p21ras、TBK1、bcl-xl在胰腺癌中的表达及意义
摘要
目的
探讨胰腺癌组织中p21ras、TBK1与bcl-xl的表达情况,研究三者表达变化的关系及三者与胰腺癌的临床分期、组织分化程度、淋巴转移、性别及年龄的关系。从而为胰腺癌的治疗寻找新靶点提供丰富的理论依据。
方法
1.对50例胰腺癌组织石蜡标本连续切片6-8张,一部分用于HE染色在光镜下观察组织形态,另一部分用于免疫组织化学染色,同时查阅临床资料确定临床分期。
2.采用免疫组织化学两步法,检测胰腺癌标本50例、癌旁正常胰腺组织20例中p21ras、TBK1和bcl-xl的蛋白表达情况,并结合临床资料对照分析。
结果
50例胰腺癌中p21ras、TBK1和bcl-xl的阳性表达率分别为76 %(38/50),70%(35/50)和66 %(33/50)。癌旁正常胰腺组织中,三者表达的阳性率分别为0%(0/20)、20%(4/20)和25%(5/20)。三种蛋白在胰腺癌组织中的表达均显著高于癌旁正常胰腺组织,胰腺癌组与癌旁正常组织组差异具有显著性(P<0.05)。TBK1、bcl-xl在不同性别、年龄、部位之间无明显差异(P>0.05),而在不同分化程度的组织表达差异明显(P<0.05)。本研究发现p21ras蛋白表达与胰腺癌淋巴转移无明显相关(P>0.05)。TBK1与p21ras、TBK1与bcl-xl的表达呈正相关(P<0.05)、p21ras与bcl-xl的表达呈正相关(P<0.05)。
结论
1.胰腺癌组织中TBK1、bcl-xl高表达,且与分化程度、临床分期及淋巴结转移关系密切,表明TBK1参与了胰腺癌的发生、发展、侵袭及转移的过程,可能是重要的肿瘤标记物及胰腺癌恶性程度的指标,表明bcl-xl与抑制胰腺癌细胞凋亡有关。
2.p21ras的表达与TBK1与bcl-xl的过表达正相关,提示K-ras基因突变可上调TBK1与bcl-xl的过表达,TBK1可能在K-ras基因突变诱导肿瘤发生发展中起了关键作用。
Objective
To study the expression of p21ras,TBK1 and bcl-xl, and study the relationship among the three ,with clinical stage, histological differentiation, lymph node metastasis, gender and age. provide a rich theoretical basis to find a new target for the treatment of pancreatic cancer. Methods
1. Fifty cases of pancreatic cancer tissue specimens were sected serial for six-eight sheets. One part for HE staining and under light microscope for morphology observation, the other part for immunohistochemical staining. At the same time access to clinical data to determine the clinical stage.
2. To detect fifty cases pancreatic cancer specimens and twenty cases of adjacent normal tissues of the protein expression of p21ras,TBK1 and bcl-xl by Two-step immunohistochemical method ,and comparative analysis the combined with clinical data.
Results
The protein expression of p21ras, TBK1, and bcl-xl were 76% (38/50), 70% (35/50) and 66% (33/50) in 50 cases of pancreatic cancer. Adjacent normal pancreatic tissue, the three proteins positive rates were 0% (0/20), 20% (4/20) and 25% (5/20). The three Proteins were significantly in pancreatic cancer tissues higher than in adjacent normal pancreatic tissue, pancreatic cancer group and normal tissues was significant difference between groups, (P <0.05). TBK1, bcl-xl in different gender, age, had no significant difference between sites (P>0.05) .the degree of differentiation in different tissues was significantly different (P<0.05). And this study did not find the protein expression of p21ras with lymph node metastasis of pancreatic cancer was significantly associated (P>0.05). TBK1 and p21ras, TBK1 and bcl-xl expression was positively correlated (P <0.05); p21ras and bcl-xl expression was positively correlated (P <0.05).
Conclusion .
