S100A4蛋白在膀胱癌中的表达及其临床意义
摘要
目的:研究S100A4基因在膀胱癌组织与正常膀胱组织中的差异表达,结合病理及临床资料明确S100A4基因表达水平与膀胱癌分化转移的关系,为膀胱癌侵袭转移的诊治提供依据。
方法:取2003年4月至2007年4月诊断为膀胱癌病人并行手术切除的组织65例,包括不同的病理分型和临床分期。运用免疫组织化学S-P方法检测S l 00A4蛋白在膀胱癌中的表达情况并进行统计学分析。
结果:在膀胱癌组织中S100A4均为高表达,统一计学分析结果均具有显著性差异,P<0. 05。在不同组织学分级中S100A4在底分化组织中的表达水平明显高于高分化组织,P<0. 05,二者有显著差异。在不同的手术一病理分期中S100A4在III , IV期组织中的表达明显高于I、II期组织中的表达,二者差异有显著性,P<0. 05。
结论1.膀胱癌组织中S 100A4基因表达明显高于癌旁正常组织,可望作为膀胱癌的病情发展及指导临床治疗的标记物之一。
2.膀胱癌低分化组病人S100A4基因阳性表达高于膀胱细胞癌高分化组病人,故S100A4基因表达与膀胱癌分化有关,癌组织S100A4测定有助于判定肿瘤的预后。
3. S100A4基因差异表达与患者年龄、性别均无明显相关性。
Objective: To investigate the differential expression of S100A4 in both bladder cancer and common bladder. To study the relationship between S100A4 expression level and differentiation and metastasis of bladder cancer combined clinical data and pathology together.
Methods: the documents of 65 cases were taken from the patients undergone lobotomy of bladder because of bladder cancer between April 2003 and April 2007,including various patho-grouping and clinical stage.Immunohistochemical staining (S-P method) for S100A4 protein in bladder cancer was performed and analyzed by statistics. To identify relation between the expression of S100A4 protein Results: S100A4 in bladder cancer all had higher expression than they were in normal bladder (P<0. 05).The expression level of S100A4 in less-differentiated group was higher than that of well-differentiated group. Moreover, the expression level in stage III、IV was higher than that of stage I、II .
Conclusions:1. Expression of S100A4 in bladder cancer tissues was higher than normal bladder tissues besides carcinoma. S100A4 may be one of markers on assessment of patient's condition developing and clinical treatment instruction in bladder cancer.
2. Expression of S100A4 in low-differentiation tissues was higher than in high-differentiation tissues .S100A4 was correlated to bladder cancer differentiation and may play an important role in prognosis of bladder cancer.
3 There was no relationship between differential expression of S100A4 and age or sex of patients.
方法:取2003年4月至2007年4月诊断为膀胱癌病人并行手术切除的组织65例,包括不同的病理分型和临床分期。运用免疫组织化学S-P方法检测S l 00A4蛋白在膀胱癌中的表达情况并进行统计学分析。
结果:在膀胱癌组织中S100A4均为高表达,统一计学分析结果均具有显著性差异,P<0. 05。在不同组织学分级中S100A4在底分化组织中的表达水平明显高于高分化组织,P<0. 05,二者有显著差异。在不同的手术一病理分期中S100A4在III , IV期组织中的表达明显高于I、II期组织中的表达,二者差异有显著性,P<0. 05。
结论1.膀胱癌组织中S 100A4基因表达明显高于癌旁正常组织,可望作为膀胱癌的病情发展及指导临床治疗的标记物之一。
2.膀胱癌低分化组病人S100A4基因阳性表达高于膀胱细胞癌高分化组病人,故S100A4基因表达与膀胱癌分化有关,癌组织S100A4测定有助于判定肿瘤的预后。
3. S100A4基因差异表达与患者年龄、性别均无明显相关性。
Objective: To investigate the differential expression of S100A4 in both bladder cancer and common bladder. To study the relationship between S100A4 expression level and differentiation and metastasis of bladder cancer combined clinical data and pathology together.
