Snail在胃癌中的差异性表达及与COX-2表达的相关性研究
摘要
研究背景和目的：胃癌是我国最常见的恶性肿瘤,发病率及死亡率均高居全部恶性肿瘤的首位。临床上绝大多数恶性肿瘤患者最终死于肿瘤转移和术后复发,胃癌也是如此,因此,对原发肿瘤浸润转移机制的研究一直是肿瘤研究领域的热点。最近研究发现,上皮细胞源性肿瘤细胞之所以获得局部浸润和远处转移的能力与上皮细胞间质转化(Epithelial-Mesenchymal Transition, EMT)的关系密切。
EMT是生理情况下,哺乳动物胚胎发育及器官形成的必需过程,也存在于如：慢性炎症、组织损伤重建、纤维化等多种病理过程,尤其与肿瘤细胞浸润及转移关系密切。EMT发生后,以E-Cad为标志的上皮基因表型丢失,进而获得间质细胞表型,立方形上皮细胞转变为梭形成纤维细胞样形态,极性丧失,同质粘附连接破坏,细胞骨架重塑,伪足形成,形成细胞-基质异质粘附,从而获得迁移能力。在诱导EMT的转录因子Slail、Slug、Twist,以及基质金属蛋白酶(MMP)等的共同作用下,导致局部浸润和远处转移。
锌指转录因子—nail能与E-Cad启动子区的E-box结合,抑制E-Cad的转录,导致EMT发生,E-Cad下调是EMT的标志性事件。正常上皮细胞E-Cad表达稳定,然而在多种上皮源性肿瘤中E-Cad则常常表达下调,细胞同质黏附功能降低,肿瘤细胞从原发部位脱落,从而导致肿瘤转移。
近年实验表明：COX-2在食管癌、胃癌及大肠癌等肿瘤中过度表达,与肿瘤的浸润和转移密切相关。研究发现,E-Cad表达除了受Snail等转录因子抑制外,也受COX-2的影响。在COX-2过度表达的非小细胞性肺癌和小肠上皮细胞中,E-Cad表达下调,上述细胞表型变化可被硫化舒林酸(COX抑制剂)处理而逆转。因此,COX-2在EMT发生过程中发挥重要作用,联合检测肿瘤中Snail、E-Cad、COX-2的表达,探讨其在肿瘤侵袭转移中的作用。
方法：随机选取术前未进行化疗、放疗及生物学治疗,经外科行胃癌根治(或姑息)性切除术后的标本标本48例,收集其完整的临床及病理学资料；采用组织免疫组化SP方法检测48例胃癌组织、切缘组织中Snail、E-Cad、COX-2的表达,探讨其表达与胃癌病理生物学行为的关系,初步阐明COX-2在上皮间质化中的作用。
结果：
1.Snail在胃癌及切缘组织中的阳性表达率分别为85.42%、27.08%。Snail高表达与胃癌分化程度、浸润深度、淋巴结转移密切相关(P<0.05)。
2.E-Cad在胃癌及切缘组织阳性表达率分别为31.25%、100%。E-Cad表达下调与胃癌分化程度、浸润深度、淋巴结转移、临床TNM分期密切相关(P<0.05)。
3.COX-2在胃癌及切缘组织的阳性表达率分别为64.58、0%。COX-2表达与肿瘤分化程度、浸润深度、淋巴结转移及临床TNM分期密切相关(P<0.05)。
4.胃癌中Snail和COX-2表达均与E-Cad的表达呈负相关,Snail表达与COX-2的表达无相关性。
结论：
1.胃癌组织中,Snail高表达及E-Cad的低表达与胃癌分化程度、浸润深度、淋巴结转移有关,E-Cad表达下调还与TNM分期有关。提示Snail高表达及E-Cad低表达在胃癌演进中发挥重要作用。
2.胃癌组织中COX-2高表达,与胃癌分化程度、浸润深度、淋巴结转移、TNM分期密切相关,提示COX-2参与胃癌的演进。
3.Snail高表达与COX-2的高表达无相关性,但二者均与E-Cad的表达呈负相关,提示Snail与COX-2在频繁发生EMT的胃癌中发挥重要作用,特别是与肿瘤的局部浸润和远处转移密切相关。
4.联合检测胃癌中Snail、E-Cad、COX-2的表达可作为胃癌生物学行为及预后判断的指标。
Background and Objective:Gastric carcinoma is frequently malignant neoplasm in our country, and it's mortality are the highest of other malignant tumors.90 percentage of neoplasm is died by tumor metastasis and postoperative recurrence, thereby, primary neoplasm inva-sion and metastasis mechanisms is the researching focus in tumor field. Recent research indicated that Epithelial-to-mesenchymal transition (EMT) plays an important role during primary cancer region invasion and secondary metastasis.
