifi c protein 1 is a specifi c prognostic marker for renal survival in patients with IgAN. Kidney Int. 68:1078–1085.
16. Lan HY: Tubular epithelial-myofibroblast transdifferentiation mechanisms in proximal tubule cells. Curr Opin Nephrol Hypertens 2003, 12:25-29.
17. Yanez-Mo M, Lara-Pezzi E, Selgas R, Ramirez-Huesca M, et al.: Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells. N Engl J Med 2003, 348:403-413.
18. Saika S, Miyamoto T, Tanaka S, Tanaka T, et al.: Response of lens epithelial cells to injury: role of lumican in epithelial–mesenchymal transition. Invest Ophthalmol Vis Sci 2003,44:2094-2102.
19. Zavadil J, Bottinger EP. TGF-beta and epithelial-to-mesenchymal transitions. Oncogene. 2005 Aug 29;24(37):5764-74.
20. Janda E, Lehmann K, Killisch I, et al: Ras and TGFb cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol 2002, 156:299-313.
21. Peinado, H., Quintanilla, M., and Cano, A. Transforming growth factor beta-1 induces Snail transcription factor in epithelial cell lines: implications for epithelial mesenchymal transitions. Oncogene ,2003,23, 21113-21123.
22. Yi, J.Y., Shin, I., and Artega, C.L. Type I transforming growth factor beta receptor binds to and activates phosphatidylinositol 3-kinase. J. Biol. Chem.2005,280, 10870-10876.
23. Janda, E., Lehmann, K., Killisch, I., et al. Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J. Cell Biol. 2002,156, 299-313.
24. Ozdamar, B., Bose, R., Barrios-Rodiles, M., et al. Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science.2005,307, 1603-1609.
25. Nicolas FJ, Lehmann K, Warne PH, et al. Epithelial-to-mesenchymal transition in Madin- Darby canine kidney cells is accompanied by down-regulation of Smad3 expression, leading to resistance to transforming growthfactor-β-induced growth arrest. J Biol Chem 2003, 278: 3251- 3256.
26. Kim JT, Joo CK: Involvement of cell–cell interactions in the rapid stimulation of Cas tyrosine phosphorylation and Src kinase activity by transforming growth factor b1. J BiolChem 2002,277:31938-31948.
27. Shimizu Y, Yamamichi N, Saitoh K, et al.: Kinetics of v-src-induced epithelial- mesenchymal transition in developing glandular stomach. Oncogene 2003, 22:884- 893.
28 Gotzmann J, Fischer AN, Zojer M, et al. A crucial function of PDGF in TGF-beta- mediated cancer progression of hepatocytes. Oncogene. 2006 May 25;25(22):3170-85
29. Edme N, Downward J, Thiery JP, Boyer B: Involvement of MAPK and Rac in epithelial cell scattering, J Cell Sci 2002, 115.
30. Janda E, Lehmann K, Killisch I, et al: Ras and TGFb cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol 2002, 156:299-313.
31. Grille SJ, Bellacosa A, Upson J, et al: The protein kinase akt induces epithelial– mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res 2003, 63:2172-2178.
32. Lamorte L, Royal I, Naujokas M, Park M: Crk adapter proteins promote an epithelial-mesenchymal-like transition and are required for HGF-mediated cell spreading and breakdown of epithelial adherens junctions. Mol Biol Cell 2002, 13:1449-1461.
33. Sahai E, Marshall CJ: ROCK and Dia have opposing effects on adherens junctions downstream of Rho. Nat Cell Biol 2002, 4:408-415.
34. Psichari E, Balmain A, Plows D, et al: High activity of serum response factor in the mesenchymal transition of epithelial tumor cells is regulated by RhoA signaling. J Biol Chem 2002, 277: 29490-29495.
35. Benitah SA, Valeron PF, Rui H, Lacal JC: STAT5a activation mediates the epithelial-to- mesenchymal transition induced by incogenic RhoA. Mol Biol Cell 2003, 14:40-53.
36. Thiery JP: Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 2003, 15:740-746.
37 Kim, K., Lu, Z., and Hay, E.D. Direct evidence for a role of beta-catenin/LEF-1 signalling pathway in the induction of EMT. Cell Biol. Int. 2002,26, 463-476.
38 Liebner S, Cattelino A, Gallini R, et al.β-catenin is required for endothelial- mesenchymal transformation during heart cushion development in the mouse. J Cell Biol 2004, 166:359-367.