Methods: the documents of 65 cases were taken from the patients undergone lobotomy of bladder because of bladder cancer between April 2003 and April 2007,including various patho-grouping and clinical stage.Immunohistochemical staining (S-P method) for S100A4 protein in bladder cancer was performed and analyzed by statistics. To identify relation between the expression of S100A4 protein Results: S100A4 in bladder cancer all had higher expression than they were in normal bladder (P<0. 05).The expression level of S100A4 in less-differentiated group was higher than that of well-differentiated group. Moreover, the expression level in stage III、IV was higher than that of stage I、II .
Conclusions:1. Expression of S100A4 in bladder cancer tissues was higher than normal bladder tissues besides carcinoma. S100A4 may be one of markers on assessment of patient's condition developing and clinical treatment instruction in bladder cancer.
2. Expression of S100A4 in low-differentiation tissues was higher than in high-differentiation tissues .S100A4 was correlated to bladder cancer differentiation and may play an important role in prognosis of bladder cancer.
3 There was no relationship between differential expression of S100A4 and age or sex of patients.
引文
1 Takenaga K, Nakanishi H, Wada K,et al.Increased expression of S100A4, a metastasis-associated gene, in human colorectal Aden carcinomas. Clin Cancer Res. 1997 Dec;3(12 Pt 1):2309-16
2 Schuyer M, Henzen-Logmans SC, van der Burg ME,et al.Genetic alterations in ovarian borderline tumors and ovarian carcinomas. Eur J Obstet Gynecol Reprod Biol. 1999 Feb;82(2):147-50.
3 Taylor S,Herrington S,PriIlle W,et a1.S100A4 (p9Ka) protein in colon carcinoma and liver metastases: association with carcinoma cells and T-lymphocytes.Br J Cancer.2002 Feb 1;86(3):409-416
4 Heizmann CW, Ackermann GE, et a1.Pathologies involving the S100 proteins and RAGE.Subcell Biochem.2007; 45:93-138.Review.
5 Oslejskova L, Grigorian M, et a1. The metastasis associated protein S100A4: a potential novel link to inflammation and consequent aggressive behavior of rheumatoid arthritis synovial fibroblasts. Ann Rheum Dis. 2007 Dec 4; [Epub ahead of print]
6 Cui JF, Liu YK, Zhang LJ,et al.Identification of metastasis candidate proteins among HCC cell lines by comparative proteome and biological function analysis of S100A4 in metastasis in vitro .Proteomics. 2006 Nov;6(22):5953-61.
7 Xie R, Loose DS, et a1 Hypsometry Latino-induced expression of S100A4 in endometrial carcinoma. Mod Pathol. 2007 Oct; 20(10):1045-54. Epub 2007 Aug
8 Huang Y, Fernandez SV, et a1.Epithelial to mesenchymal transition in human breast epithelial cells transformed by 17beta-estradiol.Cancer Res. 2007 Dec 1; 67(23):11147-57.
9 Levett D, Flecknell PA, Rudland PS,et al.Transfection of S100A4 produces metastasis variants of an orthotropic model of bladder cancer. Am J Pathol. 2002 Feb; 160(2):693-700.
10 Rudland S, Martin L, Roshanlall C, et a1.Association of S100A4 and osteopontin with specific prognostic factors and survival of patients with minimally invasive breast cancer. Clin Cancer Res.2006 Feb 15; 12(4):1192-200.
11 Zhong XY, Zhang LH, et a1.Nuclear expression of S100A4 is associated with lymph node metastasis in gastric carcinoma. Zhonghua Wei Chang Wai Ke Za Zhi.2007 Sep; 10(5):454-7.
12 Mazzucchelli L. Protein S100A4: too long overlooked by pathologists? Am J Pathol. 2002 Jan; 160(1):45-50.
13 Saleem M, Kweon MH, Johnson JJ, et al.S100A4 accelerates tumor genesis and invasion of human prostate cancer through the transcriptional regulation of matrix metalloproteinase 9. Proc Natl Acad Sci U S A. 2006 Oct 3;103(40):14825-30.
