LRIG2基因和蛋白在膀胱肿瘤中的表达及重组质粒载体pCMV-LRIG2转染BIU-87细胞株的效应研究
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摘要
目的:了解LRIG2基因在膀胱肿瘤和正常膀胱组织中的表达及其与膀胱肿瘤不同分级、分期之间的关系
方法:利用半定量RT-PCR技术检测31例膀胱肿瘤组织和16例正常膀胱粘膜组织内LRIG2基因mRNA表达情况,同时结合病例的分级、分期等对结果进行统计学分析。
结果:38例肿瘤标本中,34例检测到LRIG2mRNA的表达,表达水平(灰度比值)平均为0.39±0.22(±s );16例正常粘膜标本中均检测到LRIG2mRNA的表达,表达水平平均为0.54±0.16。两者相比较P=0.012,有统计学差异,肿瘤组织内LRIG2mRNA的表达水平显著低于正常膀胱组织。肿瘤组织中,浅表型肿瘤表达水平为0.44±0.16,浸润型为0.21±0.12,两者相比较P=0.012,有统计学差异;低级别肿瘤表达水平为0.49±0.18,中高级别为0.33±0.16,两者相比较P=0.033,有统计学差异。
结论:LRIG2基因在膀胱肿瘤组织中表达水平明显下调,且与肿瘤的分级分期相关,提示其有可能为一种抑癌基因,与肿瘤的发生、发展有密切关系。
目的:了解LRIG2蛋白在膀胱肿瘤和正常膀胱组织中的表达及其与膀胱肿瘤不同分级、分期之间的关系
方法:利用Western blot技术检测38例膀胱肿瘤组织和16例正常膀胱粘膜组织内LRIG2蛋白A表达情况,并对结果进行统计学分析。
结果:38例肿瘤标本中,33例检测到LRIG2蛋白的表达,表达水平(灰度比值)平均为0.41±0.15 (±s );16例正常粘膜标本中均检测到LRIG2蛋白的表达,表达水平平均为0.50±0.08。两者相比较P=0.038,有统计学差异,膀胱肿瘤组织内LRIG2蛋白的表达水平显著低于正常膀胱组织。肿瘤组织中,浅表型肿瘤表达水平为0.45±0.13,浸润型为0.27±0.13,两者相比较P=0.027,有统计学差异;低级别肿瘤表达水平为0.49±0.15,中高级别为0.35±0.12,两者相比较P=0.040,有统计学差异。
结论:LRIG2蛋白在膀胱肿瘤组织中表达水平明显下调,且与肿瘤的分级分期相关,提示其有可能是一种具有抑癌功能的蛋白,与肿瘤的发生、发展有密切关系。
目的:研究携带有LRIG2基因的重组质粒载体pCMV-LRIG2对膀胱癌细胞株BIU-87生物学行为的影响。
方法:用脂质体介导的基因转染技术,将携带有LRIG2基因的重组质粒载体pCMV-LRIG2转染至膀胱癌细胞株BIU-87,用G418筛选出抗性克隆后,Western检测转染前后LRIG2和EGFR蛋白表达水平变化,MTT法绘制转染前后细胞生长曲线,Transwell法检测转染前后细胞侵袭力,同质粘附实验观察转染前后细胞粘附能力。
结果:转染pCMV-LRIG2组LRIG2蛋白表达水平显著高于未转染组和空载体转染组;转染pCMV-LRIG2组细胞生长速度较未转染组和空载体转染组明显减慢,侵袭力显著低于未转染组和空载体转染组,而粘附能力显著高于未转染组和空载体转染组。
结论:LRIG2有类似于抑癌基因的作用,通过对EFG-EGFR信号转导途径发挥负反馈抑制作用,从而抑制BIU87细胞的生长、侵袭和转移。
Purpose: To investigate the expression of LRIG2 gene between bladder cancer and normal bladder tissue, and to identify the different expression in dissimilar grading and staging.
Methods: RT-PCR technique was used to detect the expression of LRIG2 mRNA in 31 cases of bladder cancer tissue and 16 cases of normal bladder tissue. Statistics analysis was combined with the staging and grading of the tumor.
Results: In the 31 cases of bladder cancer tissue, 34 cases were detected the expression of LRIG2 mRNA, and the average level was 0.39±0.22. All the 16 cases of normal bladder tissue were detected the expression of LRIG2 mRNA, and the average level was 0.54±0.16. There was significant difference between the bladder cancer group and the normal bladder tissue group (P=0.012).The expression of LRIG2 mRNA in bladder cancer was significantly lower than in the normal bladder tissue. In the bladder cancer group, the average expression level of superficial group and invasive group were 0.44±0.16 and 0.21±0.12, and there was significant difference between the two group (P=0.012). The average expression level of lower grading and higher grading were 0.49±0.18 and 0.33±0.16, and there was significant difference between the two group (P=0.033).
Conclusion: The expression of LRIG2 gene was significantly down-regulated in bladder cancer, and the expression level was correlated with the grading and staging of the tumor, suggesting that the gene maybe a kind of cancer inhibiting gene and participating the arising and developing of the cancer.
Purpose: To investigate the expression of LRIG2 protein between bladder cancer and normal bladder tissue, and to identify the different expression in dissimilar grading and staging.
Methods: Western blot technique was used to detect the expression of LRIG2 protein in 31 cases of bladder cancer tissue and 16 cases of normal bladder tissue. Statistics analysis was combined with the staging and grading of the tumor.
Results: In the 31 cases of bladder cancer tissue, 33 cases were detected the expression of LRIG2 protein, and the average level was 0.41±0.15. All the 16 cases of normal bladder tissue were detected the expression of LRIG2 protein, and the average level was 0.50±0.08. There was significant difference between the bladder cancer group and the normal bladder tissue group (P=0.038). The expression of LRIG2 protein in bladder cancer was significantly lower than in the normal bladder tissue In the bladder cancer group, the average expression level of superficial group and invasive group were 0.45±0.13 and 0.27±0.13, and there was significant difference between the two group (P=0.027). The average expression level of lower grading and higher grading were 0.49±0.15 and 0.35±0.12, and there was significant difference between the two group (P=0.040).
Conclusion: The expression of LRIG2 protein was significantly down-regulated in bladder cancer, and the expression level was correlated with the grading and staging of the tumor, suggesting that the protein maybe a kind of cancer inhibiting protein and participating the arising and developing of the cancer.