39. Pasca di Magliano M, Hebrok M: Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer 2003, 3:903-911.
40. Karhadkar SS, Bova GS, Abdallah N, et al: Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 2004, 431:707-712.
41. Louro ID, Bailey EC, Li X, et al.: Comparative gene expression profile analysis of GLI and c-MYC in an epithelial model of malignant transformation. Cancer Res 2002, 62:5867-5873.
42. Xie L, Law BK, Chytil AM, Brown KA, et al: Activation of the Erk pathway is required for TGF-β-1-induced EMT in vitro. Neoplasia 2004, 6:603-610.
43. Mullor JL, Dahmane N, Sun T, Ruiz i Altaba A: Wnt signals are targets and mediators of Gli function. Curr Biol 2001,11:769-773.
44. Radtke F, Raj K: The role of Notch in tumorigenesis: oncogene or tumour supper- ssor? Nat Rev Cancer 2003, 3:756-767.
45. Timmerman LA, Grego-Bessa J, Raya A, et al.: Notch promotes epithelialmesenc- hymal transition during cardiac development and oncogenic transformation. Genes Dev 2004, 18:99-115.
46. Grego-Bessa J, Diez J, Timmerman L, de la Pompa JL: Notch and epithelial- mesenchyme transition in development and tumor progression: another turn of the screw. Cell Cycle 2004, 3:718-721.
47. Nieto MA: The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol 2002, 3:155-166.
48. Bolos V, Peinado H, Perez-Moreno MA, et al: The transcription factor Slug represses E-cadherin expression and induces epithelial-to-mesenchymal transitions: a comparison with Snail and E47 repressors. J Cell Sci 2003, 116:499-511.
49. Peinado H, Quintanilla M, Cano A: Transforming growth factorβ-1 induces snail transcription factor in epithelial cell lines:mechanisms for epithelial mesenchymal transitions. J Biol Chem 2003, 278:21113-21123.
50. Guaita S, Puig I, Franci C, et al: Snail induction of epithelial-to-mesenchymal transition in tumor cells is accompanied by MUC1 repression and ZEB1 expression. J Biol Chem 2002, 277:39209-39216.
51. Fujita N, Jaye DL, Kajita M, et al: MTA3, a Mi-2/NuRD complex subunit, regulates an invasive growth pathway in breast cancer. Cell 2003, 113:207-219.
52. Louro ID, Bailey EC, Li X, et al.: Comparative gene expression profile analysis of GLI and c-MYC in an epithelial model of malignant transformation. Cancer Res 2002, 62:5867-5873.
53. Gschwind A, Fischer OM, Ullrich A: The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer2004, 4:361-370.
54. Yingling JM, Blanchard KL, Sawyer JS: Development of TGF-βsignalling inhibitors for cancer therapy. Nat Rev Drug Discov 2004, 3:1011-1022.
55. Pasca di Magliano M, Hebrok M: Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer 2003, 3:903-911.
56. Downward J: Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 2003, 3:11-22.
57. Karin M, Yamamoto Y, Wang QM: The IKK NF-kB system: a treasure trove for drug development. Nat Rev Drug Discov 2004, 3:17-26
1. Nakayama H, Scott IC, Cross JC. The transition to endoreduplication in trophoblast giant cells is regulated by the mRNA zinc finger transcription factor. Dev Biol, 1998,199: 150-163
2. Fuse, N., Hirose, S. and Hayashi, S. Diploidy of Drosophila imaginal cells is maintained by a transcriptional repressor encoded by escargot. Genes Dev,1994,8, 2270-2281.
3. H. L. Grimes, T. O. Chan, Patrick A. et al. The Gfi-1 proto-oncoprotein contains a novel transcriptional repressor domain, SNAG, and inhibits G1 arrest induced by IL-2 withdrawal. Molecular and Cellular Biology 1996 16(11):6263-6272.
4. Y. Nibu, H. Zhang, E. Bajor, S. Barolo, S. Small, and M. Levine dCtBP mediates transcriptional repression by Knirps, Kruppel and Snail in the Drosophila embryo EMBO J., December 1, 1998; 17(23): 7009– 7020
5. Tateno M, Fukunishi Y, Komatsu S, Okazaki Y, et al. Identification of a novel member of the snail/Gri-1 repressor family, mlt 1, which is methylated and silenced in liver tumors of SV40 T antigen transgenic mice. Cancer Res, 2001; 61: 1144-1153
6. Thiery JP. Epithelial-mesenchymal transitions in tumor progression. Nat Rev Cancer 2002, 2:442.
7. Cano, A., Pérez-Moreno, M. A., Rodrigo, I., Locascio, A., et al. The transcription factor Snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat. Cell Biol. 2000,2,76 -83.
