VCL、PPA1、AR在前列腺癌中的表达及相关性研究
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摘要
目的:研究粘着斑蛋白(Vinculin,VCL)、雄激素受体(AndrogenReceptor,AR)、无机焦磷酸酶(Inorganic pyrophosphatase,PPA1)三因子在良性前列腺增生(Benign prostatic hyperplasia,BPH)、前列腺癌(Prostate Cancer,PCa)中的表达情况,明确并分析其与前列腺癌不同临床分期、病理分级、PSA水平之间相互关系,为前列腺癌的发生、进展提供理论基础。
方法:采用免疫组织化学方法检测18例BPH组织,38例PCa组织中VCL、AR、PPA1的表达。分析VCL、AR、PPA1在BPH、PCa中表达差异;在PCa不同临床分期、病理分级、初次PSA检测水平上VCL、AR、PPA1表达情况;VCL、AR、PPA1三者之间相关性。
结果:1)VCL、AR、PPA1在BPH组织中阳性表达率分别为28%、56%、22%,在PCa组织中分别为58%、53%、39%;VCL在PCa中表达较BPH组织增多(P＜0.05),AR、PPA1表达在BPH、PCa中无明显差异(P＞0.05)。
2)VCL、AR在PCa组织中表达与肿瘤临床分期、病理分级密切相关(P＜0.05),与PSA值无明显关系(P＞0.05);PPA1在PCa组织中表达与肿瘤临床分期、病理分级、PSA均无明显相关性(P＞0.05)。
3)VCL、AR两者在PCa组织中表达存在正相关(r=0.489,P=0.002＜0.05);PPA1在PCa中表达与VCL、AR无相关性存在(P＞0.05)。
结论:1) VCL在BPH、PCa表达具有差异性,可能作为前列腺良、恶性鉴别诊断的一个潜在指标;
2) AR、VCL随PCa进展表达逐步下降,两者存在正相关,两者结合可能成为前列腺癌进展的诊断、预后评价指标;
3) PPA1非评价PCa进展有效指标。
Objective:To study the expression of three factors,Vinculin(VCL), androgen Receptor(AR),and inorganic pyrophosphatase(PPA1) in benign prostatic hyperplasia(BPH),and prostate cancer(PCa);To clear and analyze the mutual relationship between the three factors and prostate cancer's different clinical stages,histological grade,and PSA level;To provide a theory for the occurrence and the development of PCa.
Methods:To detected the expression of VCL,AR,and PPA1 in 18 cases of BPH tissue and 38 cases of PCa tissue by immunohistochemistry; To analysis the differences of VCL,AR,PPA1 in the expression of BPH and PCa;To detected the expression of VCL,AR,and PPA1 in prostate cancer's different clinical stages,histological grade,and PSA level;To analysis the correlation of VCL,AR,and PPA1.
Results:1) The positive expression rate of VCL,AR,PPA1 were 28%,56%,22%in BPH tissues,58%,53%,39%in PCa tissues.The positive rate of VCL in PCa was more than in BPH tissues(P＜0.05),the positive rate of AR and PPA1 were no significant difference in BPH and PCa(P＞0.05).
2) There was a close relationship between the expression of VCL, AR and tumor clinical stage,pathological grade in PCa tissue(P＜0.05), but without significant relationship in the value of PSA(P＞0.05).The expression of PPA1 was not significant correlation with the tumor clinical stage,pathological grade and the value of PSA(P＞0.05).
3) There was a positive correlation between the expression of VCL and the expression of AR in PCa tissue(r= 0.489,P= 0.002＜0.05).There was no correlation in the expression of PPA1,VCL,and AR in PCa tissue (P＞0.05).
Conclusions:1) The differences between the expressions of VCL in BPH and PCa predicted VCL could be used as an indicator for the differential diagnosis of benign and malignant prostate disease;
2) The expression of AR and VCL reduced gradually with the progression of PCa and there was a positive correlation between them. The combination of the two indicators could be an indicator of diagnosis and prognosis to evaluate the development of PCa;
3) PPA1 wasn't an effective indicator to evaluate the progression of PCa.
