CHK1在膀胱良恶性病变组织中的表达及其意义
摘要
目的：检测细胞周期检测点激酶1(CHK1)在人的膀胱良恶性组织中的表达,并初步探讨其临床意义。
方法：采用免疫组化EnVision法对40例膀胱移行细胞癌组织和20例慢性膀胱炎组织中的CHK1的表达进行检测,通过统计学方法分析其表达情况。
结果：CHK1在膀胱癌组的表达明显强于对照组,差异有统计学意义(P<0.01)。随着肿瘤临床病理分期的增高,CHK1的表达明显增强(P<0.05)。在膀胱癌不同病理组织学分级Ⅰ、Ⅱ、Ⅲ级组织中CHK1的表达有显著性差异(P<0.05)。
结论：CHK1在膀胱组织中呈现不同表达,在膀胱癌组织中存在高度表达；且CHK1的表达与肿瘤的临床病理分期和病理组织学分级有关,CHK1可能成为比较理想的膀胱移行细胞癌治疗靶点,并对预测肿瘤的预后有一定的意义。
Objective:To investigate the relationship of expression of CHK1in human bladder benign and malignant tissue and its significance.
Methods:immunohistochemistry was used to detect the expression of CHK1 in 40 cases of the human bladder transitional cell carcinoma tissue; and 20 cases of the human chronic cystitis tissue. Statistics was used to analyze the data. By comparing range and degree of CHK1 positive staining, judging the corrilations of CHK1 between each other.
Results:The expression of CHK1 in bladder malignant tissue group was extremely stronger than in bladder benign tissue group (p<0.01). There was significant difference for CHK1 expression in cancer cells between superficial bladder cancer and invasive bladder cancer (p<0.05). There was also significant difference for CHK1 expression in different pathologic grade(p<0.05).
Conclusions:(1)There was significant difference for CHK1 expression in different bladder tissue, and high expression in bladder cancer. (2)Be closely related with clinical stage and pathologic grade of tumor, CHK1 might be the ideal targets for bladder transitional cell carcinoma, And CHK1 might be significant in predicting clinical stage and pathologic grade.
方法：采用免疫组化EnVision法对40例膀胱移行细胞癌组织和20例慢性膀胱炎组织中的CHK1的表达进行检测,通过统计学方法分析其表达情况。
结果：CHK1在膀胱癌组的表达明显强于对照组,差异有统计学意义(P<0.01)。随着肿瘤临床病理分期的增高,CHK1的表达明显增强(P<0.05)。在膀胱癌不同病理组织学分级Ⅰ、Ⅱ、Ⅲ级组织中CHK1的表达有显著性差异(P<0.05)。
结论：CHK1在膀胱组织中呈现不同表达,在膀胱癌组织中存在高度表达；且CHK1的表达与肿瘤的临床病理分期和病理组织学分级有关,CHK1可能成为比较理想的膀胱移行细胞癌治疗靶点,并对预测肿瘤的预后有一定的意义。
Objective:To investigate the relationship of expression of CHK1in human bladder benign and malignant tissue and its significance.
Methods:immunohistochemistry was used to detect the expression of CHK1 in 40 cases of the human bladder transitional cell carcinoma tissue; and 20 cases of the human chronic cystitis tissue. Statistics was used to analyze the data. By comparing range and degree of CHK1 positive staining, judging the corrilations of CHK1 between each other.
Results:The expression of CHK1 in bladder malignant tissue group was extremely stronger than in bladder benign tissue group (p<0.01). There was significant difference for CHK1 expression in cancer cells between superficial bladder cancer and invasive bladder cancer (p<0.05). There was also significant difference for CHK1 expression in different pathologic grade(p<0.05).
Conclusions:(1)There was significant difference for CHK1 expression in different bladder tissue, and high expression in bladder cancer. (2)Be closely related with clinical stage and pathologic grade of tumor, CHK1 might be the ideal targets for bladder transitional cell carcinoma, And CHK1 might be significant in predicting clinical stage and pathologic grade.
引文
[1]Gsehwend JE, Fair WR, Vieweg J. Radical Cystectomy for invasive bladder cancer:contemporary results and remaining controversies. Eur Urol,2000,38:121-130.
[2]Kaneko YS, Watanabe N, Morisaki H, et al. Cell-cycle-dependent and ATM-independent expression of human Chkl kinase[J]. Oncogene,1999, 18(25):3673-3681.
[3]Wong CF, Guminski A, Saunders NA, et al. Exploiting novel cell cycle targets in the development of anticancer agents [J]. Curr Cancer Drug Targets,2005,5(2):85-102.