Purpose: To investigate the effects of recombinated plasmid pCMV-LRIG2 carrying LRIG2 gene on the biological behaviors of human bladder cancer BIU-87.
Method: The recombined plasmid pCMV-LRIG2 was transfected into BIU-87 cell by lipofectamine 2000, and G418 was used to screen out the positive clone. Then Western-blot was used to measure the expression of LRIG2 and EGFR protein, MTT assay was used to drawn out the growth curve of the cell, Transwell method and cell-cell adhesion were used to detect the invasion and metastasis ability among transfed cell, non-transfed cell, and pCMV-transfed cell.
Result: Among the LRIG2-transfed group, non-transfed group and pCMV-transfed group, the expression of LRIG2 protein was significantly higher in the LRIG2-transfed group than the other two groups, and the expression of EGFR in LRIG2-transfed group was significantly lower. The growth curve of the cells by MTT showed that the LRIG2-transfected group had less proliferation than the other two groups .Contrast to non-transfed gourp and pCMV-group, the invasion ability of transfed group decreased significantly,however, the adhesion ability of transfed group increased significantly.
Conclusion: The LRIG2 gene may act as a tumor suppressor gene by participating in construction of negative feedback loop of EGFR, so as to inhibits bladder cancer cells from growth, invasion and metastasis.
方法:利用半定量RT-PCR技术检测31例膀胱肿瘤组织和16例正常膀胱粘膜组织内LRIG2基因mRNA表达情况,同时结合病例的分级、分期等对结果进行统计学分析。
结果:38例肿瘤标本中,34例检测到LRIG2mRNA的表达,表达水平(灰度比值)平均为0.39±0.22(±s );16例正常粘膜标本中均检测到LRIG2mRNA的表达,表达水平平均为0.54±0.16。两者相比较P=0.012,有统计学差异,肿瘤组织内LRIG2mRNA的表达水平显著低于正常膀胱组织。肿瘤组织中,浅表型肿瘤表达水平为0.44±0.16,浸润型为0.21±0.12,两者相比较P=0.012,有统计学差异;低级别肿瘤表达水平为0.49±0.18,中高级别为0.33±0.16,两者相比较P=0.033,有统计学差异。
结论:LRIG2基因在膀胱肿瘤组织中表达水平明显下调,且与肿瘤的分级分期相关,提示其有可能为一种抑癌基因,与肿瘤的发生、发展有密切关系。
目的:了解LRIG2蛋白在膀胱肿瘤和正常膀胱组织中的表达及其与膀胱肿瘤不同分级、分期之间的关系
方法:利用Western blot技术检测38例膀胱肿瘤组织和16例正常膀胱粘膜组织内LRIG2蛋白A表达情况,并对结果进行统计学分析。
结果:38例肿瘤标本中,33例检测到LRIG2蛋白的表达,表达水平(灰度比值)平均为0.41±0.15 (±s );16例正常粘膜标本中均检测到LRIG2蛋白的表达,表达水平平均为0.50±0.08。两者相比较P=0.038,有统计学差异,膀胱肿瘤组织内LRIG2蛋白的表达水平显著低于正常膀胱组织。肿瘤组织中,浅表型肿瘤表达水平为0.45±0.13,浸润型为0.27±0.13,两者相比较P=0.027,有统计学差异;低级别肿瘤表达水平为0.49±0.15,中高级别为0.35±0.12,两者相比较P=0.040,有统计学差异。
结论:LRIG2蛋白在膀胱肿瘤组织中表达水平明显下调,且与肿瘤的分级分期相关,提示其有可能是一种具有抑癌功能的蛋白,与肿瘤的发生、发展有密切关系。
目的:研究携带有LRIG2基因的重组质粒载体pCMV-LRIG2对膀胱癌细胞株BIU-87生物学行为的影响。
方法:用脂质体介导的基因转染技术,将携带有LRIG2基因的重组质粒载体pCMV-LRIG2转染至膀胱癌细胞株BIU-87,用G418筛选出抗性克隆后,Western检测转染前后LRIG2和EGFR蛋白表达水平变化,MTT法绘制转染前后细胞生长曲线,Transwell法检测转染前后细胞侵袭力,同质粘附实验观察转染前后细胞粘附能力。
结果:转染pCMV-LRIG2组LRIG2蛋白表达水平显著高于未转染组和空载体转染组;转染pCMV-LRIG2组细胞生长速度较未转染组和空载体转染组明显减慢,侵袭力显著低于未转染组和空载体转染组,而粘附能力显著高于未转染组和空载体转染组。
结论:LRIG2有类似于抑癌基因的作用,通过对EFG-EGFR信号转导途径发挥负反馈抑制作用,从而抑制BIU87细胞的生长、侵袭和转移。
Purpose: To investigate the expression of LRIG2 gene between bladder cancer and normal bladder tissue, and to identify the different expression in dissimilar grading and staging.
Methods: RT-PCR technique was used to detect the expression of LRIG2 mRNA in 31 cases of bladder cancer tissue and 16 cases of normal bladder tissue. Statistics analysis was combined with the staging and grading of the tumor.
Results: In the 31 cases of bladder cancer tissue, 34 cases were detected the expression of LRIG2 mRNA, and the average level was 0.39±0.22. All the 16 cases of normal bladder tissue were detected the expression of LRIG2 mRNA, and the average level was 0.54±0.16. There was significant difference between the bladder cancer group and the normal bladder tissue group (P=0.012).The expression of LRIG2 mRNA in bladder cancer was significantly lower than in the normal bladder tissue. In the bladder cancer group, the average expression level of superficial group and invasive group were 0.44±0.16 and 0.21±0.12, and there was significant difference between the two group (P=0.012). The average expression level of lower grading and higher grading were 0.49±0.18 and 0.33±0.16, and there was significant difference between the two group (P=0.033).
Conclusion: The expression of LRIG2 gene was significantly down-regulated in bladder cancer, and the expression level was correlated with the grading and staging of the tumor, suggesting that the gene maybe a kind of cancer inhibiting gene and participating the arising and developing of the cancer.
Purpose: To investigate the expression of LRIG2 protein between bladder cancer and normal bladder tissue, and to identify the different expression in dissimilar grading and staging.
Methods: Western blot technique was used to detect the expression of LRIG2 protein in 31 cases of bladder cancer tissue and 16 cases of normal bladder tissue. Statistics analysis was combined with the staging and grading of the tumor.