EMT occurs in necessary physiological situations involving normal embryonic development and organogenesis of mammalian evolution, but also in many pathologies such as chronic inflammation, organizational restructuring and organ fibrosis.particly,EMT is closed correlated with tumor invasion and distant metastasis.
During EMT, epithelial cells lose certain epithelial markers such as E-Cad and gain mesenchymal phenotype. Consequently, epithelial cells is changed from cubic morphological features to fibroblastic spindle. As result of the loss of epithelial cell polarity, cell adhesion damaged between the homogeneous Contact, cytoskeleton remodeling, pseudopod formation, the formation of cell-matrix adhesion heterogeneity, final, it is gained motile capacity.Transcription factors induced EMT Snail, Slug, Twist, MMP, together the complementary role of EMT, lead to local invasion and distant metastasis.
Snail,Zinc finger transcription factor,after binding E-box of promoter region in the E-Cad, cause transcription of E-Cad and occurrence of EMT. A hallmark of EMT is the functional downregulation of the cell-cell adhesion protein E-Cad. The expression of E-Cad is stable in normal epithelial cells,but E-Cad diminished is frequently in a number of epithelial tumors. Diorder cell adhesion reduce the tumor cells from the primary site to tumor metastasis.
In recent study,COX-2 is highly expressed in many human tumors. COX-2 promote tumor invasion and metastasis by inhibiting apoptosis, enhanced tumor metastasis and induction of tumor angiogenesis, as well as the growth of the tumor.COX-2 play an important role in EMT,E-Cad expression repressed by Snail, but also by the impact of COX-2. Overexpression of COX-2 in NSCLC and intestinal epithelial cells can inhibit the expression of E-Cad, it may be reversed by sulindac sulfide (COX inhibitor). Combining detection expression of Snail, E-Cad, COX-2 in tumor, investigate between their relationships and clinical pathological data,and explore its role in tumor invasion and metastasis.
Methods:All patients that were randomly elected in department of gastrointestinal surgery in Luzhou Medical College Hospital during 2008.Oct.-2009,May, That were not treated by chemotherapy, radiother-apy, and biotherapy before operation. specimens of gastric cancer in 48 cases, which elected the complete collection of clinical and pathological data, detected Snail, E-Cad, COX-2 expression in cancer tissue and incisal edge by SP immunohistochemistry.investigating correlation their expression and pathological biological behavior.
Results:
1 The expression rates of Snail in gastric cancer and peripheral tissues were 85.42%,27.08%. The expression were closely correlated with degree of differentiation of gastric cancer, depth of invasion, lymph node metastasis. (P<0.05)
2 The expression rates of E-Cad in gastric cancer tissues and peripheral tissues were 31.2%,100%,respectively. The expression were closely related with degree of differentiation of gastric tumor, depth of invasion, gastric cancer TNM stage, lymph node metastasis.(P<0.05)
3 The expression rates of COX-2 gastric cancer and peripheral tissues were were 64.58%、0%, respectively. The expression were closely related with degree of gastric tumor, invasion depth, gastric cancer TNM stage lymph node metastasis.(P<0.05)
4 The expression of Snail and the COX-2 was negatively correlated with expression of E-Cad in gastric cancaer. Expression of Snail was not correlated with COX-2.
Conclusion:
1 The overexpression of Snail and diminished expression of E-Cad was closely related with degree of differentiation of tumor, depth of invasion, lymph node metastasis in gastric cancer, respectively.Snail was related with TNM stage,horever,E-Cad was on the contrary,which proved that Snail overexpression and E-Cad upregulated may be played an important role in the gastric cancer development.
2 The overexpression of COX-2 was closely correlated with degree of tumor differentiation, depth of invasion, lymph node metastasis in gastric cancer,TNM stage. Which proved that COX-2 may be played an important role in the gastric cancer progression.
3 The overexpression of Snail was not related with overexpression of COX-2,but, the expression of Snail and the COX-2 was negatively correlated with expression of E-Cad in gastric cancaer, respectly,which proved that the factors played an important roles of EMT feequently occured gastric cancer and involved the local invasion and distant metastasis.