1. The overexpression of TBK1, bcl-xl in pancreatic cancer, and with differentiation, clinical stage and lymph node metastasis, suggesting that TBK1 involved in pancreatic cancer development, invasion and metastasis process, may be important for tumor markers and indicators of malignant pancreatic cancer, suggesting that inhibition of bcl-xl and pancreatic cancer cell apoptosis.
2. The overexpression of p21ras and overexpression of TBK1、bcl-xl are positive correlation, suggesting that K-ras gene mutation may be increased TBK1 and bcl-xl over-expression, TBK1 may induce K-ras gene mutations in tumor development has played a key effect.
探讨胰腺癌组织中p21ras、TBK1与bcl-xl的表达情况,研究三者表达变化的关系及三者与胰腺癌的临床分期、组织分化程度、淋巴转移、性别及年龄的关系。从而为胰腺癌的治疗寻找新靶点提供丰富的理论依据。
方法
1.对50例胰腺癌组织石蜡标本连续切片6-8张,一部分用于HE染色在光镜下观察组织形态,另一部分用于免疫组织化学染色,同时查阅临床资料确定临床分期。
2.采用免疫组织化学两步法,检测胰腺癌标本50例、癌旁正常胰腺组织20例中p21ras、TBK1和bcl-xl的蛋白表达情况,并结合临床资料对照分析。
结果
50例胰腺癌中p21ras、TBK1和bcl-xl的阳性表达率分别为76 %(38/50),70%(35/50)和66 %(33/50)。癌旁正常胰腺组织中,三者表达的阳性率分别为0%(0/20)、20%(4/20)和25%(5/20)。三种蛋白在胰腺癌组织中的表达均显著高于癌旁正常胰腺组织,胰腺癌组与癌旁正常组织组差异具有显著性(P<0.05)。TBK1、bcl-xl在不同性别、年龄、部位之间无明显差异(P>0.05),而在不同分化程度的组织表达差异明显(P<0.05)。本研究发现p21ras蛋白表达与胰腺癌淋巴转移无明显相关(P>0.05)。TBK1与p21ras、TBK1与bcl-xl的表达呈正相关(P<0.05)、p21ras与bcl-xl的表达呈正相关(P<0.05)。
结论
1.胰腺癌组织中TBK1、bcl-xl高表达,且与分化程度、临床分期及淋巴结转移关系密切,表明TBK1参与了胰腺癌的发生、发展、侵袭及转移的过程,可能是重要的肿瘤标记物及胰腺癌恶性程度的指标,表明bcl-xl与抑制胰腺癌细胞凋亡有关。
2.p21ras的表达与TBK1与bcl-xl的过表达正相关,提示K-ras基因突变可上调TBK1与bcl-xl的过表达,TBK1可能在K-ras基因突变诱导肿瘤发生发展中起了关键作用。
Objective
To study the expression of p21ras,TBK1 and bcl-xl, and study the relationship among the three ,with clinical stage, histological differentiation, lymph node metastasis, gender and age. provide a rich theoretical basis to find a new target for the treatment of pancreatic cancer. Methods
1. Fifty cases of pancreatic cancer tissue specimens were sected serial for six-eight sheets. One part for HE staining and under light microscope for morphology observation, the other part for immunohistochemical staining. At the same time access to clinical data to determine the clinical stage.
2. To detect fifty cases pancreatic cancer specimens and twenty cases of adjacent normal tissues of the protein expression of p21ras,TBK1 and bcl-xl by Two-step immunohistochemical method ,and comparative analysis the combined with clinical data.
Results
The protein expression of p21ras, TBK1, and bcl-xl were 76% (38/50), 70% (35/50) and 66% (33/50) in 50 cases of pancreatic cancer. Adjacent normal pancreatic tissue, the three proteins positive rates were 0% (0/20), 20% (4/20) and 25% (5/20). The three Proteins were significantly in pancreatic cancer tissues higher than in adjacent normal pancreatic tissue, pancreatic cancer group and normal tissues was significant difference between groups, (P <0.05). TBK1, bcl-xl in different gender, age, had no significant difference between sites (P>0.05) .the degree of differentiation in different tissues was significantly different (P<0.05). And this study did not find the protein expression of p21ras with lymph node metastasis of pancreatic cancer was significantly associated (P>0.05). TBK1 and p21ras, TBK1 and bcl-xl expression was positively correlated (P <0.05); p21ras and bcl-xl expression was positively correlated (P <0.05).
