Snail和E-cadherin在膀胱癌中的表达以及相关性研究
摘要
研究目的：
1.研究Snail和E-cadherin在膀胱泌尿上皮癌癌中的表达情况,以及它们在膀胱癌不同病理分级和分期中的表达差异。
2.验证Snail与E-cadherin的表达相关性,探讨其表达与膀胱癌预后的关系。
3.为以后的研究提供理论和实验基础。
研究方法：
通过研究我院04-07膀胱泌尿上皮癌病例67例,病例资料调查,电话随访等方式得到临床资料,从病理科取出石蜡块,重新切片,进行免疫组化SP法染色,对标本按照病例分期和浸润深度和临床进展情况进行分组,采用SPSS进行统计学分析。
结果：
选择膀胱泌尿上皮癌患者标本67例,正常膀胱组织6例,手术时间2004-2007年,其中男性标本54例,女性标本13例。G1标本23例,G2标本25例,G3标本19例,TL 49例,TH 18例。膀胱正常上皮细胞E—cadherin均为细胞膜强阳性均匀致密着色。而在膀胱癌细胞中,表达则有明显异质性,胞膜染色减少或消失。Snail在正常膀胱组织中表达较弱,甚至不表达,而在肿瘤组织中表达显著高于正常膀胱组织,在细胞中弥漫于细胞胞浆。E-cadherin在G1,G2,G3病理级别膀胱癌的表达逐渐减弱,具有统计学差异(G1*G2 p=0.011, G2*G3 p=0.009, G1*G3 p<0.001),在TL组表达强于TH组(p=0.009)。而Snail在G1,G2,G3病理级别膀胱癌的表达逐渐增强,具有统计学差异(G1*G2 p=0.008 G2 *G3 p=0.023 G1*G3 p<0.001),在TL组表达弱于TH组(p<0.001).Snail和E-cadherin的表达负相关(r=-0.733,p<0.001)。肿瘤发生深层浸润或者转移的患者组与相同时间内肿瘤无复发,或者复发但浸润深度未达肌层的的患者组之间,前者Snail表达高于后组(p=0.021), E-cadherin表达低于后组(p=0.032)。
结论：
膀胱癌病理级别和临床分期的升高,E-cadherin表达减少,Snail表达增加,且Snail和E—cadherin的表达负相关,提示Snail可能参与E-cadherin的调节。TUR术后同样时间段内临床进展的膀胱癌E-cadherin表达低,Snail表达高,提示Snail可能对预后判断有一定参考意义。
Objective:
1. To study the expression of Snail and E-cadherin in urothelial bladder cancer, and the difference between pathological grades and stages.
2. To verify the corelation between expression of Snail and E-cadherin, and investigate the effect on the prognosis.
3. To provide basis for research.
Material and Method:
67 urothelial bladder cancer specimens were studied, all of which obtained during 2004-2007 by TUR or cystectomy. Clinic data was achieved by review of case history and telephone visit. Slices were cut from paraffin blocks with help of Pathology Dept, Huashan Hospital, and then used for immunochemistry coloration. Grouping specimens by pathologic grade(Gl,G2,G3),clinic stage(Ta-1,T2-4) and clinic progress data, then statistics analysis was performed with SPSS software between groups.
Results:
67 urothelial bladder cancer specimens were investigated, of which 54 from male,13 from female,23 of Gl grade,25 of G2 grade,19 of G3 grade,49 of TL stage,18 of TH stage.6 normal bladder tissues were investigated by IHC. The expression of E-cadherin decreases when grade is high, statistics analysis shows significant difference between G1,G2,G3(G1*G2 p=0.011,G2*G3 p=0.009, G1*G3 p<0.001), and higher expression in TH group than TL (p=0.009)。Inversely, Snail expresses higher when grade is higher, statistics analysis shows significant difference between G1,G2,G3(G1*G2 p=0.008 G2*G3 p=0.023 G1*G3 p<0.001), and expresses higher in TH group than TL (p<0.001). Spearman test indicates that Snail has a reverse corelation with E-cadherin expression (r=-0.733, p<0.001). Group of specimens from patients that underwent muscle invasion or metastasis after TUR in 2 year has higher expression of Snail(p=0.021),and lower expression of E-cadherin(p=0.032) than group without invasion or metastasis during the same time duration.