4 It is suggested that Snail,E-Cad and COX-2 Combined detection can be an objective marker for pathologically biological behaviors and prognosis of gastric carcinoma.
EMT是生理情况下,哺乳动物胚胎发育及器官形成的必需过程,也存在于如：慢性炎症、组织损伤重建、纤维化等多种病理过程,尤其与肿瘤细胞浸润及转移关系密切。EMT发生后,以E-Cad为标志的上皮基因表型丢失,进而获得间质细胞表型,立方形上皮细胞转变为梭形成纤维细胞样形态,极性丧失,同质粘附连接破坏,细胞骨架重塑,伪足形成,形成细胞-基质异质粘附,从而获得迁移能力。在诱导EMT的转录因子Slail、Slug、Twist,以及基质金属蛋白酶(MMP)等的共同作用下,导致局部浸润和远处转移。
锌指转录因子—nail能与E-Cad启动子区的E-box结合,抑制E-Cad的转录,导致EMT发生,E-Cad下调是EMT的标志性事件。正常上皮细胞E-Cad表达稳定,然而在多种上皮源性肿瘤中E-Cad则常常表达下调,细胞同质黏附功能降低,肿瘤细胞从原发部位脱落,从而导致肿瘤转移。
近年实验表明：COX-2在食管癌、胃癌及大肠癌等肿瘤中过度表达,与肿瘤的浸润和转移密切相关。研究发现,E-Cad表达除了受Snail等转录因子抑制外,也受COX-2的影响。在COX-2过度表达的非小细胞性肺癌和小肠上皮细胞中,E-Cad表达下调,上述细胞表型变化可被硫化舒林酸(COX抑制剂)处理而逆转。因此,COX-2在EMT发生过程中发挥重要作用,联合检测肿瘤中Snail、E-Cad、COX-2的表达,探讨其在肿瘤侵袭转移中的作用。
方法：随机选取术前未进行化疗、放疗及生物学治疗,经外科行胃癌根治(或姑息)性切除术后的标本标本48例,收集其完整的临床及病理学资料；采用组织免疫组化SP方法检测48例胃癌组织、切缘组织中Snail、E-Cad、COX-2的表达,探讨其表达与胃癌病理生物学行为的关系,初步阐明COX-2在上皮间质化中的作用。
结果：
1.Snail在胃癌及切缘组织中的阳性表达率分别为85.42%、27.08%。Snail高表达与胃癌分化程度、浸润深度、淋巴结转移密切相关(P<0.05)。
2.E-Cad在胃癌及切缘组织阳性表达率分别为31.25%、100%。E-Cad表达下调与胃癌分化程度、浸润深度、淋巴结转移、临床TNM分期密切相关(P<0.05)。
3.COX-2在胃癌及切缘组织的阳性表达率分别为64.58、0%。COX-2表达与肿瘤分化程度、浸润深度、淋巴结转移及临床TNM分期密切相关(P<0.05)。
4.胃癌中Snail和COX-2表达均与E-Cad的表达呈负相关,Snail表达与COX-2的表达无相关性。
结论：
1.胃癌组织中,Snail高表达及E-Cad的低表达与胃癌分化程度、浸润深度、淋巴结转移有关,E-Cad表达下调还与TNM分期有关。提示Snail高表达及E-Cad低表达在胃癌演进中发挥重要作用。
2.胃癌组织中COX-2高表达,与胃癌分化程度、浸润深度、淋巴结转移、TNM分期密切相关,提示COX-2参与胃癌的演进。
3.Snail高表达与COX-2的高表达无相关性,但二者均与E-Cad的表达呈负相关,提示Snail与COX-2在频繁发生EMT的胃癌中发挥重要作用,特别是与肿瘤的局部浸润和远处转移密切相关。
4.联合检测胃癌中Snail、E-Cad、COX-2的表达可作为胃癌生物学行为及预后判断的指标。
Background and Objective:Gastric carcinoma is frequently malignant neoplasm in our country, and it's mortality are the highest of other malignant tumors.90 percentage of neoplasm is died by tumor metastasis and postoperative recurrence, thereby, primary neoplasm inva-sion and metastasis mechanisms is the researching focus in tumor field. Recent research indicated that Epithelial-to-mesenchymal transition (EMT) plays an important role during primary cancer region invasion and secondary metastasis.