14 Cabezón T, Celis JE, et a1.Expression of S100A4 by a variety of cell types present in the tumor microenvironment of human breast cancer. Int J Cancer. 2007 Oct 1; 121(7):1433-44.
15 Bj?rnland K, Flatmark K, Pettersen S, et al.Matrix metalloproteinase participate in osteo sarcoma invasion. Surg Res. 2005 Aug;127(2):151-6. Epub 2005 Apr 14
16 Kimura K, Endo T, et a1.Clinical significance of S100A4 and E-cadherin-related adhesion molecules in non-small cell lung cancer .Int J Oncol. 2000 Jun; 16(6):1125-31.
17 van der Poel HG.Foreseeing cancer metastases.Eur Urol. 2006 Oct; 50(4):648-9. Epub 2006 Apr 7.
18 Tarabykina S, Griffiths TR, et a1.Metastasis-associated protein S100A4: spotlight on its role in cell migration. Cur Cancer Drug Targets. 2007 May; 7(3):217-28. Review
19 Grigorian M, Lukanidin E.Activator of metastasis in cancer cells, Mst1/S100A4 protein binds to tumor suppressor protein p53 Genetics. 2003 Jul; 39(7):900-8. Russian.
20 Schmidt-Hansen B, Klingelh?fer J, et a1.Functional significance of metastasis-inducing S100A4 (Mts1) in tumor-stoma interplay. Biol Chem. 2004 Jun 4; 279(23):24498-504. Epub 2004 Mar 26.
21 Semov A, Moreno MJ, Onichtchenko A,et al.Metastasis-associated protein S100A4 induces angiogenesis through interaction with Annexin II and accelerated plasmas formation Biol Chem. 2005 May 27;280(21):20833-41. Epub 2005 Mar 23.
22 Ambartsumian N, Grigorian M, Lukanidin E.Genetically modified mouse models to study the role of metastasis-promoting S100A4(mts1) protein in met static mammary cancer. J Dairy Res. 2005; 72 Spec No: 27-33。
23 Grigorian M, Lukanidin E.Activator of metastasis in cancer cells, Mst1/S100A4 protein binds to tumor suppressor protein p53.Genetika. 2003 Jul; 39(7):900-8.
24 Rosty C, Geradts J, Sato N,et al.p16 Inactivation in pancreatic intraepithelial neoplasias (PanINs) arising in patients with chronic pancreatitis. Am J Surg Pathol. 2003 Dec; 27(12):1495-501.
25 Klingelh?fer J, Senolt L, et a1. Up-regulation of metastasis-promoting S100A4 (Mts-1) in rheumatoid arthritis: putative involvement in the pathogenesis of rheumatoid arthritis. Arthritis Rheum.2007 Mar; 56(3):779-89.
26 Garrett SC, Varney KM, Weber DJ, Bresnick AR.S100A4, a mediator of metastasis. J Biol Chem. 2006 Jan 13;281(2):677-80.
27 Agerbaek M, Alsner J, Marcussen N, et al.Focal S100A4 protein expression is an independent predictor of development of metastasis disease in cystictomized bladder cancer patients .Eur Urol. 2006 Oct; 50(4):777-85. Epub 2006 Mar 9.
28 Kiryushko D, Novitskaya V, Soroka V,et al.Molecular mechanisms of Ca(2+) signaling in neurons induced by the S100A4 protein. Mol Cell Biol. 2006 May; 26(9):3625-38.
29 Poel HG. Foreseeing cancer metastases. Eur Urol. 2006 Oct; 50(4):648-9. Epub 2006 Apr 7
30 Matsumoto K, Irie A, Satoh T,et al.Expression of S100A2 and S100A4 predicts for disease progression and patient survival in bladder cancer. Urology. 2007 Sep;70(3):602-7.
31 Shen Y, Wilder-Smith E, et a1.A novel methodology to probe endothelial differential gene expression profile reveals novel genes. Endothelium. 2007 Nov-Dec; 14(6):303-14
32 Matsumoto K, Irie A, et a1.Expression of S100A2 and S100A4 predicts for disease progression and patient survival in bladder cancer. Urology. 2007 Sep; 70(3):602-7. Epub 2007 Aug 3.