8. Elloul, S., Bukholt Elstrand, M., Nesland, J., et al. Snail, Slug, and Smad-interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma. Cancer 2005,103,1631 -1643
9. Rosivatz, E., Becker, I., Specht, K., Fricke, et al. Differential expression of the epithelial-mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. Am. J. Pathol.,2002,61,1881 -1891.
10. Sugimachi, K., Tanaka, S., Kameyama, T., et al. Transcriptional repressor Snail and progression of human hepatocellular carcinoma. Clin. Cancer Res. 2003,9,2657 -2664.
11. Palmer, H. G., Larriba, M. J., Garcia, J. M.. et al. The transcription factor SNAIL represses vitamin D receptor expression and responsiveness in human colon cancer. Nat. Med. 2004,10,917 -919
12. Saito, T., Oda, Y., Kawaguchi, K., Sugimachi, K., et al. E-cadherin mutation and Snail overexpression as alternative mechanisms of E-cadherin inactivation in synovial sarcoma. Oncogene,2004,23,8629 -8638
13. Nieto, M. A. The snail superfamily of zinc-finger transcription factors. Nat. Rev. Mol. Cell. Biol. 2002.3,155 -166.
14. Thiery, J. P. Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2002.2, 442-454.
15. Miyoshi, A., Kitajima, Y., Kido, S., et al.Snail accelerates cancer invasion by upregulating MMP expression and is associated with poor prognosis of hepatocellular carcinoma. Br. J. Cancer.
16. De Craene B, Gilbert B, Stove C, Bruyneel E, et al. The transcription factor snail induces tumor cell invasion through modulation of the epithelial cell differentiation program.Cancer Res. 2005,65(14):6237-44.
17. Miyoshi A,Kitajima Y,Sumi K,Sato K,Hagiwara A,Koga Y,Miyazaki K.Snail and SIP1 increase cancer invasion by upregulating MMP family in hepatocellular carcinoma cells.Br J Cancer 2004; 90:1265-1273.
18. Palmer, H. G., Larriba, M. J., Garcia, J. M., et al. The transcription factor SNAIL represses vitamin D receptor expression and responsiveness in human colon cancer. Nat. Med. 2004,10,917 -919.
19. Kallay, E., Bareis, P., Bajna, E., et al. Vitamin D receptor activity and prevention of colonic hyperproliferation and oxidative stress. Food Chem. Toxicol. 2002,40,1191 -1196.
20. Yamashita, S., Miyagi, C., Fukada, T., Kagara, N., et al. Zinc transporter LIVI controls epithelial-mesenchymal transition in zebrafish gastrula organizer. Nature,2004,429,298 -302.
21. Savagner, P., Kusewitt, D., Carver, E., Magnino, F., et al. Developmental transcription factor Slug is required for effective re-epithelialization by adult keratinocytes. J. Cell. Physiol.2005, 202,858 -866.
22. Ohkubo T, Ozawa M. The transcription factor Snail downregulates the tight junction components independently of E-cadherin downregulation. J Cell Sci. 2004;117:1675.
23 Moody SE, Perez D, Pan TC, Sarkisian CJ, et al.The transcriptional repressor Snail promotes mammary tumor recurrence.Cancer Cell. 2005 Sep;8(3):197-209.
24. Guaita S,Puig I,Franci C,et al.Snail induction of epithelial to mesenchymal transition intumor cells is accompanied by MUC1 repression and ZEB1 expression.J Biol Chem,2002,277 (42):39209-39216.
25. Vega, S., Morales, A. V., Ocana, O. H., Valdes, F., Fabregat, I. and Nieto, M. A. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 2004,18,1131 -1143
26. Tribulo, C., Aybar, M. J., Sanchez, S. S. and Mayor, R. A balance between the anti-apoptotic activity of Slug and the apoptotic activity of msx1 is required for the proper development of the neural crest. Dev. Biol. 2004,275,325 -342.
27. Roy, H. K., Iversen, P., Hart, J., Liu, Y., et al.Down-regulation of SNAIL suppresses MIN mouse tumorigenesis: modulation of apoptosis, proliferation, and fractal dimension. Mol. Cancer Ther. 3,2004,1159 -1165.
28. Inukai, T., Inoue, A., Kurosawa, H.,et al. Slug, a ces-1-related zinc finger transcription factor gene with antiapoptotic activity is a downstream target of the E2A-HLF oncoprotein. Mol. Cell 1999,4,343 -352.