EMT occurs in necessary physiological situations involving normal embryonic development and organogenesis of mammalian evolution, but also in many pathologies such as chronic inflammation, organizational restructuring and organ fibrosis.particly,EMT is closed correlated with tumor invasion and distant metastasis.
During EMT, epithelial cells lose certain epithelial markers such as E-Cad and gain mesenchymal phenotype. Consequently, epithelial cells is changed from cubic morphological features to fibroblastic spindle. As result of the loss of epithelial cell polarity, cell adhesion damaged between the homogeneous Contact, cytoskeleton remodeling, pseudopod formation, the formation of cell-matrix adhesion heterogeneity, final, it is gained motile capacity.Transcription factors induced EMT Snail, Slug, Twist, MMP, together the complementary role of EMT, lead to local invasion and distant metastasis.
Snail,Zinc finger transcription factor,after binding E-box of promoter region in the E-Cad, cause transcription of E-Cad and occurrence of EMT. A hallmark of EMT is the functional downregulation of the cell-cell adhesion protein E-Cad. The expression of E-Cad is stable in normal epithelial cells,but E-Cad diminished is frequently in a number of epithelial tumors. Diorder cell adhesion reduce the tumor cells from the primary site to tumor metastasis.
In recent study,COX-2 is highly expressed in many human tumors. COX-2 promote tumor invasion and metastasis by inhibiting apoptosis, enhanced tumor metastasis and induction of tumor angiogenesis, as well as the growth of the tumor.COX-2 play an important role in EMT,E-Cad expression repressed by Snail, but also by the impact of COX-2. Overexpression of COX-2 in NSCLC and intestinal epithelial cells can inhibit the expression of E-Cad, it may be reversed by sulindac sulfide (COX inhibitor). Combining detection expression of Snail, E-Cad, COX-2 in tumor, investigate between their relationships and clinical pathological data,and explore its role in tumor invasion and metastasis.
Methods:All patients that were randomly elected in department of gastrointestinal surgery in Luzhou Medical College Hospital during 2008.Oct.-2009,May, That were not treated by chemotherapy, radiother-apy, and biotherapy before operation. specimens of gastric cancer in 48 cases, which elected the complete collection of clinical and pathological data, detected Snail, E-Cad, COX-2 expression in cancer tissue and incisal edge by SP immunohistochemistry.investigating correlation their expression and pathological biological behavior.
Results:
1 The expression rates of Snail in gastric cancer and peripheral tissues were 85.42%,27.08%. The expression were closely correlated with degree of differentiation of gastric cancer, depth of invasion, lymph node metastasis. (P<0.05)
2 The expression rates of E-Cad in gastric cancer tissues and peripheral tissues were 31.2%,100%,respectively. The expression were closely related with degree of differentiation of gastric tumor, depth of invasion, gastric cancer TNM stage, lymph node metastasis.(P<0.05)
3 The expression rates of COX-2 gastric cancer and peripheral tissues were were 64.58%、0%, respectively. The expression were closely related with degree of gastric tumor, invasion depth, gastric cancer TNM stage lymph node metastasis.(P<0.05)
4 The expression of Snail and the COX-2 was negatively correlated with expression of E-Cad in gastric cancaer. Expression of Snail was not correlated with COX-2.
Conclusion:
1 The overexpression of Snail and diminished expression of E-Cad was closely related with degree of differentiation of tumor, depth of invasion, lymph node metastasis in gastric cancer, respectively.Snail was related with TNM stage,horever,E-Cad was on the contrary,which proved that Snail overexpression and E-Cad upregulated may be played an important role in the gastric cancer development.
2 The overexpression of COX-2 was closely correlated with degree of tumor differentiation, depth of invasion, lymph node metastasis in gastric cancer,TNM stage. Which proved that COX-2 may be played an important role in the gastric cancer progression.
3 The overexpression of Snail was not related with overexpression of COX-2,but, the expression of Snail and the COX-2 was negatively correlated with expression of E-Cad in gastric cancaer, respectly,which proved that the factors played an important roles of EMT feequently occured gastric cancer and involved the local invasion and distant metastasis.
4 It is suggested that Snail,E-Cad and COX-2 Combined detection can be an objective marker for pathologically biological behaviors and prognosis of gastric carcinoma.
引文
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41 Robson EJ,Khaled WT,Abell K, et al.Epithelial-to-mesenchymal transition confers resistance to apoptosis in three murine mam-mary epithelial cell lines[J].Differentiation,2006,74(5):254-264.