Conclusion .
1. The overexpression of TBK1, bcl-xl in pancreatic cancer, and with differentiation, clinical stage and lymph node metastasis, suggesting that TBK1 involved in pancreatic cancer development, invasion and metastasis process, may be important for tumor markers and indicators of malignant pancreatic cancer, suggesting that inhibition of bcl-xl and pancreatic cancer cell apoptosis.
2. The overexpression of p21ras and overexpression of TBK1、bcl-xl are positive correlation, suggesting that K-ras gene mutation may be increased TBK1 and bcl-xl over-expression, TBK1 may induce K-ras gene mutations in tumor development has played a key effect.
引文
[1]Nakada Y, Saito S , Ohzawa K, et al . Antisense oligonucleotides specific to mutated K- ras genes inhibit invasiveness of human pancreatic cancer cell lines [J] . Pancreatology,2001,1 (4) : 314～319
[2]任玥欣,许国铭,李兆申,刘枫.k-ras基因在胰腺癌和慢性胰腺炎中突变和表达异常及其临床意义[J].世界华人消化杂志,2004,3(39):664-666
[3]李兆申,潘雪,任钥欣.慢性胰腺炎、胰腺癌组织中血管生成与ras基因产物p21蛋白表达的关系及意义[J] .胰腺学,2001,1(1) :8
[4]张瑞奎,窦科峰,李开宗.p21ras蛋白表达在胰腺癌中的临床意义[J].中国普通外科杂志,2004 ,13(6) :467)
[5]Peters RT, Maniatis T. A new family of IKK-related kinases may function as I kappa B kinase kinases[J]. Biochim Biophys Acta ,2001, 1471:M57–62.
[6] Dung-Fang Lee1, and Mien-Chie Hung. Advances in Targeting IKK and IKK-Related Kinases for CancerTherapy[J].Clin Cancer Res, 2008 , 14(18): 5656–5662.
[7]Perkins ND. Integrating cell-signalling pathways with NF-κB and IKK function[J] .Nat Rev Mol Cell Biol,2007,8:49–62.
[8]Barbie, D. A. et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1[J] .Nature ,2009,462:108–112
[9]邢飞跃,赵克森,姜勇.NF-κB的信号通路与阻断策略[J].中国病理生理杂志, 2003,19 (6) : 849 - 855。
[10]蒋奎荣,刘训良,苗毅等.逆转录病毒载体介导反义K-ras基因治疗胰腺癌的实验研究[J].世界华人消化杂志, 2004, 12( 11): 26-27
[11] Bonnard M, Mirtsos C, Suzuki S, et al. Deficiency of T2K leads to apoptotic liver dege- neration and impaired NF-κB-dependent gene transcription[J].EMBO J ,2000,19:4976–4985
[12]Tojima Y,Fujimoto A,Delhase M, et al. NAK is an IκB kinase-activating kinase[J]. Nature, 2000,404:778–782
[13]Korherr C,Gille H,Schafer R, et al. Identification of proangiogenic genes and pathways by highthrough-put functional genomics: TBK1 and the IRF3 pathway[J]. Proc Natl Acad Sci U S A ,2006,103:4240–4245
[14]Godl K,Gruss OJ,Eickhoff J,et al. Proteomic characterization of the angiogenesis inhibitor SU6668 reveals multiple impacts on cellular kinase signaling[J].Cancer Res, 2005, 65: 69 19–6926
[15]Dong QG,Sclabas GM,Fu jioka S,et al. The function of mu lt ip le Ik appaB: NF -kappaB complexes in the res is tan ce of cancer cells to T axol- indu ced apop tos is [ J ].Oncogene ,2 0 0 2, 2 1 ( 4 2 ) : 6 5 10 - 6 5 1 9.