方法:采用免疫组织化学方法检测18例BPH组织,38例PCa组织中VCL、AR、PPA1的表达。分析VCL、AR、PPA1在BPH、PCa中表达差异;在PCa不同临床分期、病理分级、初次PSA检测水平上VCL、AR、PPA1表达情况;VCL、AR、PPA1三者之间相关性。
结果:1)VCL、AR、PPA1在BPH组织中阳性表达率分别为28%、56%、22%,在PCa组织中分别为58%、53%、39%;VCL在PCa中表达较BPH组织增多(P＜0.05),AR、PPA1表达在BPH、PCa中无明显差异(P＞0.05)。
2)VCL、AR在PCa组织中表达与肿瘤临床分期、病理分级密切相关(P＜0.05),与PSA值无明显关系(P＞0.05);PPA1在PCa组织中表达与肿瘤临床分期、病理分级、PSA均无明显相关性(P＞0.05)。
3)VCL、AR两者在PCa组织中表达存在正相关(r=0.489,P=0.002＜0.05);PPA1在PCa中表达与VCL、AR无相关性存在(P＞0.05)。
结论:1) VCL在BPH、PCa表达具有差异性,可能作为前列腺良、恶性鉴别诊断的一个潜在指标;
2) AR、VCL随PCa进展表达逐步下降,两者存在正相关,两者结合可能成为前列腺癌进展的诊断、预后评价指标;
3) PPA1非评价PCa进展有效指标。
Objective:To study the expression of three factors,Vinculin(VCL), androgen Receptor(AR),and inorganic pyrophosphatase(PPA1) in benign prostatic hyperplasia(BPH),and prostate cancer(PCa);To clear and analyze the mutual relationship between the three factors and prostate cancer's different clinical stages,histological grade,and PSA level;To provide a theory for the occurrence and the development of PCa.
Methods:To detected the expression of VCL,AR,and PPA1 in 18 cases of BPH tissue and 38 cases of PCa tissue by immunohistochemistry; To analysis the differences of VCL,AR,PPA1 in the expression of BPH and PCa;To detected the expression of VCL,AR,and PPA1 in prostate cancer's different clinical stages,histological grade,and PSA level;To analysis the correlation of VCL,AR,and PPA1.
Results:1) The positive expression rate of VCL,AR,PPA1 were 28%,56%,22%in BPH tissues,58%,53%,39%in PCa tissues.The positive rate of VCL in PCa was more than in BPH tissues(P＜0.05),the positive rate of AR and PPA1 were no significant difference in BPH and PCa(P＞0.05).
2) There was a close relationship between the expression of VCL, AR and tumor clinical stage,pathological grade in PCa tissue(P＜0.05), but without significant relationship in the value of PSA(P＞0.05).The expression of PPA1 was not significant correlation with the tumor clinical stage,pathological grade and the value of PSA(P＞0.05).
3) There was a positive correlation between the expression of VCL and the expression of AR in PCa tissue(r= 0.489,P= 0.002＜0.05).There was no correlation in the expression of PPA1,VCL,and AR in PCa tissue (P＞0.05).
Conclusions:1) The differences between the expressions of VCL in BPH and PCa predicted VCL could be used as an indicator for the differential diagnosis of benign and malignant prostate disease;
2) The expression of AR and VCL reduced gradually with the progression of PCa and there was a positive correlation between them. The combination of the two indicators could be an indicator of diagnosis and prognosis to evaluate the development of PCa;
3) PPA1 wasn't an effective indicator to evaluate the progression of PCa.
