TRAIL受体DR5、DcR3和caspase-3在膀胱癌和癌前病变中的表达及其意义
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摘要
背景与目的:中国膀胱癌的发病率在泌尿系统肿瘤中占第一位,而近年来有逐渐递增。在临床上,膀胱癌的治疗方式以手术为主(主要包括膀胱肿瘤电切术和开放性手术),同时给予术后辅助性化疗以及免疫治疗等,虽然临床效果较好,但术后的复发率仍然居高不下。本研究采用免疫组织化学SP法和RT-PCR检测膀胱癌组织、膀胱乳头状瘤组织和正常膀胱粘膜组织中DR5、DcR3和caspase-3的表达水平;探讨DR5、DcR3和caspase-3是否共同参与了膀胱癌的形成和进展,为膀胱癌的治疗提供新的思路。
方法:采用免疫组织化学SP法和RT-PCR检测30例膀胱癌组织、20例膀胱乳头状瘤组织和15例正常膀胱粘膜组织中DR5、DcR3和caspase-3的表达。
结果:①DR5在膀胱正常粘膜、乳头状瘤、膀胱癌组织中的阳性表达率分别为70%、45%和30%,呈递减趋势;DcR3在膀胱正常粘膜、乳头状瘤、膀胱癌组织中的阳性表达率分别为20%、37%和88%,呈递增趋势;caspase-3在膀胱正常粘膜、乳头状瘤、膀胱癌组织中的阳性表达率分别为86%、65%和22%,呈递减趋势。
②DR5 mRNA、DcR3 mRNA和caspase-3 mRNA定量分析进一步支持免疫组化结果。
结论:本实验提示DR5、DcR3和caspase-3可能共同参与了膀胱癌的发生发展,检测三者的表达对于膀胱癌的早期诊断可能有一定的价值。
Background and Objective:the incidence of bladder cancer tumors in the urinary system accounted for the first one in china . Clinically, the treatment of bladder cancer based on surgery, Including bladder tumors resection and open surgery, While giving the postoperative adjuvant chemotherapy and immune therapy. Although it had good clinical results, But the recurrence rate remained high. Expression of DR5, DcR3, and caspase-3 in bladder cancer, bladder papilloma and normal bladder mucosa were detected by immunohistochemical SP method and RT-PCR,In our Experiment,DR5, DcR3, and caspase-3 might contribute to the occurrence and development of bladder cancer,which provided new ideas to treat of bladder cancer.
Methods:Expression of DR5, DcR3, and caspase-3 in 30 cases of bladder cancer, 20 cases of bladder papilloma and 15 cases of normal bladder mucosa were detected by immunohistochemical SP method and RT-PCR .
Results:Positive expression rate of DR5 in normal bladder mucosa, papilloma, bladder cancer were 70%, 45% and 30%,repectively,which showing a decreasing trend; Positive expression rate of DcR3 in normal bladder mucosa, papilloma, bladder cancer were 20%, 37% and 88%, repectively,which showing a increasing trend; Positive expression rate of caspase-3 in normal bladder mucosa, papilloma, bladder cancer were 86%, 65% and 22%,repectively,which showing a decreasing trend; Quantitative analysis of DR5mRNA, DcR3 mRNA and caspase-3 mRNA further support the results of immunohistochemistry.
Conclusion:DR5, DcR3, and caspase-3 might contribute to the occurrence and development of bladder cancer. The test of DR5, DcR3, and caspase-3’s expression may have a certain value for the early diagnosis of bladder cancer.
方法:采用免疫组织化学SP法和RT-PCR检测30例膀胱癌组织、20例膀胱乳头状瘤组织和15例正常膀胱粘膜组织中DR5、DcR3和caspase-3的表达。
结果:①DR5在膀胱正常粘膜、乳头状瘤、膀胱癌组织中的阳性表达率分别为70%、45%和30%,呈递减趋势;DcR3在膀胱正常粘膜、乳头状瘤、膀胱癌组织中的阳性表达率分别为20%、37%和88%,呈递增趋势;caspase-3在膀胱正常粘膜、乳头状瘤、膀胱癌组织中的阳性表达率分别为86%、65%和22%,呈递减趋势。
②DR5 mRNA、DcR3 mRNA和caspase-3 mRNA定量分析进一步支持免疫组化结果。
结论:本实验提示DR5、DcR3和caspase-3可能共同参与了膀胱癌的发生发展,检测三者的表达对于膀胱癌的早期诊断可能有一定的价值。
Background and Objective:the incidence of bladder cancer tumors in the urinary system accounted for the first one in china . Clinically, the treatment of bladder cancer based on surgery, Including bladder tumors resection and open surgery, While giving the postoperative adjuvant chemotherapy and immune therapy. Although it had good clinical results, But the recurrence rate remained high. Expression of DR5, DcR3, and caspase-3 in bladder cancer, bladder papilloma and normal bladder mucosa were detected by immunohistochemical SP method and RT-PCR,In our Experiment,DR5, DcR3, and caspase-3 might contribute to the occurrence and development of bladder cancer,which provided new ideas to treat of bladder cancer.