Conclusion:
E-cadherin expresses lower, while Snail expresses higher, when clinic stage and pathologic grade is higher, and the result that Snail reversely express with E—cadherin in urothelial bladder cancer, suggests Snail would participate regulation of E-cadherin, which sustain the premier researches。The low expression of E-cadherin, high expression of Snail of invasive and metastasis group to some extent suggests the prognosis effect of the two factors.
1.研究Snail和E-cadherin在膀胱泌尿上皮癌癌中的表达情况,以及它们在膀胱癌不同病理分级和分期中的表达差异。
2.验证Snail与E-cadherin的表达相关性,探讨其表达与膀胱癌预后的关系。
3.为以后的研究提供理论和实验基础。
研究方法：
通过研究我院04-07膀胱泌尿上皮癌病例67例,病例资料调查,电话随访等方式得到临床资料,从病理科取出石蜡块,重新切片,进行免疫组化SP法染色,对标本按照病例分期和浸润深度和临床进展情况进行分组,采用SPSS进行统计学分析。
结果：
选择膀胱泌尿上皮癌患者标本67例,正常膀胱组织6例,手术时间2004-2007年,其中男性标本54例,女性标本13例。G1标本23例,G2标本25例,G3标本19例,TL 49例,TH 18例。膀胱正常上皮细胞E—cadherin均为细胞膜强阳性均匀致密着色。而在膀胱癌细胞中,表达则有明显异质性,胞膜染色减少或消失。Snail在正常膀胱组织中表达较弱,甚至不表达,而在肿瘤组织中表达显著高于正常膀胱组织,在细胞中弥漫于细胞胞浆。E-cadherin在G1,G2,G3病理级别膀胱癌的表达逐渐减弱,具有统计学差异(G1*G2 p=0.011, G2*G3 p=0.009, G1*G3 p<0.001),在TL组表达强于TH组(p=0.009)。而Snail在G1,G2,G3病理级别膀胱癌的表达逐渐增强,具有统计学差异(G1*G2 p=0.008 G2 *G3 p=0.023 G1*G3 p<0.001),在TL组表达弱于TH组(p<0.001).Snail和E-cadherin的表达负相关(r=-0.733,p<0.001)。肿瘤发生深层浸润或者转移的患者组与相同时间内肿瘤无复发,或者复发但浸润深度未达肌层的的患者组之间,前者Snail表达高于后组(p=0.021), E-cadherin表达低于后组(p=0.032)。
结论：
膀胱癌病理级别和临床分期的升高,E-cadherin表达减少,Snail表达增加,且Snail和E—cadherin的表达负相关,提示Snail可能参与E-cadherin的调节。TUR术后同样时间段内临床进展的膀胱癌E-cadherin表达低,Snail表达高,提示Snail可能对预后判断有一定参考意义。
Objective:
1. To study the expression of Snail and E-cadherin in urothelial bladder cancer, and the difference between pathological grades and stages.
2. To verify the corelation between expression of Snail and E-cadherin, and investigate the effect on the prognosis.
3. To provide basis for research.
Material and Method:
67 urothelial bladder cancer specimens were studied, all of which obtained during 2004-2007 by TUR or cystectomy. Clinic data was achieved by review of case history and telephone visit. Slices were cut from paraffin blocks with help of Pathology Dept, Huashan Hospital, and then used for immunochemistry coloration. Grouping specimens by pathologic grade(Gl,G2,G3),clinic stage(Ta-1,T2-4) and clinic progress data, then statistics analysis was performed with SPSS software between groups.