1 Donato R.SlOO:a mutagenic family of calcium—modulated proteins of the EF-hand type with intracellular and extra—cellular functional roles.Int J Biochem Cell Biol,2001,33(7):637—668.
2 Schafer BW ,Wicki R,Engelkamp D,et a1.Isolation of a YAC clone covering a cluster of nine$100 genes on human chromosome lq21:rationale for a new nomenclature of the $100 calcium-binding protein family.Genomics,1995 ,25(3):638-643.
3 Taylor S.Herrington S,Prim e W ,et a1.S100A4 (p9Ka)protein in colon carcinoma and liver metastases:association with carcinoma cells and T—lymphocytes. Br J Cancer.2002,86(3):409—416.
4 Sherbet GV ,Lakshmi MS.S100A4(MTS1) calcium binding protein in cancer growth,invasion and metastasis. Anticancer Res.1998.18(4A):2415—2421.
5 Mazzuccheli L.Protein S100A4: too long overlooked by pathologists? Am J Pathol,2002,16O(1):7-13.
6 Schafer BW ,Heizmann CW。The SlOO family of EF-hand calcium-binding proteins:functions and pathology.Trends Biochem Sic,1996,21(4):134—140.
7 Kordowska J,Stafford WF,Wang CL.Ca2+ and Zn2+ bind to different sites and induce different conformational changes in human calcyclin.Eur J Biochem,1998,253(1):57—66.
8 姬竣芳.S100蛋白家族与肿瘤.国外医学肿瘤学分册,2002,29(4):261-263.
9 Gribenko AV,Hopper JE, Makhatadze GI. Molecular characterization and tissue distribution of a novel member of the S100 family of EF-hand proteins . Biochemistry,2001 ,4O(51):15538—15548.
10 Lakshmi MS,Parker C,Sherbet GV .Expression of the Tran membrane glycoprotein CD44 and metastasis associated 18A2/MTS1 gene in B16 murine melanoma cells.Anticancer Res.1997,17(5A):3451-3455.
11 Bjorn land K,Winberg JO,Odegaard OT, et a1.S100A4 involvement in metastasis:deregulation of matrix metalloproteinase and tissue inhibitors of matrix metalloproteinase in osteosarcoma cells transected with an anti-S100A4 ribosome.Cancer Res.1999,59(18):4702—4708.
12 Ambansumian N,Klingelhofer J,Grigorian M , et a1. The metastasis-associated Mts1(S1OOA4) protein could act as an antigenic factor.0ncogene,2OO1,2O(34) :4685—4695.
2 Schuyer M, Henzen-Logmans SC, van der Burg ME,et al.Genetic alterations in ovarian borderline tumors and ovarian carcinomas. Eur J Obstet Gynecol Reprod Biol. 1999 Feb;82(2):147-50.
3 Taylor S,Herrington S,PriIlle W,et a1.S100A4 (p9Ka) protein in colon carcinoma and liver metastases: association with carcinoma cells and T-lymphocytes.Br J Cancer.2002 Feb 1;86(3):409-416
4 Heizmann CW, Ackermann GE, et a1.Pathologies involving the S100 proteins and RAGE.Subcell Biochem.2007; 45:93-138.Review.
5 Oslejskova L, Grigorian M, et a1. The metastasis associated protein S100A4: a potential novel link to inflammation and consequent aggressive behavior of rheumatoid arthritis synovial fibroblasts. Ann Rheum Dis. 2007 Dec 4; [Epub ahead of print]
6 Cui JF, Liu YK, Zhang LJ,et al.Identification of metastasis candidate proteins among HCC cell lines by comparative proteome and biological function analysis of S100A4 in metastasis in vitro .Proteomics. 2006 Nov;6(22):5953-61.