[4]GATEL M, SLOPER K, SORENSEN C, et al.ATM and DBS1 dependent phosphorylation of Chkl on S317 in response to IR[J]. J Biol Chem,2003, 278(17):14806-14811.
[5]Bartek J, Lukas J. CHK1 and CHK2 kinases in checkpoint control and cancer[J]. Cancer Cell,2003,3(5):421-429.
[6]Zhou BB, Bartek J. Targeting the checkpoint kinases; hemosensitization versus chemoprotection[J]. Nat Rev Cancer,2004, 4(3):216-225.
[7]Kawabe T. G2 checkpoint abrogators as anticancer drugs. Mol Cancer Ther,2004,3:513-519.
[1]江瑞胜等。细胞生物学杂志,2004,26：209.
[2]Zhou BB et al. Nature,2000,408:433.
[3]Chen Y et al. DNA Repair(Amst),2004,3:1025.
[4]GATEL M, SLOPER K, SORENSEN C, et al.ATM and DBS1 dependent phosphorylation of Chkl on S317 in response to IR[J]. J Biol Chem,2003,278(17): 14806-14811.
[5]Bartek J, Lukas J. CHK1 and CHK2 kinases in checkpoint control and cancer[J]. Cancer Cell,2003,3(5):421-429.
[6]Katsuragi Y et al.Mol Biol Cell,2004,15:1680.
[7]Ng CP et al. J Biol Chem,2004,279:8808
[8 Zhao B et al. J Biol Chem,2002,277:46609.
[9]Kaneko YS, Watanabe N, Morisaki H, et al. Cell-cycle-dependent and ATM-independent expression of human Chkl kinase[J]. Oncogene,1999, 18(25):3673-3681.
[10]Wong CF, Guminski A, Saunders NA, et al. Exploiting novel cell cycle targets in the development of anticancer agents[J]. Curr Cancer Drug Targets, 2005,5(2):85-102.
[11]Ward IM, Minn K,Chen J. UV-induced ataxia-telangiec-tasia-mutated and Rad3Vrelated(ATR) activation requires replication stress[J].J Biol Chem, 2004,279(11):1178-1187.
[12]Pichierri P, Rosselli F. The DNA crosslink-induced Sphase checkpoint depends on ATR-CHK1 and ATR-NBS1-FANCD2 pathways[J].EMBO J, 2004,23(5):1178-1187.
[13]Jazayeri A, Falck J,Luckas C, et al. ATM and cell cycle depentent regulation of ATR in response to DNA double strand breaks Nat Cell Biol,2006,8(1):37.
[14]Helleday T, Petermann T, Lundinl C, et al. DNA repair pathways as targets for cancer therapy. Nat Rev Cancer,2008,8(3):193.
[15]Feijoo C, Hall-Jackson C,Wu R, et al. Activation of mammalian Chkl during DNA replication arrest:a role for Chk1 in the intra-S phase checkpoint monitoring replication origin firing[J].J Cell Biol,2001,154(5):913-923.
[16]Sorensen CS,Syljuasen RG, Lukas J, et al.ATR, Claspin and the Rad9-Radl-Husl complex regulate Chkl and Cdc25A in the absence of DNA damage [J]. Cell Cycle,2004,3(7):941-945.
[17]Zhou XY,Wang X,Hu B, et al. An ATM-independent sphase checkpoint response involves CHK1 pathway [J].Cancer Res,2002,62(6):1598-1603.
[18]Sorensen CS,Syljuasen RG, Falck J, et al. Chkl regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A[J]. Cancer Cell,2003,3(3):247-258.
[19]Wang H, Hu B, Liu R, et al.CHK1 Affecting Cell radiosensitivity is independent of non-homologous end joining[J]. Cell Cycle,2005,4(2):In press.
[20]Wang X, Khadpe J, Hu B, et al. An overactivated ATR/CHK1 pathway is responsible for the prolonged G2 accumulation in irradiated AT cell[J] J Biol Chem, 2003,278(33):30869-30874.
[21]Luo Y, Rockow-Magnone SK, Kroeger PE, et al. Blocking Chkl expression induces apoptosis and abrogates the G2 checkpoint mechanism[J]. Neoplasia, 2001,3(5):411-419.
[22]Shao RG, Cao CX, Pommier Y. Abrogation of CHK1-mediated S/G2 checkpoint by UCN-01 enhances ara-C-induced cytotoxicity in human colon cancer cekks[J]. Acta Pharmacol Sin,2004,25(6):756-762.
[23]Ward IM et al. J Biol Chem,2004,279:9677.
[24]Jurvansuu J et al. J Virol,2005,79:569.