Results: In the 31 cases of bladder cancer tissue, 33 cases were detected the expression of LRIG2 protein, and the average level was 0.41±0.15. All the 16 cases of normal bladder tissue were detected the expression of LRIG2 protein, and the average level was 0.50±0.08. There was significant difference between the bladder cancer group and the normal bladder tissue group (P=0.038). The expression of LRIG2 protein in bladder cancer was significantly lower than in the normal bladder tissue In the bladder cancer group, the average expression level of superficial group and invasive group were 0.45±0.13 and 0.27±0.13, and there was significant difference between the two group (P=0.027). The average expression level of lower grading and higher grading were 0.49±0.15 and 0.35±0.12, and there was significant difference between the two group (P=0.040).
Conclusion: The expression of LRIG2 protein was significantly down-regulated in bladder cancer, and the expression level was correlated with the grading and staging of the tumor, suggesting that the protein maybe a kind of cancer inhibiting protein and participating the arising and developing of the cancer.
Purpose: To investigate the effects of recombinated plasmid pCMV-LRIG2 carrying LRIG2 gene on the biological behaviors of human bladder cancer BIU-87.
Method: The recombined plasmid pCMV-LRIG2 was transfected into BIU-87 cell by lipofectamine 2000, and G418 was used to screen out the positive clone. Then Western-blot was used to measure the expression of LRIG2 and EGFR protein, MTT assay was used to drawn out the growth curve of the cell, Transwell method and cell-cell adhesion were used to detect the invasion and metastasis ability among transfed cell, non-transfed cell, and pCMV-transfed cell.
Result: Among the LRIG2-transfed group, non-transfed group and pCMV-transfed group, the expression of LRIG2 protein was significantly higher in the LRIG2-transfed group than the other two groups, and the expression of EGFR in LRIG2-transfed group was significantly lower. The growth curve of the cells by MTT showed that the LRIG2-transfected group had less proliferation than the other two groups .Contrast to non-transfed gourp and pCMV-group, the invasion ability of transfed group decreased significantly,however, the adhesion ability of transfed group increased significantly.
Conclusion: The LRIG2 gene may act as a tumor suppressor gene by participating in construction of negative feedback loop of EGFR, so as to inhibits bladder cancer cells from growth, invasion and metastasis.
引文
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1. Nilsson J, Vallbo C, Guo DS, et al. Cloning,Characterization, and Expression of human LIG1. Biochem Biophys Res Commun 2001; 284: 1155-1161.
2. Holmlund C, Nilsson J, Guo DS, et al. Characterization and tissue-specific expression of human LRIG2. Gene 2004; 332; 35–43.
3. Guo DS, Holmlund C, Henriksson, et al. The LRIG gene family has three vertebrate paralogs widely expressed in human and mouse tissues and a homolog in Ascidiacea. Genomics 2004 ; 84; 157–165.
4. Hedman H, Nilsson J,Guo DS, et al. Is LRIG1 a Tumor Suppressor Gene at Chromosome 3p14.3? Acta Oncologica .2002; 41:352–354.
5. Thomasson M, Hedman H, Guo DS, et al. LRIG1 and epidermal growth factor receptor in renal cell carcinoma: a quantitative RT-PCR and immunohistochemical analysis. British J Cancer 2003; 89:1285-1289.
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7. Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 2000; 103: 211–225.
8. Gal G, Chanan R, Menachem K, et al. LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation. The EMBO Journal 2004; 23: 3270-3281.
1. Dikic I, Giordano S. Negative receptor signaling. Curr Opin Cell Biol 2003; 15: 128–135.
2. Gal G, Chanan R, Menachem K, et al. LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation. The EMBO Journal 2004; 23: 3270-3281.
3. Yarden Y, Sliwkowski MX .Untangling the ErbB signaling network. Nat Rev Mol Cell Biol 2001;2:127–137
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9. Nilsson J, Vallbo C, Guo DS, et al. Cloning,Characterization, and Expression of human LIG1. Biochem Biophys Res Commun 2001; 284:1155-1161.
10. Holmlund C, Nilsson J, Guo DS, et al. Characterization and tissue-specific expression of human LRIG2. Gene 2004;332;35–43.
11. Guo DS, Holmlund C, Henriksson, et al. The LRIG gene family has three vertebrate paralogs widely expressed in human and mouse tissues and a homolog in Ascidiacea. Genomics 2004 ;84;157–165.
1. Nilsson J, Vallbo C, Guo DS, et al. Cloning,Characterization, and Expression of human LIG1. Biochem Biophys Res Commun 2001; 284:1155-1161.
2. Holmlund C, Nilsson J, Guo DS, et al. Characterization and tissue-specific expression of human LRIG2. Gene 2004; 332:35–43.
3. Hedman H, Nilsson J,Guo DS, et al. Is LRIG1 a Tumor Suppressor Gene at Chromosome 3p14.3? Acta Oncologica 2002; 41:352–354.
4. Kolibaba, KS, Druker, BJ Protein tyrosine kinases and cancer. Biochim Biophys. Acta 1997; 1333:217–248.
5. Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 2000; 103: 211–225.
6. Guo DS, Holmlund C, Henriksson, et al. The LRIG gene family has three vertebrate paralogs widely expressed in human and mouse tissues and a homolog in Ascidiacea. Genomics 2004 ; 84: 157–165.
7. Gal G, Chanan R, Menachem K, et al. LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation. The EMBO Journal 2004; 23:3270-3281.
8. Liebmann C. Regulation of MAP kinase activity by peptide receptor signalling pathway: paradigms of multiplicity. Cell Signal. 2001; 13:777-785.
9. Thomasson M, Hedman H, Guo D, et al.LRIG1 and epidermal growth factor receptor in renal cell carcinoma: a quantitative RT-PCR and immunohistochemical analysis. Br J Cancer.2003, 89:1285-1289.
1. Kolibaba, KS, Druker, BJ . Protein tyrosine kinases and cancer. Biochim Biophys. Acta 1997; 1333:217–248.
2. Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 2000; 103:211–225.
3. Nilsson J, Vallbo C, Guo DS, et al. Cloning,Characterization, and Expression of human LIG1. Biochem Biophys Res Commun 2001; 284:1155-1161.
4. Holmlund C, Nilsson J, Guo DS, et al. Characterization and tissue-specific expression of human LRIG2. Gene 2004; 332;35–43.
5. Guo DS, Holmlund C, Henriksson, et al. The LRIG gene family has three vertebrate paralogs widely expressed in human and mouse tissues and a homolog in Ascidiacea. Genomics 2004 ; 84;157–165.