7 Xie R, Loose DS, et a1 Hypsometry Latino-induced expression of S100A4 in endometrial carcinoma. Mod Pathol. 2007 Oct; 20(10):1045-54. Epub 2007 Aug
8 Huang Y, Fernandez SV, et a1.Epithelial to mesenchymal transition in human breast epithelial cells transformed by 17beta-estradiol.Cancer Res. 2007 Dec 1; 67(23):11147-57.
9 Levett D, Flecknell PA, Rudland PS,et al.Transfection of S100A4 produces metastasis variants of an orthotropic model of bladder cancer. Am J Pathol. 2002 Feb; 160(2):693-700.
10 Rudland S, Martin L, Roshanlall C, et a1.Association of S100A4 and osteopontin with specific prognostic factors and survival of patients with minimally invasive breast cancer. Clin Cancer Res.2006 Feb 15; 12(4):1192-200.
11 Zhong XY, Zhang LH, et a1.Nuclear expression of S100A4 is associated with lymph node metastasis in gastric carcinoma. Zhonghua Wei Chang Wai Ke Za Zhi.2007 Sep; 10(5):454-7.
12 Mazzucchelli L. Protein S100A4: too long overlooked by pathologists? Am J Pathol. 2002 Jan; 160(1):45-50.
13 Saleem M, Kweon MH, Johnson JJ, et al.S100A4 accelerates tumor genesis and invasion of human prostate cancer through the transcriptional regulation of matrix metalloproteinase 9. Proc Natl Acad Sci U S A. 2006 Oct 3;103(40):14825-30.
14 Cabezón T, Celis JE, et a1.Expression of S100A4 by a variety of cell types present in the tumor microenvironment of human breast cancer. Int J Cancer. 2007 Oct 1; 121(7):1433-44.
15 Bj?rnland K, Flatmark K, Pettersen S, et al.Matrix metalloproteinase participate in osteo sarcoma invasion. Surg Res. 2005 Aug;127(2):151-6. Epub 2005 Apr 14
16 Kimura K, Endo T, et a1.Clinical significance of S100A4 and E-cadherin-related adhesion molecules in non-small cell lung cancer .Int J Oncol. 2000 Jun; 16(6):1125-31.
17 van der Poel HG.Foreseeing cancer metastases.Eur Urol. 2006 Oct; 50(4):648-9. Epub 2006 Apr 7.
18 Tarabykina S, Griffiths TR, et a1.Metastasis-associated protein S100A4: spotlight on its role in cell migration. Cur Cancer Drug Targets. 2007 May; 7(3):217-28. Review
19 Grigorian M, Lukanidin E.Activator of metastasis in cancer cells, Mst1/S100A4 protein binds to tumor suppressor protein p53 Genetics. 2003 Jul; 39(7):900-8. Russian.
20 Schmidt-Hansen B, Klingelh?fer J, et a1.Functional significance of metastasis-inducing S100A4 (Mts1) in tumor-stoma interplay. Biol Chem. 2004 Jun 4; 279(23):24498-504. Epub 2004 Mar 26.
21 Semov A, Moreno MJ, Onichtchenko A,et al.Metastasis-associated protein S100A4 induces angiogenesis through interaction with Annexin II and accelerated plasmas formation Biol Chem. 2005 May 27;280(21):20833-41. Epub 2005 Mar 23.
22 Ambartsumian N, Grigorian M, Lukanidin E.Genetically modified mouse models to study the role of metastasis-promoting S100A4(mts1) protein in met static mammary cancer. J Dairy Res. 2005; 72 Spec No: 27-33。
23 Grigorian M, Lukanidin E.Activator of metastasis in cancer cells, Mst1/S100A4 protein binds to tumor suppressor protein p53.Genetika. 2003 Jul; 39(7):900-8.
24 Rosty C, Geradts J, Sato N,et al.p16 Inactivation in pancreatic intraepithelial neoplasias (PanINs) arising in patients with chronic pancreatitis. Am J Surg Pathol. 2003 Dec; 27(12):1495-501.
25 Klingelh?fer J, Senolt L, et a1. Up-regulation of metastasis-promoting S100A4 (Mts-1) in rheumatoid arthritis: putative involvement in the pathogenesis of rheumatoid arthritis. Arthritis Rheum.2007 Mar; 56(3):779-89.