[16]Sh arm a J,S rin ivasan R, M ajum dar S,et al. Bcl-XL p rotein levels determ in e apoptotic index in pan creat ic carcin om a[ J ].Pancreas,2 0 0 5,3 0 ( 4 ) : 3 3 7 - 3 4 2
[17]Meylan, E. et al.Requirement for NF-B signalling in a mouse model of lung adenoc arci- noma[J].Nature ,2009,462: 104–107
[1]Liu B,Park E,Zhu F,et al. A critical role for I kappaB kinase alpha in the development of human and mouse squamous cell carcinomas[J].Proc Natl Acad Sci USA,2005,103: 17202–17207
[2] Bamborough P, Callahan JF, Christopher JA, et al. Progress towards the development of anti-inflammatory inhibitors of IKK beta [ J].Curr Top Med Chem, 2009,9(7) : 623
[3]安琨,荣海钦.炎症因子与2型糖尿病及其并发症[ J ].山东医药, 2004, 44 (13) : 62-63.
[4] Perkins ND. Integrating cell2signaling pathways with NF-κB and IKK function[ J ]. Nature, 2007, 8 (1) : 49-62
[5]Perkins ND. Integrating cell-signalling pathways with NF-κB and IKK function[J]. Nat Rev Mol Cell Biol, 2007,8:49–62.
[6]Burke JR. Targeting IκB kinase for the treatment of inflammatory and other disorders[J]. Curr Opin Drug Discov Devel ,2003,6:720–728.
[7]Hu MC,Lee DF,Xia W,et al. IκB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a[J]. Cell,2004,117:225–237.
[8]Luo JL,Tan W,Ricono JM, et al. Nuclear cytokine-activated IKKαcontrols prostate cancer metastasis by repressing Maspin[J]. Nature, 2007,446:690–694.
[9]Boehm JS, Zhao JJ, Yao J, et al. Integrative genomic approaches identify IKBKE as a breast cancer oncogene[J]. Cell, 2007,129:1065–1079.
[10]Chien Y, Kim S, Bumeister R, et al. RalB GTPase-mediated activation of the IκB family kinaseTBK1 couples innate immune signaling tumor cell survival[J]. Cell, 2006,127:157–170
[11]Gasparian AV, Yao YJ, Kowalczyk D,et al. The role of IKK in constitutive activation ofNF - kappaB transcrip tion factor in p rostate carcinoma cells [ J ]. Cell Sci, 2002, 115 ( Pt 1) : 141 - 151.
[12]Tamatani T, Azuma M, Aota K, et al. Enhanced IkappaB kinase activity is responsible for the augmented activity of NF - kappaB in human head and neck carcinoma cells [ J ]. Cancer Lett, 2001, 171 (2) : 165 - 172
[13]Luo JL,TanW,Ricono JM,et al. Nuclear cytokine activated IKKa controls prostate cancer metastasis by rep ressing masp in[J]. Nature, 2007, 446: 690-694.
[14]张东涛,袁静,杨力OPN、IKK-β、NF-κB p65和MMP-9在胃癌细胞中的表达及意义[J].实用医学杂志, 2009 ,25 (9 ):1359-1361
[15]马彦娟,冯常炜,卢丹IKKβ和NF-κB p65在食管癌及癌前病变中的表达[J].胃肠病学和肝病学杂志,2009,18(6):512-514
[16]Bonnard M,Mirtsos C,Suzuki S,et al. Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-κB-dependent gene transcription[J]. EMBO J ,2000, 19:49 76–4985.
[17]Tojima Y,Fujimoto A,Delhase M,et al. NAK is an IκB kinase-activating kinase[J]. Nature, 2000,404:778–782.
[18]Fitzgerald KA, McWhirter SM, Faia KL, et al. IKKεand TBK1 are essential components of the IRF3 signaling pathway[J]. Nat Immunol, 2003,4:491–496.
[19]McWhirter SM,Fitzgerald KA,Rosains J,Rowe DC,Golenbock DT, Maniatis T.IFN-regulatoryfactor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts[J]. Proc Natl Acad Sci US A,2004,101:233–238
[20]Korherr C,Gille H,Schafer R, et al. Identification of proangiogenic genes and pathways by highthrough-put functional genomics: TBK1 and the IRF3 pathway[J]. Proc Natl Acad Sci U S A ,2006,103:4240–4245.