[25]Zimmerman ES et al. Mol Cell Biol,2004,24:9286.
[26]Ou YH et al. Mol Biol Cell,2005,16:1684.
[27]Zhou Bbet al. Nature,2000,408:433.
[28]Das KC et al. Am J Physiol Lung Cell Mol Physiol,2004,286:87.
[29]George Z.Michael DR. David AFC. CHK1-deficient tumor cells are viable but exhibit multiple checkpoint and survival defecy. EMBO J,2003,22:713-723.
[30]Wang Y. Deeker SJ. Sebolt-Leopold J. Knockdown of chkl, Weel and Myll by RNA interference abrogates G(2) checkpoint and induces apoptosis. Cancer Biol Ther.2004,3:305-313.
[31]Chen Z. Xiao Zh, Chen J, et al. Human chkl expession is dispensable for somatic cell death and critical for sustaining G2 DNA damage checkpoint. Mol Cancer Ther,2003,2:543-48.
[32]Carrassa L, Broggmi M, Erba E, et al. Chkl but not Chk2, is involved in the cellular response to DNA damaging agents:differential activity in cells expressing, or not p53. Cell Cycle,2004,3(9):1177-81.
[33]Lam MH, Lin Q, Elledge SJ, Chkl is haploinsufficient for multiple functions critical to tumor suppression. Cancer Cell,2004,6:45-58.
[34]Liu Q,Guntuku S, Cui XS. Et al. Chkl is an essential kinase that is regulated by Atr and required for the G2/M DNA damage checkpoint. Genes Dev.2000,14: 1448-59.
[35]Yin MB, Hapke G,Wu J, et al. Chkl signaling pathways that mediated G2/M checkpoint in relation to cellular resistance to the novel topoisomerase 1 poison BNP1350. Bio-chem Biophus Res Commun,2002,295:435-44.
[36]Hattori H, Kuroda M, Ishida T, et al. Human DNA damage checkpoints and their relevance to soft tissue sarcoma. Int Pathol,2004,54:26-31.
[37]黄伟等。中国实验血液学杂志,2004,12：563.
[2]Kaneko YS, Watanabe N, Morisaki H, et al. Cell-cycle-dependent and ATM-independent expression of human Chkl kinase[J]. Oncogene,1999, 18(25):3673-3681.
[3]Wong CF, Guminski A, Saunders NA, et al. Exploiting novel cell cycle targets in the development of anticancer agents [J]. Curr Cancer Drug Targets,2005,5(2):85-102.
[4]GATEL M, SLOPER K, SORENSEN C, et al.ATM and DBS1 dependent phosphorylation of Chkl on S317 in response to IR[J]. J Biol Chem,2003, 278(17):14806-14811.
[5]Bartek J, Lukas J. CHK1 and CHK2 kinases in checkpoint control and cancer[J]. Cancer Cell,2003,3(5):421-429.
[6]Zhou BB, Bartek J. Targeting the checkpoint kinases; hemosensitization versus chemoprotection[J]. Nat Rev Cancer,2004, 4(3):216-225.
[7]Kawabe T. G2 checkpoint abrogators as anticancer drugs. Mol Cancer Ther,2004,3:513-519.
[1]江瑞胜等。细胞生物学杂志,2004,26：209.
[2]Zhou BB et al. Nature,2000,408:433.
[3]Chen Y et al. DNA Repair(Amst),2004,3:1025.
[4]GATEL M, SLOPER K, SORENSEN C, et al.ATM and DBS1 dependent phosphorylation of Chkl on S317 in response to IR[J]. J Biol Chem,2003,278(17): 14806-14811.
[5]Bartek J, Lukas J. CHK1 and CHK2 kinases in checkpoint control and cancer[J]. Cancer Cell,2003,3(5):421-429.
[6]Katsuragi Y et al.Mol Biol Cell,2004,15:1680.
[7]Ng CP et al. J Biol Chem,2004,279:8808
[8 Zhao B et al. J Biol Chem,2002,277:46609.
[9]Kaneko YS, Watanabe N, Morisaki H, et al. Cell-cycle-dependent and ATM-independent expression of human Chkl kinase[J]. Oncogene,1999, 18(25):3673-3681.
[10]Wong CF, Guminski A, Saunders NA, et al. Exploiting novel cell cycle targets in the development of anticancer agents[J]. Curr Cancer Drug Targets, 2005,5(2):85-102.
[11]Ward IM, Minn K,Chen J. UV-induced ataxia-telangiec-tasia-mutated and Rad3Vrelated(ATR) activation requires replication stress[J].J Biol Chem, 2004,279(11):1178-1187.