42 Escriva M,Peiro S, Herranz N,et al.Repression of PTEN Phosp-hatse by Snail1 transcriptional Factor during Gamma Radiatio-ninduced Apoptosis[J].Mol Cell Biol,2008,28(5):1528-1540.
43 Lippman SM,Gibson N,Subbaramaiah K,et al.Combined Targeting of the Epidermal Growth Factor Receptor and Cyclooxygenase-2 Pathways[J].Clin Cancer Res,2005,11(17):6097-6099.
1 Robert L. The extracellular matrix in development and regener-ation[J]. Int J Dev Biol,2004,48(8):687-694.
2 Lester R D,Jo M, Montel V,et al.uPAR induces epithelial- mesenchymal transition in hypoxic breast cancer cells[J].Cell Biol, 2007,178(3):425-436.
3 Ai J H, Zheng S G, Zhang L D, et al. Vascular endothelial growth factor receptor-1 activation induces epithelial to mesenchmal transition in hepatocellular carcinoma cell line MHCC97-H[J].Chin Hepatol,2009,17(2):112-116.
4 封明轩,骆明德,费哲为等.TGF-p长期诱导胰腺癌细胞发生上皮间质化而增加其侵袭性[J].现代肿瘤杂志,2007,15(6)：766-768.
5 Neil JR, Johnson KM, Nemenoff RA, et al. Cox-2 inactivates Smad signaling and enhances EMT stimulated by TGF-β through a PGE2-dependen mechanism [J]. Carcinogenesis,2008,29(11):2227-2235
6 Joseph MJ, Dangi- S, Shields MA,et al. Slug is a downstream mediator of transforming growth factor-beta1-induced matrix metalloproteinase-9 expression and invasion of oral cancer cells[J]. Cell Biochem,2009,108(3):726-36.
7 Zhong L P, L i J, Zhang C P, et al. Expression of E-cadherin in cervical lymph nodes from primary oral squamous cell carcinoma patients[J]. Arch Oral Biol,2007,52(8):740-747.
8 Lippman SM,Gibson N,Subbaramaiah K,et al.Combined Targeting of the Epidermal Growth Factor Receptor and Cyclooxygenase-2 Pathways[J].Clin Cancer Res,2005,11(17):6097-6099.
9 Sobrado VR, Moreno-Bueno G,Cubillo E,et al.The class I bHLH factors E2-2A and E2-2B regulate EMT[J]. J Cell Sci.2009, 122(Pt7):1014-1024.
10 Bienz M.beta-Catenin:a pivot between cell adherin Wnt sing-alling[J].Curr Biol,2005,65(20):9455-9462.
11 Shioiri M,Shida T,Koda K,et al.Slug expression in an independent prognostic parameter for poor survival in colorectal carcinoma patients[J].Br J Cancer,2006,94(12):1816-1822.
12 金丽,耿敬妹.Snail蛋白表达与胃癌浸润转移的相关性研究[J].肿瘤预防与治疗,2008,21(1)：22-24.
13 Kang MH, Kang HN, Kim JL,et al. Inhibition of PI3 kinase/Akt pathway is required for BMP2-induced EMT and invasion[J]. Oncol Rep.2009,22(3):525-534.
14 Yang L, Huang J, Ren X, et al. Abrogation of TGF-(3 signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis[J].Cancer Cell,2008,13(1):23-35.
15 Bao J, Wu ZS, Qi Y,et al. Expression of TGF-betal and the mechanism of invasiveness and metastasis induced by TGF-betal in breast cancer[J]. Chin J Oncol,2009,31(9):679-682.
16 Yang J, Mani S A, Weinberg R A. Exploring a new twist on tumor metastasis[J]. Cancer Res,2006,66(9):4549-4552.
17 Yang J,Mani S A, Donaher J L, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis [J].Cell,2004,117(7):927-939.
18 Mironchik Y, Winnard PT Jr, Vesuna F, et al.Twist over-expression induces in vivo angiogenesis and correlates with chromosomal instability in breast cancer[J].Cancer Res,2005, 65(23):10801-10809.
19冯美燕,宁晓明,刘婷等.Twist在胃癌黏膜组织的表达及在上皮间质转化中的作用[J].现代肿瘤医学,2008,16(11)：1949-1952.
20 Gun K, Li J, Tang J P, et al. Catalytic domain of PRL-3 plays an essential role in tumor metastasis:formation of PRL-3 tumors inside the blood vessels[J]. Cancer Biol Ther,2004,3(10): 945-951.