引文
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[1] Weller PA,Ogryzko EP, Corben EB, et al. Complete sequence of human vinculin and assignment of the gene to chromosome 10. Proc Natl Acad Sci U.S.A. 1990,87(15):5667-5671
[2] Ziegler WH, Liddington RC, Critchley DR. The structure and regulation of vinculin. Trends in Cell Biol.2006,16(9):453-60
[3] Borgon RA, Vonrhein C, Bricogne G, et al. Crystal structure of human vinculin. Structure. 2004, 12(7): 1189-1197
[4] Bakolitsa C, Cohen DM, Bankston LA, et al. Structural basis for VCL activation at sites of cell adhesion. Nature. 2004,430(6999):583-586
[5] Bois PR, O'Hara BP, Nietlispach D, et al. The vinculin binding sites of talin and alphaactinin are sufficient to activate vinculin. J Biol Chem. 2006,281(11):7228-36
[6] Johnson, R.P., Craig, S.W. Actin activates a cryptic dimerization potential of the vinculin tail domain. J Biol Chem.2000,275(1): 95-105
[7] Subauste MC, Pertz O, Adamson ED, et al. VCL modulation of paxillin-FAK interactions regulates ERK to control survival and motility. J Cell Biol. 2004,165(3)371-381
[8] Munevar S, Wang YL, Dembo M. Regulation of mechanical interactions between fibroblasts and the substratum by stretch-activated Ca2+ entry. J Cell Sci. 2004,117(Pt 1):85-92
[9] Gallant ND, Michael KE, Garcia AJ. Cell adhesion strengthening: contributions of adhesive area, integrin binding, and focal adhesion assembly. Mol Biol Cell. 2005,16(9):4329-40
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[20]钟狂飚,桂明,蒋先镇,等.雄激素依赖及非依赖性前列腺癌细胞差异蛋白质组的初步研究.中国男科学.2008,22(5):5-9
[21]Algaba F,Arce Y,Fernandez S,et al.Adhesion molecules expression as a potential marker of prostate cancer aggressivity.A TMA study of radical prostatectomy specimens.Arch Ital Urol Androl.2006,78(4):130-4
[22]Schmelz M,Cress AE,Scott KM,et al.Different phenotypes in human prostate cancer:alpha6 or alpha3 integrin in cell-extracellular adhesion sites.Neoplasia.2002,4(3):243-54.
[23] Mukherjee R, Bartlett J.M.S, Krishna N.S., et al. Raf-1 Expression May Influence Progressionto Androgen Insensitive Prostate Cancer. The Prostate. 2005,64(1): 101-107
[24] Perez-Castineira JR, Lopez-Marques RL, Villalba JM, et al. Functional complementation of yeast cytosolic pyrophosphatase by bacterial and plant H+translocating pyrophosphatase. Proc Natl Acad Sci U.S.A., 2002,99(25): 15914-15919
[25] Kornberg A. Inorganic polyphosphate: a molecule of many functions. Prog Mol Subcell Biol. 1999;23:1-18
[26] Tomonaga T, Matsushita K, Yamaguchi S, et al. Identification of altered protein expression and post-translational modifications in primary colorectal cancer by using agarose two-dimensional gel electrophoresis. Clin Cancer Res. 2004,10(6):2007-14
[27] Chen G, Gharib TG, Huang CC, et al. Proteomic analysis of lung adenocarcinoma: identification of a highly expressed set of proteins in tumors. Clin Cancer Res. 2002,8(7):2298-305
[28] Lexander H, Palmberg C, Auer G, et al. Proteomic analysis of protein expression in prostate cancer. Anal Quant Cytol Histol. 2005,27(5):263-72
[29] Wilson CM, McPhaul MJ. A and B forms of the androgen receptor are present in human genital skin fibroblasts. Proc Natl Acad Sci USA, 1994, 91(4): 1234-1238
[30] Lu ML, Schneider MC, Zheng Y, et al. Caveolin-1 interacts with androgen receptor. A positive modulator of androgen receptor mediated transactivation. J Biol Chem. 2001,276(16):13442-51
[31] Sweat SD, Pacelli A, Bergstralh E, et al. Androgen receptor expression in prostatic intraepithelial neoplasia and cancer. J Urol. 1999,161 (4); 1229-1232