Methods:Expression of DR5, DcR3, and caspase-3 in 30 cases of bladder cancer, 20 cases of bladder papilloma and 15 cases of normal bladder mucosa were detected by immunohistochemical SP method and RT-PCR .
Results:Positive expression rate of DR5 in normal bladder mucosa, papilloma, bladder cancer were 70%, 45% and 30%,repectively,which showing a decreasing trend; Positive expression rate of DcR3 in normal bladder mucosa, papilloma, bladder cancer were 20%, 37% and 88%, repectively,which showing a increasing trend; Positive expression rate of caspase-3 in normal bladder mucosa, papilloma, bladder cancer were 86%, 65% and 22%,repectively,which showing a decreasing trend; Quantitative analysis of DR5mRNA, DcR3 mRNA and caspase-3 mRNA further support the results of immunohistochemistry.
Conclusion:DR5, DcR3, and caspase-3 might contribute to the occurrence and development of bladder cancer. The test of DR5, DcR3, and caspase-3’s expression may have a certain value for the early diagnosis of bladder cancer.
引文
[1] Wiley SR, Schcooley K,Smolak PJ,et a1.Identification and characterization of a new member of the TNF family that induces apoptosis[J].Immunity,1995;3(6):673-682.
[2] Pitti RM,Marsters SA,Lawrence DA,et al. Genomic amplification of a decay receptor for Fas ligand in lung and colon cancer[J].Nature, 1998, 396(6712): 699-703.
[3] Victor J,Witcher DR,Becker GW, et al. Decoy receptor3(DcR3) is proteolytically processed to a metabolic fragment having differential activities against Fas ligand and LIGHT[J]. Biochem Pharmacol, 2003, 65(3): 657-667.
[4] Ling J,Herbst RS,Mendelson DS,et a1.Apo2L/TRAIL pharmacokinetics in a phase I a trial in advanced cancer and lymphoma[J].ASCO Meeting Abstracts,2006;24(18S):3047.
[5] Pan G, Ni J, Wei YF, et a1 . An antagonist decoy receptor and a death domain-containing receptor for TRAIL.Science,1997,27(5327):815-818.
[6] Horinaka M,Yoshida T,Shiraishi T,et al.Luteolin induces apoptosis via death receptor 5 up-regulation in human malignant tumor cells [J].Ongene,2005;138(1):7l-77.
[7] Shiraishi T,Yoshida T,Nakata S,et al.Tunicamycin enhances tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human prostate cancer cells[J].Cancer Res,2005;65(14):6364-6370.
[8] Verbert L,Lee B,Kocks S,et a1.Caspase-3-truncated typeⅠinositol 1,4,5-trisphosphate receptor enhances intraeellular Ca2+ leak and disturbs Ca2+ signalling[J].Biol ceII,2008,1O0(1):39-49.
[9] Medema JP, ScaffidiC, KischkelFC,ey al. FLICE is activated by association with the CD95 death-inducing signaling complex (DISC)[J]. Embo J, 1997, 16(10): 2794-2804.
[10] Shan GP,Xu MR,Lv QS,et a1.Expression of DcR3 in breast cancer and its clinical significance[J].Chin J Clin 0ncol Rehabil,2007;14(2):97-103.
[11] Wu Y,Han B,Sheng H,et a1.Clinical significance of detecting elevated serum DCR3/TR6/M68 in malignant tumor patients[J].Int J Cancer,2003,105(5):724-732.
[12] Chang PM,Chen PM,Hsieh SL,et a1.Expression of a soluble decoy receptor 3 in patients with difuse large B-cell lymphoma predicts clinical outcome[J].Int J Oncol,2008;33(3):549-554.
[13] Bai C,Connolly B,Metzker ML,et a1.Overexpression of M68/DcR3 in human gastrointestinal tract tumors independent of gene amplification and its location in a four-gene cluster[J].Proc Natl Acad Sci USA,2000;97(3):1230-1235.
[14] TakahamaY, YamadaY, Emoto K, et al. The prognostic signnificance Of overexpression of the decoy receptor for Fas ligand(DeR3) in patients with gatric carcinomas. Gasttie Caneer, 2002, 5(2): 61-68.