6. Gal G, Chanan R, Menachem K, et al. LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation. The EMBO Journal 2004; 23:3270-3281.
7. Dikic I, Giordano S. Negative receptor signaling. Curr Opin Cell Biol 2003; 15:128–135.
8. Yarden Y, Sliwkowski MX .Untangling the ErbB signaling network. Nat Rev Mol Cell Biol 2001;2:127–137
9. Liebmann C. Regulation of MAP kinase activity by peptide receptor signalling pathway: paradigms of multiplicity. Cell Signal. 2001; 13:777-785.
10. Klapper LN, Kirschbaum MH, Sela M,et al. Biochemical and clinical implications of the ErbB/HER signaling network of growth factor receptors. Adv Cancer Res 2000; 77:25-79.
11. Musacchio, M,Perrimon, N. The Drosophila kekkon genes:novel members of both the leucine-rich repeat and immunoglobulin superfamilies expressed in the CNS. Dev. Biol 1996; 178:63-76.
12. Ghiglione G, Kermit L, Laufey T, et al. The transmembrane molecule kekkon 1 acts in a feedback loop to negatively regulate the activity of the drosophila EGF receptor during oogenesis. Cell 1999; 96:847-856.
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23. Welsh JB, Sapinoso LM, Su AI, et al. Analysis of gene expression identifies candidate markers and pharmacological targets in prostate cancer. Cancer Res 2001; 61: 5974–6978.
24. Laederich MB, Funes-Duran M, Yen L, et al. The leucinerich repeat protein LRIG1 is a negative regulator of ErbB family receptor tyrosine kinases. J Biol Chem 2004; 279: 47050–47056.
25. Jensen KB,Watt FM. Single-cell expression profiling of human epidermal stem and transit-amplifying cells: Lrig1 is a regulator of stem cell quiescence. Proc Natl Acad Sci USA 2006; 103: 11958–11963.
26. Yang WM, Yan ZJ, Ye ZQ, Guo DS. LRIG1, a candidate tumoursuppressor gene in human bladder cancer cell line BIU87. BJU Int 2006; 98: 898–902.
27. Bhattacharjee A, Richards WG, Staunton J, et al. Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci USA 2001; 98: 13790–13795.
28. Hedman H, Henriksson R. LRIG inhibitors of growth factor signaling——double-edged swords in human cancer? Euro J Cancer 2007; 43: 676-682.
29. Salomon DS, Brandt R, Ciardiello F, et al. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995; 19: 183–232.
30. Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 2006; 7: 505–516.
31. Barnes DW. Epidermal growth factor inhibits growth of A431 human epidermoid carcinoma in serum-free cell culture. J Cell Biol 1982; 93: 1–4.
32. Gulli LF, Palmer KC, Chen YQ, et al. Epidermal growth factorinduced apoptosis in A431 cells can be reversed by reducingthe tyrosine kinase activity. Cell Growth Differ 1996; 7: 173–178.
33. Gullick WJ. c-erbB-4/HER4: friend or foe? J Pathol 2003; 200: 279–281.
34. Witton CJ, Reeves JR, Going JJ, et al. Expression of the HER1-4 family of receptor tyrosine kinases in breast cancer. J Pathol 2003; 200: 290–297.
35. Williams EE, Trout LJ, Gallo RM, et al. A constitutively active ErbB4 mutant inhibits drug-resistant colony formation by the DU-145 and PC-3 human prostate tumor cell lines. Cancer Lett 2003; 192: 67–74.
36. Thomasson M, Hedman H, Junttila TT, et al. ErbB4 is downregulated in renal cell carcinoma: a quantitative RT-PCR and immunohistochemical analysis of the epidermal growth factor receptor family. Acta Oncol 2004; 43: 453–459.
37. Guo D, Nilsson J, Haapasalo H, et al. Perinuclear leucine-rich repeats and immunoglobulin-like domain proteins (LRIG1-3) as prognostic indicators in astrocytic tumors. Acta Neuropathol 2006; 111: 238–246.
38. Febbo PG, Lowenberg M, Thorner AR, et al. Androgen mediated regulation and functional implications of fkbp51 expression in prostate cancer. J Urol 2005; 173: 1772–1777.
39. Ljuslinder I, Malmer B, Golovleva I, et al. Increased copy number at 3p14 in breast cancer. Breast Cancer Res 2005; 7: 719–727.
40. Kauraniemi P, Barlund M, Monni O, et al. New amplified and highly expressed genes discovered in the ERBB2 amplicon in breast cancer by cDNA microarrays. Cancer Res 2001; 61: 8235–8240.
1. El-Gabry EA, Strup SE, Gomella LG, et al. Superficial bladder cancer-current treatment modalities and future directions part I&II. AUA Updates Series 2000:20.
2. Gonzalgo ML, Schoenberg MP, Rodriguez R. Biological pathways to bladder carcinogenesis. Semin Urol Oncol 2000; 18:256-263.
3. Brandau S, Bohle A. Bladder cancer I molecular and genetic bassi of carcinogenesis Eruo Urol 2001; 39: 491-497.
4. Reznikoff CA, Sarkar S, Julicher KP, et al. Genetic alterations and biological pathways in human bladder cancer pathogenesis. Urol Oncol 2000; 5: 191-203.
5. Barbacid M. Ras genes. Annu Rev Biochem 1987; 56: 779-827.
6. Rabbani F, Cordon-Cardo C. Mutation of cell cycle regulations and their impact on superficial bladder cancer. Urol Clin Nroth Am 2000; 27: 83-89.
7. Moriyama M, Akiyama T, Yamamoto T, et al. Expression of c-erbB-2 gene product in urinary bladder cancer. J Urol 1991; 145: 423-427.
8. Jimenez RE, Hussain M, Binaco FJ Jr, et al. Her-2/neu overexpression in muscle-invasive urothelial carcinoma of the bladder: prognostic significance and comparative analysis in primary and metastatic tumors. Clin Cancer Res 2001; 7: 2440-2447.
9. Messing EM. Clinical implications of the expression of epidermal growth factor receptors in human transitional cell carcinoma. Cancer Res 1990; 50: 2530-2537.
10. Mellon K, Wright C, Kelly P, et al. Long-term outcome related to epidermal growth factor receptor status in bladder cancer. J Urol 1995; 153: 919-925.
11. Oliner JD, Kinzler KW, Meltzer PS, et al. Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature 1992; 358: 80-83.