[21]Godl K,Gruss OJ,Eickhoff J,et al. Proteomic characterization of the angiogenesis inhibitor SU6668 reveals multiple impacts on cellular kinase signaling[J]. Cancer Res 2005,65:6 919–6926.
[22]Chien Y, Kim S, Bumeister R, et al. RalB GTPase-mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival[J].Cell,2006; 127:157–170.
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[2]任玥欣,许国铭,李兆申,刘枫.k-ras基因在胰腺癌和慢性胰腺炎中突变和表达异常及其临床意义[J].世界华人消化杂志,2004,3(39):664-666
[3]李兆申,潘雪,任钥欣.慢性胰腺炎、胰腺癌组织中血管生成与ras基因产物p21蛋白表达的关系及意义[J] .胰腺学,2001,1(1) :8
[4]张瑞奎,窦科峰,李开宗.p21ras蛋白表达在胰腺癌中的临床意义[J].中国普通外科杂志,2004 ,13(6) :467)
[5]Peters RT, Maniatis T. A new family of IKK-related kinases may function as I kappa B kinase kinases[J]. Biochim Biophys Acta ,2001, 1471:M57–62.
[6] Dung-Fang Lee1, and Mien-Chie Hung. Advances in Targeting IKK and IKK-Related Kinases for CancerTherapy[J].Clin Cancer Res, 2008 , 14(18): 5656–5662.
[7]Perkins ND. Integrating cell-signalling pathways with NF-κB and IKK function[J] .Nat Rev Mol Cell Biol,2007,8:49–62.
[8]Barbie, D. A. et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1[J] .Nature ,2009,462:108–112
[9]邢飞跃,赵克森,姜勇.NF-κB的信号通路与阻断策略[J].中国病理生理杂志, 2003,19 (6) : 849 - 855。
[10]蒋奎荣,刘训良,苗毅等.逆转录病毒载体介导反义K-ras基因治疗胰腺癌的实验研究[J].世界华人消化杂志, 2004, 12( 11): 26-27
[11] Bonnard M, Mirtsos C, Suzuki S, et al. Deficiency of T2K leads to apoptotic liver dege- neration and impaired NF-κB-dependent gene transcription[J].EMBO J ,2000,19:4976–4985
[12]Tojima Y,Fujimoto A,Delhase M, et al. NAK is an IκB kinase-activating kinase[J]. Nature, 2000,404:778–782
[13]Korherr C,Gille H,Schafer R, et al. Identification of proangiogenic genes and pathways by highthrough-put functional genomics: TBK1 and the IRF3 pathway[J]. Proc Natl Acad Sci U S A ,2006,103:4240–4245
[14]Godl K,Gruss OJ,Eickhoff J,et al. Proteomic characterization of the angiogenesis inhibitor SU6668 reveals multiple impacts on cellular kinase signaling[J].Cancer Res, 2005, 65: 69 19–6926
[15]Dong QG,Sclabas GM,Fu jioka S,et al. The function of mu lt ip le Ik appaB: NF -kappaB complexes in the res is tan ce of cancer cells to T axol- indu ced apop tos is [ J ].Oncogene ,2 0 0 2, 2 1 ( 4 2 ) : 6 5 10 - 6 5 1 9.
[16]Sh arm a J,S rin ivasan R, M ajum dar S,et al. Bcl-XL p rotein levels determ in e apoptotic index in pan creat ic carcin om a[ J ].Pancreas,2 0 0 5,3 0 ( 4 ) : 3 3 7 - 3 4 2
[17]Meylan, E. et al.Requirement for NF-B signalling in a mouse model of lung adenoc arci- noma[J].Nature ,2009,462: 104–107
[1]Liu B,Park E,Zhu F,et al. A critical role for I kappaB kinase alpha in the development of human and mouse squamous cell carcinomas[J].Proc Natl Acad Sci USA,2005,103: 17202–17207
[2] Bamborough P, Callahan JF, Christopher JA, et al. Progress towards the development of anti-inflammatory inhibitors of IKK beta [ J].Curr Top Med Chem, 2009,9(7) : 623
[3]安琨,荣海钦.炎症因子与2型糖尿病及其并发症[ J ].山东医药, 2004, 44 (13) : 62-63.