[1] Pan G, Ni J, Wei YF, et a1.An antagonist decoy receptor and a death domain containing receptor for TRAIL.Science,1997,27(5327):815-818.
[2] Pitti RM,Marsters SA,Lawrence DA,et al. Genomic amplification of a decay receptor for Fas ligand in lung and colon cancer[J].Nature, 1998, 396(6712): 699-703.
[3] Bai C,Connoly B,M etzker ML,et a1.Overexpression of M 68/DcR3 in human gastrointestinal tract tumors independent of gene amplification and its location in a four-gene cluster [J].Proc Nad Acad Sci USA,2000;97(3):1230-1235.
[4] Gill RM , Hunt JS . Soluble receptor(DcR3) and celular inhibitor of apoptosis-2(cIAP-2) protect human cytotrophoblast cells against LIGHT-mediated apoptosis[J].Am J Pathol,2004;165(1):309-317.
[5] Yang CR ,Hsieh SL,Ho FM ,et a1.Decoy receptor 3 increases monocyte adhesion to endothelial cells via NF-kappaB dependent up-regulation of intercellular adhesion molecule-1,VCAM-1,and IL-8 expression[J].J Immunol,2005;174(3):1647-1656.
[6] Wu YY,Chang YC,Hsu TL,et a1.Sensitization of cells toTRAIL-induced apoptosis by decoy receptor 3[J].J Biol Chem,2004,279(42):44211-44218.
[7] Yamaha K,Bilim V,Ham N.Prognostic impact of FAS/CD95/APO-1 in urothelial cancers:decreased expression of Fas is associated with disease progression[J].Br J Cancer,2005;93(5):544-551.
[8] Hsu TL,Wu YY,Chang YC,et a1.Attenuation of Thl response in decoy receptor 3 transgenic mice[J].J Immunol,2005;175(8):5135-5145.
[9] Chen, CY, Yang, KY, Chem M.Y,et al. Decoy receptor 3 Levels in peripheral blood predict outcomes of acute respiratory distress syndrome. Am J Respir Crit Care Med 2009: 180, 751-760.
[10] Shan GP,Xu MR,Lv QS,et a1.Expression of DcR3 in breast cancer and its clinical significance[J].Chin J Clin 0ncol Rehabil,2007;14(2):97-103.
[11] Chang PM,Chen PM,Hsieh SL,et a1.Expression of a soluble decoy receptor 3 in patients with difuse large B-cell lymphoma predicts clinical outcome[J].Int J Oncol,2008;33(3):549-554.
[12] Wu Y,Han B,Sheng H,et a1.Clinical significance of detecting elevated serum DCR3/TR6/M68 in malignant tumor patients[J].Int J Cancer,2003,105(5):724-732.
[13] Ozawa F,Friess H,Kleef J,et a1.Effect and expression of TRAIL and its apoptosis-promoting receptors in human pancreatic cancer[J].Cancer Lett,2001,163(1):71-81.
[14] Arakawa Y, Tachibana O, Hasegawa M, Miyamori T, Yamashita J, Hayashi Y. Frequent gene amplification and overexpression of decoy receptor 3 in glioblastoma. Acta Neuropathol 2005; 109(3): 294-298.
[15] Connor JP,Felder M.Ascites from epithelial ovarian cancer contain high levels of functional decoy receptor 3(DcR3)and is associated with platinum resistance [J].Gynecol Oncol,2008;111(2):330-335.
[16] Macher-Goeppinger S,Aulmann S,Wagener N,et a1.Decoy receptor 3 is a prognostic factor in renal cell cancer[J].Neoplasia,2OO8;1O(10):1049-1056.
[17] Medema JP,Scaffidi C,Kisehkel FC.FLICE is activated by association with the CD95 death-inducing signaling complex(DISC)[J].Embo J,1997,16(10):2794-2804.
[18] Barczyk K,Kreuter M,Pryjma J,et a1.Serum cytochrome cindicates in vivo apoptosis and can serve as a prognostic marker during cancer therapy[J].Int J Cancer,2005,116(2):167-173.
[19] Yu JK,Kwon B,NiJ,et a1.A newly identified member of tumor necrosis factor receptor superfamily(TR6) suppresses LIGHT-mediated apoptosis [J].J Biol Chem,1999;274(20):13733-13736.
[20] Tsuji S,Hosotani R,Yonehara S,et a1.Endogenous decoy receptor 3 blocks the growth inhibition signals mediated by Fas ligand in hunum pan creatic adenocareinoma[J].Int J Cancer,2003;106(1):17-25.