12. Shiina H, Igawa M, Shigeno K, et al. Clinical significance of mdm2 and p53expression in bladder cancer: A comparison with cell proliferation and apoptosis. Oncology 1999; 56: 239-247.
13. Zhou H, Kuang J, Zhong L, et al. Tumor amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet 1998; 20:189-193.
14. Sen S, Zhou H, Zhang RD, et al. Amplification/overexpression of a mitotic kinase gene in human bladder cancer. J Natl Cancer Inst 2002; 94: 1320-1329.
15. Kretzner L, Blackwood EM, Eisenman RN. Myc and Max proteins possess distinct transcriptional activities. Nature 1992; 359: 426-429.
16. Mahdy E, Pan Y, Wang N, et al. Chromosome 8 numerical aberration and C-MYC copy number gain in bladder cancer are linked to stage and grade. Anticancer Res 2001; 21: 3167-3173.
17. Bringuier PP, Tamimi Y, Schuuring E, et al. Expression of cyclin D1 and EMS1 in bladder tumors: relationship with chromosome 11q13 amplification. Oncogene 1996; 12: 1747-1753.
18. Watters AD, Latif Z, Forsyth A, et al. Genetic aberrations of c-myc and CCND1 in the development of invasive bladder cancer. Br J Cancer 2002; 87: 654-658.
19. Duggan BJ, Kelly JD, Keane PF, et al. Molecular targets for the therapeutic manipulation of apoptosis in bladder cancer. J Urol 2001; 165: 946-965.
20. Lu ML, Wikman F, Orntoft TF, et al. Impact of alterations affecting the p53 pathway in bladder cancer on clinical outcome, assessed by conventional and array-based methods. Clin Cancer Res 2002; 8: 171-179.
21. Sarkis AS, Bajorin DF, Reuter VE, et al. Prognostic value of p53 nuclear overexpression in patients with invasive bladder cancer treated with neoadjuvant MVAC. J Clin Oncol 1995; 13: 1384-1390.
22. Cote RJ, Datar RH. Therapeutic approaches to bladder cancer: identifying targets and mechanisms. Crit Rev Oncol Hematol 2003; 46 Suppl: 67-83.
23. Nevins JR, Leone G, Degregori J, et al. Role of the RB/E2F pathway in cell growth control. J Cell Physiol 1997; 173: 233-236.
24. Xu HJ, Cairns P, Hu SX, et al. Loss of RB protein expression in primary bladder cancer correlates with loss of heterozygosity at the RB locus and tumor progression. Int J Cancer 1993; 53: 781-784.
25. Grossman HB, Liebert M, Antelo M, et al. p53 and RB expression predict progression in T1 bladder cancer. Clin Cancer Res 1998; 4: 829-834.
26. Lacombe L, Orlow I, Silver D, et al. Analysis of p21AAF1/CIP1 in primary bladder tumors. Oncol Res 1996; 8: 409-414.
27. Shariat SF, Kim J, Raptidis G, et al. Association of p53 and p21 expression with clinical outcome in patients with carcinoma in situ of the urinary bladder. Urology 2003; 61: 1140-1145.
28. Korkolopoulou P, Christodoulou P, Konstantinidou AE, et al. Cell cycle regulators in bladder cancer: a multivariate survival study with emphasis on p27Kip1. Hum Pathol 2000; 31: 751-760.
29. Orlow I ,Larue H, Osman I, et al. Deletions of the INK4A gene in superficial bladder tumors: Association with recurrence. Am J Pathol 1999; 155: 105-113.
30. Aveyard JS, Skilleter A, Habuchi T, et al. Somatic mutation of PTEN in bladder carcinoma. Br J Cancer 1999; 80: 904-908.
31. Baffa R, Gomella LG, Vecchione A, et al. Loss of FHIT expression in transitional cell carcinoma of the urinary bladder. Am J Patho 2000; 156: 419-424.
32. Vecchione A, Sevignani C, Giamieri E, et al. Inactivation of the FHIT gene favors bladder cancer development. Clin Cancer Res 2004; 10: 7607-7612.
33. Gromova I, Gromov P, Celis JE. bc10: A noval human bladder cancer-associated protein with a conserved genomic structure downregulated in invasive cancer. Int J Cancer 2002; 98: 539-546.
34. Droller MJ. Current concepts of tumor markers in bladder cancer. Urol Clin North Am 2002; 29: 229-234.
35. Baffa B, Letko J, McClung C,et al. Molecular genetics of bladder cancer: targets for diagnosis and thrapy. J Exp Clin Cancer Res 2006; 25: 145-160.
36. Grossman HB, Messing E, Soloway M, et al. Detection of bladder cancer using a point-of-care proteomic assay. Jama 2005; 293: 810-816.
37. Sanchini MA, Gunelli R, Nanni O, et al. Relevance of urine telomerase in the diagnosis of bladder cancer. Jama 2005; 294: 2052-2056.
38. Orlow I, larue H, Osman I, et al. Deletion of the INK4A gene in superficial bladder tumors: association with recurrence. Am J Pathol 1999; 155: 105-113.
39. Zhao H, Liang D, Grossman HE, et al. Glutathione peroxidase 1 genepolymorphism and risk of recurrence in patients with superficial bladder cancer. Urology 2005; 66: 769-774.
40. Dyrskjot L, Thykjaer T, Kruhoffer M, et al. Identifying distinct classes of bladder carcinoma using microarrays. Nat genet. 2003; 33: 90-96.
41. Kipp BR, Karnes RJ, Brankley SM, et al. Monitoring intravesical therapy for superficial bladder cancer using fluorescence in situ hybridization. J Urol 2005; 173: 401-404.
42. Li M, Gu FL, L WB, et al. Introduction of wild-type p53 gene downregulates the expression of H-ras gene and suppresses the growth of bladder cancer cells. Urol Res 1995; 23: 311-314.
43. Pagliaro LC, Keyhani A, Williams D, et al. Repeated intravesical instillations of an adenoviral vector in patients with locally advanced bladder cancer : a phase I study of p53 gene therapy. J Clin Oncol 2003; 21: 2247-2253.
44. Ries S, Korn WM. ONYX-015: mechanisms of action and clinical potential of a replication-selective adenovirus. Br J Cancer 2002; 86: 5-11.
45. Pan CX, Koeneman KS. A novel tumor-specific gene therapy for bladder cancer. Med Hypotheses 1999; 53: 130-135.
46. Chen SA, Tsai MH, Wu FT, et al. Induction of antitumor immunity with combination of HER2/neu DNA vaccine and interleukin 2 gene-modified tumor vaccine. Clin Cancer Res 2000; 6: 4381-4388.