[32] Chodak GW, Kranc DM , Puy LA , et al. Nuclear localization of androgen receptor in heterogeneous samples of normal, hyperplastic and neoplastic human prostate. J Urol, 1992 , 147(3):798-803
[33] Linja MJ, Savinainen KJ, Saramaki OR, et al. Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer. Cancer Res 2001,61(9):3550-3555
[34] Kinoshita H , Shi Y, Sandefur C , et al. Methylation of the androgen receptor minimal promoter silences transcription in human prostate cancer. Cancer Res ,2000, 60(13):3623-3630
[2]孙颖浩.我国前列腺癌的研究现状.中华泌尿外科杂志.2004,25(2):77-80
[3]吴阶平.吴阶平泌尿外科学.第二版.济南:山东科学技术出版社,2004
[4]Kish JA,Bukkapatnam R,Palazzo F.The treatment challenge of hormonerefractory prostate cancer.Cancer Control.2001,8(6):487-95
[5]Rubben H,Bex A,Otto T.Systemic treatment of hormone refractory prostate cancer.World J Urol.2001,19(2):99-110
[6]Tammela T.Endocrine treatment of prostate cancer.J Steroid Biochem Mol Biol.2004,92(4):287-95
[7]钟狂飚,桂明,蒋先镇,等.雄激素依赖及非依赖性前列腺癌细胞差异蛋白质组的初步研究.中国男科学.2008,22(5):5-9
[8]Ziegler WH,Liddington RC,Critchley DR.The structure and regulation of vinculin.Trends in Cell Biol.2006,16(9):453-60
[9]Borgon RA,Vonrhein C,Bricogne G,et al.Crystal structure of human vinculin.Structure.2004,12(7):1189-1197
[10]Algaba F,Arce Y,Fernandez S,et al.Adhesion molecules expression as a potential marker of prostate cancer aggressivity.A TMA study of radical prostatectomy specimens.Arch Ital Urol Androl.2006,78(4):130-4
[11]Perez-Castineira JR,Lopez-Marques RL,Villalba JM,et al.Functional complementation of yeast cytosolic pyrophosphatase by bacterial and plant H+translocating pyrophosphatase.Proc Natl Acad Sci U.S.A.,2002,99(25):15914-15919
[12]Kornberg A.Inorganic polyphosphate:a molecule of many functions.Prog Mol Subcell Biol.1999;23:1-18
[13]Lexander H,Palmberg C,Auer G,et al.Proteomic analysis of protein expression in prostate cancer.Anal Quant Cytol Histol.2005,27(5):263-72
[14]Giwercman YL,Richthoff J,Lilja H,et al.Androgen receptor CAG repeat length correlates with semen PSA levels in adolescence. Prostate. 2004,59(3):227-33
[15] Barrack ER, Tindall DJ. A critical evaluation of the use of androgen receptor assays to predict the androgen responsiveness of prostatic cancer. Prog Clin Biol Res 1987;239(1):155-187
[16] Robnett TJ, Whittington R, Malkowicz SB, et al. Long-term use of combined radiation therapy and hormonal therapy in the management of stage D1 prostate cancer. Int JRadiat Oncol Biol Phys. 2002,53(5).1146-51.
[17] Kawasaki H, Altieri DC, Lu CD, et al. Inhibition of apoptosis by surviving predicts shorter survivial rates in colorectal cancer. Cancer Res.1998 , 58(22):5071-5074
[18] Weller PA ,Ogryzko EP, Corben EB, et al. Complete sequence of human vinculin and assignment of the gene to chromosome 10. Proc Natl Acad Sci U.S.A. 1990,87(15):5667-5671
[19] Bakolitsa C, Cohen DM, Bankston LA, et al. Structural basis for VCL activation at sites of cell adhesion. Nature. 2004,430(6999):583-586
[20] Gallant, N.D.,Michael KE, Garcia AJ. Cell adhesion strengthening: contributions of adhesive area, integrin binding, and focal adhesion assembly. Mol. Biol. Cell.2005. 16(9), 4329-4340
[21] Subauste MC, Pertz O, Adamson ED, et al. VCL modulation of paxillin-FAK interactions regulates ERK to control survival and motility. J Cell Biol.2004,165(3):371-381
[22] Cooper CR, Chay CH, Pienta KJ. The role of alpha(v) beta(3) in prostate cancer progression. Neoplasia. 2002, 4(3): 191-194,6
[23] Christofori G. New signals from the invasive front. Nature. 2006,441(7092):444-450
[24] Critchley DR. Focal adhesions - the cytoskeletal connection. Curr Opin Cell Biol. 2000,12(1):133-9
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