[4] Perkins ND. Integrating cell2signaling pathways with NF-κB and IKK function[ J ]. Nature, 2007, 8 (1) : 49-62
[5]Perkins ND. Integrating cell-signalling pathways with NF-κB and IKK function[J]. Nat Rev Mol Cell Biol, 2007,8:49–62.
[6]Burke JR. Targeting IκB kinase for the treatment of inflammatory and other disorders[J]. Curr Opin Drug Discov Devel ,2003,6:720–728.
[7]Hu MC,Lee DF,Xia W,et al. IκB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a[J]. Cell,2004,117:225–237.
[8]Luo JL,Tan W,Ricono JM, et al. Nuclear cytokine-activated IKKαcontrols prostate cancer metastasis by repressing Maspin[J]. Nature, 2007,446:690–694.
[9]Boehm JS, Zhao JJ, Yao J, et al. Integrative genomic approaches identify IKBKE as a breast cancer oncogene[J]. Cell, 2007,129:1065–1079.
[10]Chien Y, Kim S, Bumeister R, et al. RalB GTPase-mediated activation of the IκB family kinaseTBK1 couples innate immune signaling tumor cell survival[J]. Cell, 2006,127:157–170
[11]Gasparian AV, Yao YJ, Kowalczyk D,et al. The role of IKK in constitutive activation ofNF - kappaB transcrip tion factor in p rostate carcinoma cells [ J ]. Cell Sci, 2002, 115 ( Pt 1) : 141 - 151.
[12]Tamatani T, Azuma M, Aota K, et al. Enhanced IkappaB kinase activity is responsible for the augmented activity of NF - kappaB in human head and neck carcinoma cells [ J ]. Cancer Lett, 2001, 171 (2) : 165 - 172
[13]Luo JL,TanW,Ricono JM,et al. Nuclear cytokine activated IKKa controls prostate cancer metastasis by rep ressing masp in[J]. Nature, 2007, 446: 690-694.
[14]张东涛,袁静,杨力OPN、IKK-β、NF-κB p65和MMP-9在胃癌细胞中的表达及意义[J].实用医学杂志, 2009 ,25 (9 ):1359-1361
[15]马彦娟,冯常炜,卢丹IKKβ和NF-κB p65在食管癌及癌前病变中的表达[J].胃肠病学和肝病学杂志,2009,18(6):512-514
[16]Bonnard M,Mirtsos C,Suzuki S,et al. Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-κB-dependent gene transcription[J]. EMBO J ,2000, 19:49 76–4985.
[17]Tojima Y,Fujimoto A,Delhase M,et al. NAK is an IκB kinase-activating kinase[J]. Nature, 2000,404:778–782.
[18]Fitzgerald KA, McWhirter SM, Faia KL, et al. IKKεand TBK1 are essential components of the IRF3 signaling pathway[J]. Nat Immunol, 2003,4:491–496.
[19]McWhirter SM,Fitzgerald KA,Rosains J,Rowe DC,Golenbock DT, Maniatis T.IFN-regulatoryfactor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts[J]. Proc Natl Acad Sci US A,2004,101:233–238
[20]Korherr C,Gille H,Schafer R, et al. Identification of proangiogenic genes and pathways by highthrough-put functional genomics: TBK1 and the IRF3 pathway[J]. Proc Natl Acad Sci U S A ,2006,103:4240–4245.
[21]Godl K,Gruss OJ,Eickhoff J,et al. Proteomic characterization of the angiogenesis inhibitor SU6668 reveals multiple impacts on cellular kinase signaling[J]. Cancer Res 2005,65:6 919–6926.
[22]Chien Y, Kim S, Bumeister R, et al. RalB GTPase-mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival[J].Cell,2006; 127:157–170.
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