47. Tanaka M, Koul D, Davies MA, et al. MMAC1/PTEN inhibits cell growth and induces chemosensitivity to doxorubicin in human bladder cancer cells. Oncogene 2000; 19: 5406-5412.
48. Small EJ, Halbi S, Dalbagni G, et al. Overview of bladder cancer trials in the cancer and leukemia group B. Cancer 2003; 97: 2090-2098.
2. Pront GR, Kaufman DS. The national bladder cancer group’s experience: invasive and metastatic bladder cancer selected reports. Seminars in Urology Oncology.2001; 19: 66-68.
3. Kurschat P, Mauch C. Mechanisms of metastasis. Clin Exp Dermatol.2000; 25: 482-489.
4. Dikic I, Giordano S. Negative receptor signaling. Curr Opin Cell Biol 2003; 15: 128–135.
5. Gal G, Chanan R, Menachem K, et al. LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation. The EMBO Journal 2004; 23: 3270-3281.
6. Yarden Y, Sliwkowski MX .Untangling the ErbB signaling network. Nat Rev Mol Cell Biol 2001; 2:1 27–137.
7. Yarden Y. The EGFR family and its ligands in human cancer: signaling mechanisms and therapeutic opportunities. Eur J Cancer.2001; 37: 3-8.
8. Nilsson J, Vallbo C, Guo DS, et al. Cloning,Characterization, and Expression of human LIG1. Biochem Biophys Res Commun 2001; 284: 1155-1161.
9. Holmlund C, Nilsson J, Guo DS, et al. Characterization and tissue-specific expression of human LRIG2. Gene 2004; 332: 35–43.
10. Guo DS, Holmlund C, Henriksson, et al. The LRIG gene family has three vertebrate paralogs widely expressed in human and mouse tissues and a homolog in Ascidiacea. Genomics 2004; 84: 157–165.
1. Nilsson J, Vallbo C, Guo DS, et al. Cloning,Characterization, and Expression of human LIG1. Biochem Biophys Res Commun 2001; 284: 1155-1161.
2. Holmlund C, Nilsson J, Guo DS, et al. Characterization and tissue-specific expression of human LRIG2. Gene 2004; 332; 35–43.
3. Guo DS, Holmlund C, Henriksson, et al. The LRIG gene family has three vertebrate paralogs widely expressed in human and mouse tissues and a homolog in Ascidiacea. Genomics 2004 ; 84; 157–165.
4. Hedman H, Nilsson J,Guo DS, et al. Is LRIG1 a Tumor Suppressor Gene at Chromosome 3p14.3? Acta Oncologica .2002; 41:352–354.
5. Thomasson M, Hedman H, Guo DS, et al. LRIG1 and epidermal growth factor receptor in renal cell carcinoma: a quantitative RT-PCR and immunohistochemical analysis. British J Cancer 2003; 89:1285-1289.
6. Kolibaba, KS, Druker, BJ Protein tyrosine kinases and cancer. Biochim Biophys. Acta 1997; 1333: 217–248.
7. Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 2000; 103: 211–225.
8. Gal G, Chanan R, Menachem K, et al. LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation. The EMBO Journal 2004; 23: 3270-3281.
1. Dikic I, Giordano S. Negative receptor signaling. Curr Opin Cell Biol 2003; 15: 128–135.
2. Gal G, Chanan R, Menachem K, et al. LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation. The EMBO Journal 2004; 23: 3270-3281.
3. Yarden Y, Sliwkowski MX .Untangling the ErbB signaling network. Nat Rev Mol Cell Biol 2001;2:127–137
4. Liebmann C. Regulation of MAP kinase activity by peptide receptor signalling pathway: paradigms of multiplicity. Cell Signal. 2001; 13: 777-785.
5. Klapper LN, Kirschbaum MH, Sela M,et al. Biochemical and clinical implications of the ErbB/HER signaling network of growth factor receptors. Adv Cancer Res 2000; 77: 25-79.
6. Musacchio, M,Perrimon, N. The Drosophila kekkon genes:novel members of both the leucine-rich repeat and immunoglobulin superfamilies expressed in the CNS. Dev. Biol 1996; 178: 63-76.
7. Ghiglione G, Kermit L, Laufey T, et al. The transmembrane molecule kekkon 1 acts in a feedback loop to negatively regulate the activity of the drosophila EGF receptor during oogenesis. Cell 1999; 96: 847-856.
8. Ghiglione G., Laufey T,Margret A, et al. Mechanism of inhibition of the drosophila and mammalian EGF receptors by the transmembrane protein kekkon 1. Development 2003; 130: 4483-4493.
9. Nilsson J, Vallbo C, Guo DS, et al. Cloning,Characterization, and Expression of human LIG1. Biochem Biophys Res Commun 2001; 284:1155-1161.
10. Holmlund C, Nilsson J, Guo DS, et al. Characterization and tissue-specific expression of human LRIG2. Gene 2004;332;35–43.
11. Guo DS, Holmlund C, Henriksson, et al. The LRIG gene family has three vertebrate paralogs widely expressed in human and mouse tissues and a homolog in Ascidiacea. Genomics 2004 ;84;157–165.
1. Nilsson J, Vallbo C, Guo DS, et al. Cloning,Characterization, and Expression of human LIG1. Biochem Biophys Res Commun 2001; 284:1155-1161.
2. Holmlund C, Nilsson J, Guo DS, et al. Characterization and tissue-specific expression of human LRIG2. Gene 2004; 332:35–43.
3. Hedman H, Nilsson J,Guo DS, et al. Is LRIG1 a Tumor Suppressor Gene at Chromosome 3p14.3? Acta Oncologica 2002; 41:352–354.
4. Kolibaba, KS, Druker, BJ Protein tyrosine kinases and cancer. Biochim Biophys. Acta 1997; 1333:217–248.
5. Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 2000; 103: 211–225.
6. Guo DS, Holmlund C, Henriksson, et al. The LRIG gene family has three vertebrate paralogs widely expressed in human and mouse tissues and a homolog in Ascidiacea. Genomics 2004 ; 84: 157–165.
7. Gal G, Chanan R, Menachem K, et al. LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation. The EMBO Journal 2004; 23:3270-3281.
8. Liebmann C. Regulation of MAP kinase activity by peptide receptor signalling pathway: paradigms of multiplicity. Cell Signal. 2001; 13:777-785.