29. Inoue, A., Seidel, M. G., Wu, W., Kamizono, S., et al. Slug, a highly conserved zinc finger transcriptional repressor, protects hematopoietic progenitor cells from radiation-induced apoptosis in vivo. Cancer Cell,2002,2, 279-288.
30. Kajita, M., McClinic, K. N. and Wade, P. A. Aberrant expression of the transcription factors Snail and Slug alters the response to genotoxic stress. Mol. Cell. Biol. 2004, 24,7559 -7566.
31. Vega, S., Morales, A. V., Ocana, O. H., Valdes, F., et al. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 2004, 18, 1131 -1143.
32. Spagnoli, F. M., Cicchini, C., Tripodi, M. et al. Inhibition of MMH (Met murine hepatocyte) cell differentiation by TGF-? is abrogated by pretreatment with the inheritable differentiation factor FGF1. J. Cell Sci.2000,113,3639 -3647
33. Tribulo, C., Aybar, M. J., Sanchez, S. S. and Mayor, R. A balance between the anti-apoptotic activity of Slug and the apoptotic activity of msx1 is required for the proper development of the neural crest. Dev. Biol. 2004, 275,325 -342.
34. Martinez-Alvarez, C., Blanco, M. J., Perez, R., et al. Snail family members and cell survival in physiological and pathological cleft palates. Dev. Biol. 2004, 265,207 -218
35. Inoue A, Seidel MG, Wu W, Kamizono S,et al.Slug, a highly conserved zinc finger transcriptional repressor, protects hematopoietic progenitor cells from radiation-induced apoptosis in vivo. Cancer Cell. 2002 Oct;2(4):279-88.
36. Perez-Losada J, Sanchez-Martin M, Perez-Caro M et al. The radioresistance biological function of the SCF/kit signaling pathway is mediated by the zinc-finger transcription factor Slug. Oncogene. 2003 Jul 3;22(27):4205-11.
37. M Peinado, H., Quintanilla, M. and Cano, A. Transforming Growth Factor {beta}-1 induces Snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transitions. J. Biol. Chem. 2003,278,21113 -21123.
38. Vega, S., Morales, A. V., Ocana, O. H., Valdes, F., et al. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 2004,18,1131 -1143.
39. Burstyn-Cohen, T. and Kalcheim, C. Association between cell cycle and neural crest delamination through specific regulation of G1/S transition. Dev. Cell ,2002.3, 383-395
40. Foe, V. E. Mitotic domains reveals early commitment of cells in Drosophila embryos. Development 107,1989,1 -22.
41. Jung, A., Schrauder, M., Oswald, U., Knoll, C., et al. The invasion front of human colorectal adenocarcinomas shows co-localization of nuclear ?-catenin, cyclin D1, and p16INK4A and is a region of low proliferation. Am. J. Pathol. 159,2001,1613 -1617.
42. Jamora, C., Lee, P., Kocieniewski, P., Azhar, M., et al.. A signaling pathway involving TGF-?2 and Snail in hair follicle morphogenesis. PLoS Biol. 2005,3,e11 .
43. Dominguez, D., Montserrat-Sentis, B., Virgos-Soler, A.,et al, Phosphorylation regulates the subcellular location and activity of the snail transcriptional repressor. Mol. Cell. Biol. 2003,23,5078 -5089.
44. Zhou, B., Deng, J., Xia, W., et al, Dual regulation of Snail by GSK-3?-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat. Cell Biol. 2004, 6,931-940.
45. Yook, J. I., Li, X.-Y., Ota, I., et al, Wnt-dependent regulation of the E-cadherin repressor snail. J. Biol. Chem. 2005,280,11740 -11748.
46. Bachelder, R. E., Yoon, S.-O., Franci, C., et al, Glycogen synthase kinase-3 is an endogenous inhibitor of Snail transcription: implications for the epithelial-mesenchymal transition. J. Cell Biol. 2005,168, 29-33.
47. Yang, Z., Rayala, S., Nguyen, D., et al.. Pak1 phosphorylation of Snail, a master regulator of epithelial-to-mesenchyme transition, modulates Snail's subcellular localization and functions. Cancer Res. 2005,65,3179 -3184
48. Kim, K., Lu, Z. and Hay, E. (2002). Direct evidence for a role of beta-catenin/LEF-1 signaling pathway in induction of EMT. Cell Biol. Int. 2002,26,463 -476.