21 Li ZR, Wang Z, Zhu BH,et al. Association of tyrosine PRL-3 phosphatase protein expression with peritoneal metastasis of gastric carcinoma and prognosis[J]. Surg Today.2007;37(8):646-651.
22 Bardelli A, Saha S, Sager J A, et al.PRL-3 expression in metastatic cancers[J]. Clin Cancer Res,2003,9(15):5607-5615.
23 Wang H, Quah S Y, Dong J M, et al, PRL-3 down-regulates PTEN expression and Signals through PI3K to Promote Epithelial-Mesenchymal Transition [J]. Cancer Res,2007,67(7):2922-2926.
24 Robson EJ,Khaled WT,Abell K, et al.Epithelial- to-mesenchymal transition confers resistance to apoptosis in three murine mammary epithelial cell lines[J]. Differentiation,2006,74(5):254-264.
25 Escriva M, Peiro S, Herranz N, et al.Repression of PTEN Phosphatase by Snail1 transcriptional Factor during Gamma Radiation-induced Apoptosis[J].Mol Cell Biol,2008,28(5): 1528-1540.
26 Del Castillo G,Murillo M M, Alvarez-Barrientos A,et al.Autocrine production of TGF- beta confers resistance to apoptosis after an epithelial-mesenchymal transition process in hepatocytes:Role of EGF receptor ligands [J].Exp Cell Res,2006,312(15):2860-2871.
27 Dohadwala M,Seok-Chul Y,Sharma S,et al. CyclooxyGenase-2-dependent regulation of E-cadherin,ZEB1, and SNAIL expression in NSCLC[J].Proc Am Assoc Cancer Res,2005,46:58.
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38 陈兆峰,胃癌细胞中COX-2调控NF-κB及Snail机制的研究,兰州大学学位论文,2009.
39 Dohadwala M,Seok-Chul Y,Sharma S,et al.Cyclooxy Genase-2-dependent regulation of E-Cad,ZEB1,and SNAIL expression in NSCLC[J].Proc Am Assoc Cancer Res,2005,46:58.
40 Del Castillo G,Murillo M M,Alvarez-Barrientos A,et al. Autocri-ne production of TGF-beta confers resistance to apoptosis after an epithelial-mesenchymal transition process in hepatocytes:Role of EGF receptor ligands [J].Exp Cell Res,2006,312(15):2860-2871
41 Robson EJ,Khaled WT,Abell K, et al.Epithelial-to-mesenchymal transition confers resistance to apoptosis in three murine mam-mary epithelial cell lines[J].Differentiation,2006,74(5):254-264.
42 Escriva M,Peiro S, Herranz N,et al.Repression of PTEN Phosp-hatse by Snail1 transcriptional Factor during Gamma Radiatio-ninduced Apoptosis[J].Mol Cell Biol,2008,28(5):1528-1540.
43 Lippman SM,Gibson N,Subbaramaiah K,et al.Combined Targeting of the Epidermal Growth Factor Receptor and Cyclooxygenase-2 Pathways[J].Clin Cancer Res,2005,11(17):6097-6099.
1 Robert L. The extracellular matrix in development and regener-ation[J]. Int J Dev Biol,2004,48(8):687-694.
2 Lester R D,Jo M, Montel V,et al.uPAR induces epithelial- mesenchymal transition in hypoxic breast cancer cells[J].Cell Biol, 2007,178(3):425-436.
3 Ai J H, Zheng S G, Zhang L D, et al. Vascular endothelial growth factor receptor-1 activation induces epithelial to mesenchmal transition in hepatocellular carcinoma cell line MHCC97-H[J].Chin Hepatol,2009,17(2):112-116.
4 封明轩,骆明德,费哲为等.TGF-p长期诱导胰腺癌细胞发生上皮间质化而增加其侵袭性[J].现代肿瘤杂志,2007,15(6)：766-768.
5 Neil JR, Johnson KM, Nemenoff RA, et al. Cox-2 inactivates Smad signaling and enhances EMT stimulated by TGF-β through a PGE2-dependen mechanism [J]. Carcinogenesis,2008,29(11):2227-2235
6 Joseph MJ, Dangi- S, Shields MA,et al. Slug is a downstream mediator of transforming growth factor-beta1-induced matrix metalloproteinase-9 expression and invasion of oral cancer cells[J]. Cell Biochem,2009,108(3):726-36.