9. Thomasson M, Hedman H, Guo D, et al.LRIG1 and epidermal growth factor receptor in renal cell carcinoma: a quantitative RT-PCR and immunohistochemical analysis. Br J Cancer.2003, 89:1285-1289.
1. Kolibaba, KS, Druker, BJ . Protein tyrosine kinases and cancer. Biochim Biophys. Acta 1997; 1333:217–248.
2. Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 2000; 103:211–225.
3. Nilsson J, Vallbo C, Guo DS, et al. Cloning,Characterization, and Expression of human LIG1. Biochem Biophys Res Commun 2001; 284:1155-1161.
4. Holmlund C, Nilsson J, Guo DS, et al. Characterization and tissue-specific expression of human LRIG2. Gene 2004; 332;35–43.
5. Guo DS, Holmlund C, Henriksson, et al. The LRIG gene family has three vertebrate paralogs widely expressed in human and mouse tissues and a homolog in Ascidiacea. Genomics 2004 ; 84;157–165.
6. Gal G, Chanan R, Menachem K, et al. LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation. The EMBO Journal 2004; 23:3270-3281.
7. Dikic I, Giordano S. Negative receptor signaling. Curr Opin Cell Biol 2003; 15:128–135.
8. Yarden Y, Sliwkowski MX .Untangling the ErbB signaling network. Nat Rev Mol Cell Biol 2001;2:127–137
9. Liebmann C. Regulation of MAP kinase activity by peptide receptor signalling pathway: paradigms of multiplicity. Cell Signal. 2001; 13:777-785.
10. Klapper LN, Kirschbaum MH, Sela M,et al. Biochemical and clinical implications of the ErbB/HER signaling network of growth factor receptors. Adv Cancer Res 2000; 77:25-79.
11. Musacchio, M,Perrimon, N. The Drosophila kekkon genes:novel members of both the leucine-rich repeat and immunoglobulin superfamilies expressed in the CNS. Dev. Biol 1996; 178:63-76.
12. Ghiglione G, Kermit L, Laufey T, et al. The transmembrane molecule kekkon 1 acts in a feedback loop to negatively regulate the activity of the drosophila EGF receptor during oogenesis. Cell 1999; 96:847-856.
13. Ghiglione G., Laufey T,Margret A, et al. Mechanism of inhibition of the drosophila and mammalian EGF receptors by the transmembrane protein kekkon 1. Development 2003; 130: 4483-4493.
14. Iozzo RV, Moscatello DK, McQuillan DJ, et al. Decorin is a biological ligand for the epidermal growth factor receptor. J Biol Chem 1999; 274: 4489–4492.
15. Zhu JX, Goldoni S, Bix G, et al. Decorin evokes protracted internalization and degradation of the epidermal growth factor receptor via caveolar endocytosis. J Biol Chem 2005; 280:3 2468–32479.
16. Suzuki, Y., Sato, N., Tohyama, M., et al. cDNA cloning of a novel membrane glycoprotein that is expressed specifically in glial cells in the mouse brain. LIG-1, aprotein with leucine-rich repeats and immunoglobulin-like domains. J. Biol. Chem 1996; 271: 22522–22527.
17. Petersen I., Bujard M., Petersen S, et al. Patterns of chromosomal imbalances in adenocarcinoma and squamous cell carcinoma of the lung. Cancer Res.1997; 57:2331–2335.
18. S. Knuutila. DNA copy number losses in human neoplasms, Am. J. Pathol. 1999; 155 : 683– 694.
19. G. Reifenberger. Refined mapping of 12q13– q15 amplicons in human malignant gliomas suggests CDK4/SAS and MDM2 as independent amplification targets. Cancer Res.1996; 56: 5141– 5145.
20. Hedman H, Nilsson J,Guo DS, et al. Is LRIG1 a Tumor Suppressor Gene at Chromosome 3p14.3? Acta Oncologica .2002; 41:352–354.
21. Thomasson M, Hedman H, Guo DS, et al. LRIG1 and epidermal growth factor receptor in renal cell carcinoma: a quantitative RT-PCR and immunohistochemical analysis. British J Cancer 2003; 89:1285-1289.
22. Tanemura A, Nagasawa T, Inui S, et al. LRIG-1 provides a novel prognostic predictor in squamous cell carcinoma of the skin: immunohistochemical analysis for 38 cases. Dermatal Surg 2005; 31: 423-430.
23. Welsh JB, Sapinoso LM, Su AI, et al. Analysis of gene expression identifies candidate markers and pharmacological targets in prostate cancer. Cancer Res 2001; 61: 5974–6978.
24. Laederich MB, Funes-Duran M, Yen L, et al. The leucinerich repeat protein LRIG1 is a negative regulator of ErbB family receptor tyrosine kinases. J Biol Chem 2004; 279: 47050–47056.
25. Jensen KB,Watt FM. Single-cell expression profiling of human epidermal stem and transit-amplifying cells: Lrig1 is a regulator of stem cell quiescence. Proc Natl Acad Sci USA 2006; 103: 11958–11963.
26. Yang WM, Yan ZJ, Ye ZQ, Guo DS. LRIG1, a candidate tumoursuppressor gene in human bladder cancer cell line BIU87. BJU Int 2006; 98: 898–902.
27. Bhattacharjee A, Richards WG, Staunton J, et al. Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci USA 2001; 98: 13790–13795.
28. Hedman H, Henriksson R. LRIG inhibitors of growth factor signaling——double-edged swords in human cancer? Euro J Cancer 2007; 43: 676-682.
29. Salomon DS, Brandt R, Ciardiello F, et al. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995; 19: 183–232.
30. Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 2006; 7: 505–516.
31. Barnes DW. Epidermal growth factor inhibits growth of A431 human epidermoid carcinoma in serum-free cell culture. J Cell Biol 1982; 93: 1–4.
32. Gulli LF, Palmer KC, Chen YQ, et al. Epidermal growth factorinduced apoptosis in A431 cells can be reversed by reducingthe tyrosine kinase activity. Cell Growth Differ 1996; 7: 173–178.
33. Gullick WJ. c-erbB-4/HER4: friend or foe? J Pathol 2003; 200: 279–281.
34. Witton CJ, Reeves JR, Going JJ, et al. Expression of the HER1-4 family of receptor tyrosine kinases in breast cancer. J Pathol 2003; 200: 290–297.