[12]Pichierri P, Rosselli F. The DNA crosslink-induced Sphase checkpoint depends on ATR-CHK1 and ATR-NBS1-FANCD2 pathways[J].EMBO J, 2004,23(5):1178-1187.
[13]Jazayeri A, Falck J,Luckas C, et al. ATM and cell cycle depentent regulation of ATR in response to DNA double strand breaks Nat Cell Biol,2006,8(1):37.
[14]Helleday T, Petermann T, Lundinl C, et al. DNA repair pathways as targets for cancer therapy. Nat Rev Cancer,2008,8(3):193.
[15]Feijoo C, Hall-Jackson C,Wu R, et al. Activation of mammalian Chkl during DNA replication arrest:a role for Chk1 in the intra-S phase checkpoint monitoring replication origin firing[J].J Cell Biol,2001,154(5):913-923.
[16]Sorensen CS,Syljuasen RG, Lukas J, et al.ATR, Claspin and the Rad9-Radl-Husl complex regulate Chkl and Cdc25A in the absence of DNA damage [J]. Cell Cycle,2004,3(7):941-945.
[17]Zhou XY,Wang X,Hu B, et al. An ATM-independent sphase checkpoint response involves CHK1 pathway [J].Cancer Res,2002,62(6):1598-1603.
[18]Sorensen CS,Syljuasen RG, Falck J, et al. Chkl regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A[J]. Cancer Cell,2003,3(3):247-258.
[19]Wang H, Hu B, Liu R, et al.CHK1 Affecting Cell radiosensitivity is independent of non-homologous end joining[J]. Cell Cycle,2005,4(2):In press.
[20]Wang X, Khadpe J, Hu B, et al. An overactivated ATR/CHK1 pathway is responsible for the prolonged G2 accumulation in irradiated AT cell[J] J Biol Chem, 2003,278(33):30869-30874.
[21]Luo Y, Rockow-Magnone SK, Kroeger PE, et al. Blocking Chkl expression induces apoptosis and abrogates the G2 checkpoint mechanism[J]. Neoplasia, 2001,3(5):411-419.
[22]Shao RG, Cao CX, Pommier Y. Abrogation of CHK1-mediated S/G2 checkpoint by UCN-01 enhances ara-C-induced cytotoxicity in human colon cancer cekks[J]. Acta Pharmacol Sin,2004,25(6):756-762.
[23]Ward IM et al. J Biol Chem,2004,279:9677.
[24]Jurvansuu J et al. J Virol,2005,79:569.
[25]Zimmerman ES et al. Mol Cell Biol,2004,24:9286.
[26]Ou YH et al. Mol Biol Cell,2005,16:1684.
[27]Zhou Bbet al. Nature,2000,408:433.
[28]Das KC et al. Am J Physiol Lung Cell Mol Physiol,2004,286:87.
[29]George Z.Michael DR. David AFC. CHK1-deficient tumor cells are viable but exhibit multiple checkpoint and survival defecy. EMBO J,2003,22:713-723.
[30]Wang Y. Deeker SJ. Sebolt-Leopold J. Knockdown of chkl, Weel and Myll by RNA interference abrogates G(2) checkpoint and induces apoptosis. Cancer Biol Ther.2004,3:305-313.
[31]Chen Z. Xiao Zh, Chen J, et al. Human chkl expession is dispensable for somatic cell death and critical for sustaining G2 DNA damage checkpoint. Mol Cancer Ther,2003,2:543-48.
[32]Carrassa L, Broggmi M, Erba E, et al. Chkl but not Chk2, is involved in the cellular response to DNA damaging agents:differential activity in cells expressing, or not p53. Cell Cycle,2004,3(9):1177-81.
[33]Lam MH, Lin Q, Elledge SJ, Chkl is haploinsufficient for multiple functions critical to tumor suppression. Cancer Cell,2004,6:45-58.
[34]Liu Q,Guntuku S, Cui XS. Et al. Chkl is an essential kinase that is regulated by Atr and required for the G2/M DNA damage checkpoint. Genes Dev.2000,14: 1448-59.
[35]Yin MB, Hapke G,Wu J, et al. Chkl signaling pathways that mediated G2/M checkpoint in relation to cellular resistance to the novel topoisomerase 1 poison BNP1350. Bio-chem Biophus Res Commun,2002,295:435-44.
[36]Hattori H, Kuroda M, Ishida T, et al. Human DNA damage checkpoints and their relevance to soft tissue sarcoma. Int Pathol,2004,54:26-31.
[37]黄伟等。中国实验血液学杂志,2004,12：563.