7 Zhong L P, L i J, Zhang C P, et al. Expression of E-cadherin in cervical lymph nodes from primary oral squamous cell carcinoma patients[J]. Arch Oral Biol,2007,52(8):740-747.
8 Lippman SM,Gibson N,Subbaramaiah K,et al.Combined Targeting of the Epidermal Growth Factor Receptor and Cyclooxygenase-2 Pathways[J].Clin Cancer Res,2005,11(17):6097-6099.
9 Sobrado VR, Moreno-Bueno G,Cubillo E,et al.The class I bHLH factors E2-2A and E2-2B regulate EMT[J]. J Cell Sci.2009, 122(Pt7):1014-1024.
10 Bienz M.beta-Catenin:a pivot between cell adherin Wnt sing-alling[J].Curr Biol,2005,65(20):9455-9462.
11 Shioiri M,Shida T,Koda K,et al.Slug expression in an independent prognostic parameter for poor survival in colorectal carcinoma patients[J].Br J Cancer,2006,94(12):1816-1822.
12 金丽,耿敬妹.Snail蛋白表达与胃癌浸润转移的相关性研究[J].肿瘤预防与治疗,2008,21(1)：22-24.
13 Kang MH, Kang HN, Kim JL,et al. Inhibition of PI3 kinase/Akt pathway is required for BMP2-induced EMT and invasion[J]. Oncol Rep.2009,22(3):525-534.
14 Yang L, Huang J, Ren X, et al. Abrogation of TGF-(3 signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis[J].Cancer Cell,2008,13(1):23-35.
15 Bao J, Wu ZS, Qi Y,et al. Expression of TGF-betal and the mechanism of invasiveness and metastasis induced by TGF-betal in breast cancer[J]. Chin J Oncol,2009,31(9):679-682.
16 Yang J, Mani S A, Weinberg R A. Exploring a new twist on tumor metastasis[J]. Cancer Res,2006,66(9):4549-4552.
17 Yang J,Mani S A, Donaher J L, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis [J].Cell,2004,117(7):927-939.
18 Mironchik Y, Winnard PT Jr, Vesuna F, et al.Twist over-expression induces in vivo angiogenesis and correlates with chromosomal instability in breast cancer[J].Cancer Res,2005, 65(23):10801-10809.
19冯美燕,宁晓明,刘婷等.Twist在胃癌黏膜组织的表达及在上皮间质转化中的作用[J].现代肿瘤医学,2008,16(11)：1949-1952.
20 Gun K, Li J, Tang J P, et al. Catalytic domain of PRL-3 plays an essential role in tumor metastasis:formation of PRL-3 tumors inside the blood vessels[J]. Cancer Biol Ther,2004,3(10): 945-951.
21 Li ZR, Wang Z, Zhu BH,et al. Association of tyrosine PRL-3 phosphatase protein expression with peritoneal metastasis of gastric carcinoma and prognosis[J]. Surg Today.2007;37(8):646-651.
22 Bardelli A, Saha S, Sager J A, et al.PRL-3 expression in metastatic cancers[J]. Clin Cancer Res,2003,9(15):5607-5615.
23 Wang H, Quah S Y, Dong J M, et al, PRL-3 down-regulates PTEN expression and Signals through PI3K to Promote Epithelial-Mesenchymal Transition [J]. Cancer Res,2007,67(7):2922-2926.
24 Robson EJ,Khaled WT,Abell K, et al.Epithelial- to-mesenchymal transition confers resistance to apoptosis in three murine mammary epithelial cell lines[J]. Differentiation,2006,74(5):254-264.
25 Escriva M, Peiro S, Herranz N, et al.Repression of PTEN Phosphatase by Snail1 transcriptional Factor during Gamma Radiation-induced Apoptosis[J].Mol Cell Biol,2008,28(5): 1528-1540.
26 Del Castillo G,Murillo M M, Alvarez-Barrientos A,et al.Autocrine production of TGF- beta confers resistance to apoptosis after an epithelial-mesenchymal transition process in hepatocytes:Role of EGF receptor ligands [J].Exp Cell Res,2006,312(15):2860-2871.
27 Dohadwala M,Seok-Chul Y,Sharma S,et al. CyclooxyGenase-2-dependent regulation of E-cadherin,ZEB1, and SNAIL expression in NSCLC[J].Proc Am Assoc Cancer Res,2005,46:58.