35. Williams EE, Trout LJ, Gallo RM, et al. A constitutively active ErbB4 mutant inhibits drug-resistant colony formation by the DU-145 and PC-3 human prostate tumor cell lines. Cancer Lett 2003; 192: 67–74.
36. Thomasson M, Hedman H, Junttila TT, et al. ErbB4 is downregulated in renal cell carcinoma: a quantitative RT-PCR and immunohistochemical analysis of the epidermal growth factor receptor family. Acta Oncol 2004; 43: 453–459.
37. Guo D, Nilsson J, Haapasalo H, et al. Perinuclear leucine-rich repeats and immunoglobulin-like domain proteins (LRIG1-3) as prognostic indicators in astrocytic tumors. Acta Neuropathol 2006; 111: 238–246.
38. Febbo PG, Lowenberg M, Thorner AR, et al. Androgen mediated regulation and functional implications of fkbp51 expression in prostate cancer. J Urol 2005; 173: 1772–1777.
39. Ljuslinder I, Malmer B, Golovleva I, et al. Increased copy number at 3p14 in breast cancer. Breast Cancer Res 2005; 7: 719–727.
40. Kauraniemi P, Barlund M, Monni O, et al. New amplified and highly expressed genes discovered in the ERBB2 amplicon in breast cancer by cDNA microarrays. Cancer Res 2001; 61: 8235–8240.
1. El-Gabry EA, Strup SE, Gomella LG, et al. Superficial bladder cancer-current treatment modalities and future directions part I&II. AUA Updates Series 2000:20.
2. Gonzalgo ML, Schoenberg MP, Rodriguez R. Biological pathways to bladder carcinogenesis. Semin Urol Oncol 2000; 18:256-263.
3. Brandau S, Bohle A. Bladder cancer I molecular and genetic bassi of carcinogenesis Eruo Urol 2001; 39: 491-497.
4. Reznikoff CA, Sarkar S, Julicher KP, et al. Genetic alterations and biological pathways in human bladder cancer pathogenesis. Urol Oncol 2000; 5: 191-203.
5. Barbacid M. Ras genes. Annu Rev Biochem 1987; 56: 779-827.
6. Rabbani F, Cordon-Cardo C. Mutation of cell cycle regulations and their impact on superficial bladder cancer. Urol Clin Nroth Am 2000; 27: 83-89.
7. Moriyama M, Akiyama T, Yamamoto T, et al. Expression of c-erbB-2 gene product in urinary bladder cancer. J Urol 1991; 145: 423-427.
8. Jimenez RE, Hussain M, Binaco FJ Jr, et al. Her-2/neu overexpression in muscle-invasive urothelial carcinoma of the bladder: prognostic significance and comparative analysis in primary and metastatic tumors. Clin Cancer Res 2001; 7: 2440-2447.
9. Messing EM. Clinical implications of the expression of epidermal growth factor receptors in human transitional cell carcinoma. Cancer Res 1990; 50: 2530-2537.
10. Mellon K, Wright C, Kelly P, et al. Long-term outcome related to epidermal growth factor receptor status in bladder cancer. J Urol 1995; 153: 919-925.
11. Oliner JD, Kinzler KW, Meltzer PS, et al. Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature 1992; 358: 80-83.
12. Shiina H, Igawa M, Shigeno K, et al. Clinical significance of mdm2 and p53expression in bladder cancer: A comparison with cell proliferation and apoptosis. Oncology 1999; 56: 239-247.
13. Zhou H, Kuang J, Zhong L, et al. Tumor amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet 1998; 20:189-193.
14. Sen S, Zhou H, Zhang RD, et al. Amplification/overexpression of a mitotic kinase gene in human bladder cancer. J Natl Cancer Inst 2002; 94: 1320-1329.
15. Kretzner L, Blackwood EM, Eisenman RN. Myc and Max proteins possess distinct transcriptional activities. Nature 1992; 359: 426-429.
16. Mahdy E, Pan Y, Wang N, et al. Chromosome 8 numerical aberration and C-MYC copy number gain in bladder cancer are linked to stage and grade. Anticancer Res 2001; 21: 3167-3173.
17. Bringuier PP, Tamimi Y, Schuuring E, et al. Expression of cyclin D1 and EMS1 in bladder tumors: relationship with chromosome 11q13 amplification. Oncogene 1996; 12: 1747-1753.
18. Watters AD, Latif Z, Forsyth A, et al. Genetic aberrations of c-myc and CCND1 in the development of invasive bladder cancer. Br J Cancer 2002; 87: 654-658.
19. Duggan BJ, Kelly JD, Keane PF, et al. Molecular targets for the therapeutic manipulation of apoptosis in bladder cancer. J Urol 2001; 165: 946-965.
20. Lu ML, Wikman F, Orntoft TF, et al. Impact of alterations affecting the p53 pathway in bladder cancer on clinical outcome, assessed by conventional and array-based methods. Clin Cancer Res 2002; 8: 171-179.
21. Sarkis AS, Bajorin DF, Reuter VE, et al. Prognostic value of p53 nuclear overexpression in patients with invasive bladder cancer treated with neoadjuvant MVAC. J Clin Oncol 1995; 13: 1384-1390.
22. Cote RJ, Datar RH. Therapeutic approaches to bladder cancer: identifying targets and mechanisms. Crit Rev Oncol Hematol 2003; 46 Suppl: 67-83.
23. Nevins JR, Leone G, Degregori J, et al. Role of the RB/E2F pathway in cell growth control. J Cell Physiol 1997; 173: 233-236.
24. Xu HJ, Cairns P, Hu SX, et al. Loss of RB protein expression in primary bladder cancer correlates with loss of heterozygosity at the RB locus and tumor progression. Int J Cancer 1993; 53: 781-784.
25. Grossman HB, Liebert M, Antelo M, et al. p53 and RB expression predict progression in T1 bladder cancer. Clin Cancer Res 1998; 4: 829-834.
26. Lacombe L, Orlow I, Silver D, et al. Analysis of p21AAF1/CIP1 in primary bladder tumors. Oncol Res 1996; 8: 409-414.
27. Shariat SF, Kim J, Raptidis G, et al. Association of p53 and p21 expression with clinical outcome in patients with carcinoma in situ of the urinary bladder. Urology 2003; 61: 1140-1145.
28. Korkolopoulou P, Christodoulou P, Konstantinidou AE, et al. Cell cycle regulators in bladder cancer: a multivariate survival study with emphasis on p27Kip1. Hum Pathol 2000; 31: 751-760.
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