49. Liebner, S., Cattelino, A., Gallini, R., Rudini, N., Iurlaro, M., Piccolo, S. and Dejana, E.. ?-Catenin is required for endothelial-mesenchymal transformation during heart cushion development in the mouse. J. Cell Biol. 2004,166,359 -367.
50. Bastidas, F., De Calisto, J. and Mayor, R. (2004). Identification of neural crest competence territory: role of Wnt signaling. Dev. Dyn. 229,109 -117
51. Meulemans, D. and Bronner-Fraser, M. (2004). Gene-regulatory interactions in neural crest evolution and development. Dev. Cell 7,291 -299.
52. Yamashita, S., Miyagi, C., Fukada, T., Kagara, N., et al. (2004). Zinc transporter LIVI controls epithelial-mesenchymal transition in zebrafish gastrula organizer. Nature 429,298 -302.
53. P. Savagner, K. M. Yamada, and J. P. Thiery. The Zinc-Finger Protein Slug Causes Desmosome Dissociation, an Initial and Necessary Step for Growth Factor-induced Epithelial-Mesenchymal Transition.J. Cell Biol., June 16, 1997; 137(6): 1403 - 1419.
54. Shah, O. J., Ghosh, S., and Hunter, T. 2003. Mitotic regulation of ribosomal S6 kinase 1 involves Ser/Thr,Pro phosphorylation of consensus and non-consensus sites by Cdc2. J. Biol. Chem.278:16433-16442.
55. A. Isaac, M.J. Cohn, P. Ashby, P. Ataliotis, D.B. Spicer, J. Cooke, C. Tickle. FGF and genes encoding transcription factors in early limb specification. Mech. Dev.2000.93: 41-48.
56. Valdes, A. M. Alvarez, A. Locascio, S. et al. The Epithelial Mesenchymal Transition Confers Resistance to the Apoptotic Effects of Transforming Growth Factor {beta} in Fetal Rat Hepatocytes. Mol. Cancer Res., November 1, 2002; 1(1): 68 - 78.
57. Spagnoli, C Cicchini, M Tripodi, and MC Weiss. Inhibition of MMH (Met murine hepatocyte) cell differentiation by TGF(beta) is abrogated by pre-treatment with the heritable differentiation effector FGF1. J Cell Sci 2000 113: 3639-3647.
58. J. Gotzmann, H. Huber, C. Thallinger, M. Wolschek, et al. Hepatocytes convert to a fibroblastoid phenotype through the cooperation of TGF-{beta}1 and Ha-Ras: steps towards invasiveness. J. Cell Sci., March 15, 2002; 115(6): 1189 - 1202.
59. Bolos V, Peinado H, Perez-Moreno MA. The transcription factor Slug represses E-cadherin expression and induces epithelial-to-mesenchymal transitions: a comparison with Snail and E47 repressors. J Cell Sci, 2003, 499-511.
60. Grille SJ,Bellacosa A,Upson J,Klein-Szanto AJ,van Roy F,Lee-Kwon W,Donowitz M,Tsichlis PN,Larue L.The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res 2003; 63:2172-2178.
61. Saika S,Kono-Saika S,Ohnishi Y,Sato M,Muragaki Y,Ooshima A,Flanders KC,Yoo J,Anzano M,Liu CY,Kao WWY,Roberts AB,Smad3 signaling is required for epithelial mesenchymal transition of lens epithelium postinjury.Am J Pathol,2004 ;164:651-663.
62.Tan C, Costello P, Sanghera J, et al.: Inhibition of integrin linked kinase (ILK) suppresses beta-catenin-Lef/Tcf-dependent transcription and expression of the E-cadherin repressor, snail, in APC-/- human colon carcinoma cells. Oncogene,2001,20:133–140.
63. Wali RK, L. KJ, Bissonnette M, et al.: Polyethylene glycol (PEG) suppresses transcriptional factor SNAIL in azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) and human colon cancer cell line HCT-116. Gastroenterology,2003,124:A-604.
64. Wali RK, Khare S, Tretiakova M, et al.: Ursodeoxycholic acid and F(6)-D(3) inhibit aberrant crypt proliferation in the rat azoxymethane model of colon cancer: Roles of cyclin D1 and E-cadherin. Cancer Epidemiol Biomarkers Prev ,2002, 11:1653–1662.
65. Olmeda D, Jorda M, Peinado H, Fabra A, et al. Snail silencing effectively suppresses tumour growth and invasiveness. Oncogene. 2007 Mar 22;26(13):1862-74.