Results:
67 urothelial bladder cancer specimens were investigated, of which 54 from male,13 from female,23 of Gl grade,25 of G2 grade,19 of G3 grade,49 of TL stage,18 of TH stage.6 normal bladder tissues were investigated by IHC. The expression of E-cadherin decreases when grade is high, statistics analysis shows significant difference between G1,G2,G3(G1*G2 p=0.011,G2*G3 p=0.009, G1*G3 p<0.001), and higher expression in TH group than TL (p=0.009)。Inversely, Snail expresses higher when grade is higher, statistics analysis shows significant difference between G1,G2,G3(G1*G2 p=0.008 G2*G3 p=0.023 G1*G3 p<0.001), and expresses higher in TH group than TL (p<0.001). Spearman test indicates that Snail has a reverse corelation with E-cadherin expression (r=-0.733, p<0.001). Group of specimens from patients that underwent muscle invasion or metastasis after TUR in 2 year has higher expression of Snail(p=0.021),and lower expression of E-cadherin(p=0.032) than group without invasion or metastasis during the same time duration.
Conclusion:
E-cadherin expresses lower, while Snail expresses higher, when clinic stage and pathologic grade is higher, and the result that Snail reversely express with E—cadherin in urothelial bladder cancer, suggests Snail would participate regulation of E-cadherin, which sustain the premier researches。The low expression of E-cadherin, high expression of Snail of invasive and metastasis group to some extent suggests the prognosis effect of the two factors.
引文
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2 Angeliki Voulgari, Alexander Pintzas. Epithelial-mesenchymal transition in cancer metastasis:Mechanisms, markers and strategies to overcome drug resistance in the clinic. Biochimica et Biophysica Acta-Reviews on Cancer,2009;1796(2):75-90
3. Rommel A. Mathias, Richard J. Simpson.Towards understanding epithelial mesenchymal transition:A proteomics perspective Biochimica et Biophysica Acta (BBA)-Proteins & Proteomics,2009;1794(9):1325-1331
4. Hee Jun Cho, Kyoung Eun Baek, Shizuya Saika,etc.Snail is required for transforming growth factor-β-induced epithelial-mesenchymal transition by activating PI3 kinase/Akt signal pathway.Biochemical and Biophysical Research Communications.2007; 353(2):337-343
5. Harald J. Maier, Uta Schmidt-Straβburger, Margit A. Huber,etc. NF-κB promotes epithelial-mesenchymal transition, migration and invasion of pancreatic carcinoma cells.Cancer Letters, In Press, Corrected Proof, Available online 29 March 2010
6.A. Cano, M.A. Perez-Moreno, I. Rodrigo, A. Locascio, M.J. Blanco, M.G. del Barrio,F. Portillo, M.A. Nieto, The transcription factor snail controls epithelial mesenchymal transitions by repressing E-cadherin expression, Nat. Cell Biol. 2000;(2):76-83
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9. Sylvester RJ, Oosterlinck W, van der Meijden APM. A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer:a meta-analysis of published results of randomized clinical trials. J Urol 2004; 171:2186-2190,
10. Sylvester RJ, Oosterlinck W, van der Meijden AP. A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer:a metaanalysis of published results of randomized clinical trials. J Urol 2004;171(6 Pt 1):2186-90.
11. Babjuk M, Oosterlinck W, Sylvester R, et al. EAU guidelines on nonmuscle invasive urothelial carcinoma of the bladder. Eur Urol 2008; 54:303-314.
12. Malmstrom P-U, Sylvester RJ, Crawford DE, et al. An individual patient datameta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guerin for nonmuscle-invasive bladder cancer. Eur Urol 2009; 56:247-256
13. Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer:long-term results in 1,054 patients. J Clin Oncol.2001; 19:666-675.
14. Raghavan D, Shipley WU, Garnick MB, et al. The biology and management of bladder cancer. N Engl J Med 1990; 322:1129-1138
15. Andius P, Johansson SL, Holma "ng S. Prognostic factors in stage T1 bladder cancer:tumor pattern (solid or papillary) and vascular invasion more important than depth of invasion. Urology 2007; 70:758-762.
16. Cho K, Seo H, Joung J, et al. Lymphovascular invasion in transurethral resection specimens as predictor of progression and metastasis in patients with newly diagnosed T1 bladder urothelial cancer. J Urol 2009; 182:2625-2631.