[21] Yang CR,Hsieh SL,Teng CM,et a1.Soluble decoy receptor 3 induces angiogenesis by neutralization of TL1A.a cytokine belonging to tumor necrosis factor superfamily and exhibiting angiostatic action [J].Cancer ReS,2004;64(3):1122-1129.
[22] Ichikawa K,Liu W,Zhao L,et a1.Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity[J].Nat Med,2001,7(8):954.
[23] Bai J,Sui J,Demirjian A,et a1.Predominant Bcl-XL knockdown disables antiapoptofic mechanisms : tumor necrosis factor-related apoptosis-inducing ligand-based triple chemotherapy overcomes chemoresistance in pancreadc cancer cells in vitro[J].Cancer Res,2005;65(6):2344-2352.
[24] Shi G,Mao J,Yu G,et a1.Tumor vaccine based on cell surface expression of DcR3/TR6[J].J Immunol,2005;174(8):4727-4735.
[2] Pitti RM,Marsters SA,Lawrence DA,et al. Genomic amplification of a decay receptor for Fas ligand in lung and colon cancer[J].Nature, 1998, 396(6712): 699-703.
[3] Victor J,Witcher DR,Becker GW, et al. Decoy receptor3(DcR3) is proteolytically processed to a metabolic fragment having differential activities against Fas ligand and LIGHT[J]. Biochem Pharmacol, 2003, 65(3): 657-667.
[4] Ling J,Herbst RS,Mendelson DS,et a1.Apo2L/TRAIL pharmacokinetics in a phase I a trial in advanced cancer and lymphoma[J].ASCO Meeting Abstracts,2006;24(18S):3047.
[5] Pan G, Ni J, Wei YF, et a1 . An antagonist decoy receptor and a death domain-containing receptor for TRAIL.Science,1997,27(5327):815-818.
[6] Horinaka M,Yoshida T,Shiraishi T,et al.Luteolin induces apoptosis via death receptor 5 up-regulation in human malignant tumor cells [J].Ongene,2005;138(1):7l-77.
[7] Shiraishi T,Yoshida T,Nakata S,et al.Tunicamycin enhances tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human prostate cancer cells[J].Cancer Res,2005;65(14):6364-6370.
[8] Verbert L,Lee B,Kocks S,et a1.Caspase-3-truncated typeⅠinositol 1,4,5-trisphosphate receptor enhances intraeellular Ca2+ leak and disturbs Ca2+ signalling[J].Biol ceII,2008,1O0(1):39-49.
[9] Medema JP, ScaffidiC, KischkelFC,ey al. FLICE is activated by association with the CD95 death-inducing signaling complex (DISC)[J]. Embo J, 1997, 16(10): 2794-2804.
[10] Shan GP,Xu MR,Lv QS,et a1.Expression of DcR3 in breast cancer and its clinical significance[J].Chin J Clin 0ncol Rehabil,2007;14(2):97-103.
[11] Wu Y,Han B,Sheng H,et a1.Clinical significance of detecting elevated serum DCR3/TR6/M68 in malignant tumor patients[J].Int J Cancer,2003,105(5):724-732.
[12] Chang PM,Chen PM,Hsieh SL,et a1.Expression of a soluble decoy receptor 3 in patients with difuse large B-cell lymphoma predicts clinical outcome[J].Int J Oncol,2008;33(3):549-554.
[13] Bai C,Connolly B,Metzker ML,et a1.Overexpression of M68/DcR3 in human gastrointestinal tract tumors independent of gene amplification and its location in a four-gene cluster[J].Proc Natl Acad Sci USA,2000;97(3):1230-1235.
[14] TakahamaY, YamadaY, Emoto K, et al. The prognostic signnificance Of overexpression of the decoy receptor for Fas ligand(DeR3) in patients with gatric carcinomas. Gasttie Caneer, 2002, 5(2): 61-68.
[1] Pan G, Ni J, Wei YF, et a1.An antagonist decoy receptor and a death domain containing receptor for TRAIL.Science,1997,27(5327):815-818.
[2] Pitti RM,Marsters SA,Lawrence DA,et al. Genomic amplification of a decay receptor for Fas ligand in lung and colon cancer[J].Nature, 1998, 396(6712): 699-703.
[3] Bai C,Connoly B,M etzker ML,et a1.Overexpression of M 68/DcR3 in human gastrointestinal tract tumors independent of gene amplification and its location in a four-gene cluster [J].Proc Nad Acad Sci USA,2000;97(3):1230-1235.
[4] Gill RM , Hunt JS . Soluble receptor(DcR3) and celular inhibitor of apoptosis-2(cIAP-2) protect human cytotrophoblast cells against LIGHT-mediated apoptosis[J].Am J Pathol,2004;165(1):309-317.