26 Garrett SC, Varney KM, Weber DJ, Bresnick AR.S100A4, a mediator of metastasis. J Biol Chem. 2006 Jan 13;281(2):677-80.
27 Agerbaek M, Alsner J, Marcussen N, et al.Focal S100A4 protein expression is an independent predictor of development of metastasis disease in cystictomized bladder cancer patients .Eur Urol. 2006 Oct; 50(4):777-85. Epub 2006 Mar 9.
28 Kiryushko D, Novitskaya V, Soroka V,et al.Molecular mechanisms of Ca(2+) signaling in neurons induced by the S100A4 protein. Mol Cell Biol. 2006 May; 26(9):3625-38.
29 Poel HG. Foreseeing cancer metastases. Eur Urol. 2006 Oct; 50(4):648-9. Epub 2006 Apr 7
30 Matsumoto K, Irie A, Satoh T,et al.Expression of S100A2 and S100A4 predicts for disease progression and patient survival in bladder cancer. Urology. 2007 Sep;70(3):602-7.
31 Shen Y, Wilder-Smith E, et a1.A novel methodology to probe endothelial differential gene expression profile reveals novel genes. Endothelium. 2007 Nov-Dec; 14(6):303-14
32 Matsumoto K, Irie A, et a1.Expression of S100A2 and S100A4 predicts for disease progression and patient survival in bladder cancer. Urology. 2007 Sep; 70(3):602-7. Epub 2007 Aug 3.
1 Donato R.SlOO:a mutagenic family of calcium—modulated proteins of the EF-hand type with intracellular and extra—cellular functional roles.Int J Biochem Cell Biol,2001,33(7):637—668.
2 Schafer BW ,Wicki R,Engelkamp D,et a1.Isolation of a YAC clone covering a cluster of nine$100 genes on human chromosome lq21:rationale for a new nomenclature of the $100 calcium-binding protein family.Genomics,1995 ,25(3):638-643.
3 Taylor S.Herrington S,Prim e W ,et a1.S100A4 (p9Ka)protein in colon carcinoma and liver metastases:association with carcinoma cells and T—lymphocytes. Br J Cancer.2002,86(3):409—416.
4 Sherbet GV ,Lakshmi MS.S100A4(MTS1) calcium binding protein in cancer growth,invasion and metastasis. Anticancer Res.1998.18(4A):2415—2421.
5 Mazzuccheli L.Protein S100A4: too long overlooked by pathologists? Am J Pathol,2002,16O(1):7-13.
6 Schafer BW ,Heizmann CW。The SlOO family of EF-hand calcium-binding proteins:functions and pathology.Trends Biochem Sic,1996,21(4):134—140.
7 Kordowska J,Stafford WF,Wang CL.Ca2+ and Zn2+ bind to different sites and induce different conformational changes in human calcyclin.Eur J Biochem,1998,253(1):57—66.
8 姬竣芳.S100蛋白家族与肿瘤.国外医学肿瘤学分册,2002,29(4):261-263.
9 Gribenko AV,Hopper JE, Makhatadze GI. Molecular characterization and tissue distribution of a novel member of the S100 family of EF-hand proteins . Biochemistry,2001 ,4O(51):15538—15548.
10 Lakshmi MS,Parker C,Sherbet GV .Expression of the Tran membrane glycoprotein CD44 and metastasis associated 18A2/MTS1 gene in B16 murine melanoma cells.Anticancer Res.1997,17(5A):3451-3455.
11 Bjorn land K,Winberg JO,Odegaard OT, et a1.S100A4 involvement in metastasis:deregulation of matrix metalloproteinase and tissue inhibitors of matrix metalloproteinase in osteosarcoma cells transected with an anti-S100A4 ribosome.Cancer Res.1999,59(18):4702—4708.
12 Ambansumian N,Klingelhofer J,Grigorian M , et a1. The metastasis-associated Mts1(S1OOA4) protein could act as an antigenic factor.0ncogene,2OO1,2O(34) :4685—4695.