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18. Jing Yang, Sendurai A.Mani, Robert A. WeinbergExploring a New Twist on Tumor Metastasis.Cancer Res.2006; 66:(9).
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2 Angeliki Voulgari, Alexander Pintzas. Epithelial-mesenchymal transition in cancer metastasis:Mechanisms, markers and strategies to overcome drug resistance in the clinic. Biochimica et Biophysica Acta-Reviews on Cancer,2009;1796(2):75-90
3. Rommel A. Mathias, Richard J. Simpson.Towards understanding epithelial mesenchymal transition:A proteomics perspective Biochimica et Biophysica Acta (BBA)-Proteins & Proteomics,2009;1794(9):1325-1331
4. Hee Jun Cho, Kyoung Eun Baek, Shizuya Saika,etc.Snail is required for transforming growth factor-β-induced epithelial-mesenchymal transition by activating PI3 kinase/Akt signal pathway.Biochemical and Biophysical Research Communications.2007; 353(2):337-343
5. Harald J. Maier, Uta Schmidt-Straβburger, Margit A. Huber,etc. NF-κB promotes epithelial-mesenchymal transition, migration and invasion of pancreatic carcinoma cells.Cancer Letters, In Press, Corrected Proof, Available online 29 March 2010
6.A. Cano, M.A. Perez-Moreno, I. Rodrigo, A. Locascio, M.J. Blanco, M.G. del Barrio,F. Portillo, M.A. Nieto, The transcription factor snail controls epithelial mesenchymal transitions by repressing E-cadherin expression, Nat. Cell Biol. 2000;(2):76-83
7. Hall MC, Chang SS, Dalbagni G, et al. Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis):2007 update. J Urol 2007; 178:2314-2330
8. Brausi M, Collette L, Kurth K, van der Meijden A, Oosterlinck W, Witjes JA, Newling D, Bouffioux C, Sylvester R; EORTC Genito-Urinary Tract Cancer Collaborative Group. Variability in the recurrence rate at first follow-up cystoscopy after TUR in stage Ta T1 transitional cell carcinoma of the bladder:a combined analysis of seven EORTC studies. Eur Urol 2002;41(5):523-31.
9. Sylvester RJ, Oosterlinck W, van der Meijden APM. A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer:a meta-analysis of published results of randomized clinical trials. J Urol 2004; 171:2186-2190,
10. Sylvester RJ, Oosterlinck W, van der Meijden AP. A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer:a metaanalysis of published results of randomized clinical trials. J Urol 2004;171(6 Pt 1):2186-90.
11. Babjuk M, Oosterlinck W, Sylvester R, et al. EAU guidelines on nonmuscle invasive urothelial carcinoma of the bladder. Eur Urol 2008; 54:303-314.
12. Malmstrom P-U, Sylvester RJ, Crawford DE, et al. An individual patient datameta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guerin for nonmuscle-invasive bladder cancer. Eur Urol 2009; 56:247-256
13. Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer:long-term results in 1,054 patients. J Clin Oncol.2001; 19:666-675.
14. Raghavan D, Shipley WU, Garnick MB, et al. The biology and management of bladder cancer. N Engl J Med 1990; 322:1129-1138
15. Andius P, Johansson SL, Holma "ng S. Prognostic factors in stage T1 bladder cancer:tumor pattern (solid or papillary) and vascular invasion more important than depth of invasion. Urology 2007; 70:758-762.
16. Cho K, Seo H, Joung J, et al. Lymphovascular invasion in transurethral resection specimens as predictor of progression and metastasis in patients with newly diagnosed T1 bladder urothelial cancer. J Urol 2009; 182:2625-2631.
17. Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes A, Bouffioux C, Denis L, Newling DW, Kurth K. Predicting recurrence and progression in individual patients with stage TaT1 bladder cancerusing EORTC risk tables:a combined analysis of 2596 patients from seven EORTC trials. Eur Urol.2006;49(3):466-77
18. Jing Yang, Sendurai A.Mani, Robert A. WeinbergExploring a New Twist on Tumor Metastasis.Cancer Res.2006; 66:(9).
19. Hugo H et al. Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol.2007; 213(2):374-83
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