[5] Yang CR ,Hsieh SL,Ho FM ,et a1.Decoy receptor 3 increases monocyte adhesion to endothelial cells via NF-kappaB dependent up-regulation of intercellular adhesion molecule-1,VCAM-1,and IL-8 expression[J].J Immunol,2005;174(3):1647-1656.
[6] Wu YY,Chang YC,Hsu TL,et a1.Sensitization of cells toTRAIL-induced apoptosis by decoy receptor 3[J].J Biol Chem,2004,279(42):44211-44218.
[7] Yamaha K,Bilim V,Ham N.Prognostic impact of FAS/CD95/APO-1 in urothelial cancers:decreased expression of Fas is associated with disease progression[J].Br J Cancer,2005;93(5):544-551.
[8] Hsu TL,Wu YY,Chang YC,et a1.Attenuation of Thl response in decoy receptor 3 transgenic mice[J].J Immunol,2005;175(8):5135-5145.
[9] Chen, CY, Yang, KY, Chem M.Y,et al. Decoy receptor 3 Levels in peripheral blood predict outcomes of acute respiratory distress syndrome. Am J Respir Crit Care Med 2009: 180, 751-760.
[10] Shan GP,Xu MR,Lv QS,et a1.Expression of DcR3 in breast cancer and its clinical significance[J].Chin J Clin 0ncol Rehabil,2007;14(2):97-103.
[11] Chang PM,Chen PM,Hsieh SL,et a1.Expression of a soluble decoy receptor 3 in patients with difuse large B-cell lymphoma predicts clinical outcome[J].Int J Oncol,2008;33(3):549-554.
[12] Wu Y,Han B,Sheng H,et a1.Clinical significance of detecting elevated serum DCR3/TR6/M68 in malignant tumor patients[J].Int J Cancer,2003,105(5):724-732.
[13] Ozawa F,Friess H,Kleef J,et a1.Effect and expression of TRAIL and its apoptosis-promoting receptors in human pancreatic cancer[J].Cancer Lett,2001,163(1):71-81.
[14] Arakawa Y, Tachibana O, Hasegawa M, Miyamori T, Yamashita J, Hayashi Y. Frequent gene amplification and overexpression of decoy receptor 3 in glioblastoma. Acta Neuropathol 2005; 109(3): 294-298.
[15] Connor JP,Felder M.Ascites from epithelial ovarian cancer contain high levels of functional decoy receptor 3(DcR3)and is associated with platinum resistance [J].Gynecol Oncol,2008;111(2):330-335.
[16] Macher-Goeppinger S,Aulmann S,Wagener N,et a1.Decoy receptor 3 is a prognostic factor in renal cell cancer[J].Neoplasia,2OO8;1O(10):1049-1056.
[17] Medema JP,Scaffidi C,Kisehkel FC.FLICE is activated by association with the CD95 death-inducing signaling complex(DISC)[J].Embo J,1997,16(10):2794-2804.
[18] Barczyk K,Kreuter M,Pryjma J,et a1.Serum cytochrome cindicates in vivo apoptosis and can serve as a prognostic marker during cancer therapy[J].Int J Cancer,2005,116(2):167-173.
[19] Yu JK,Kwon B,NiJ,et a1.A newly identified member of tumor necrosis factor receptor superfamily(TR6) suppresses LIGHT-mediated apoptosis [J].J Biol Chem,1999;274(20):13733-13736.
[20] Tsuji S,Hosotani R,Yonehara S,et a1.Endogenous decoy receptor 3 blocks the growth inhibition signals mediated by Fas ligand in hunum pan creatic adenocareinoma[J].Int J Cancer,2003;106(1):17-25.
[21] Yang CR,Hsieh SL,Teng CM,et a1.Soluble decoy receptor 3 induces angiogenesis by neutralization of TL1A.a cytokine belonging to tumor necrosis factor superfamily and exhibiting angiostatic action [J].Cancer ReS,2004;64(3):1122-1129.
[22] Ichikawa K,Liu W,Zhao L,et a1.Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity[J].Nat Med,2001,7(8):954.
[23] Bai J,Sui J,Demirjian A,et a1.Predominant Bcl-XL knockdown disables antiapoptofic mechanisms : tumor necrosis factor-related apoptosis-inducing ligand-based triple chemotherapy overcomes chemoresistance in pancreadc cancer cells in vitro[J].Cancer Res,2005;65(6):2344-2352.
[24] Shi G,Mao J,Yu G,et a1.Tumor vaccine based on cell surface expression of DcR3/TR6[J].J Immunol,2005;174(8):4727-4735.