MRP4在骨肉瘤组织中的表达及临床意义
摘要
背景和目的：目前有研究表明MRP4基因参与了多种肿瘤的耐药机制，如胃癌、肺癌及乳癌等。本研究试图探讨MRP4基因在骨肉瘤组织中的表达及其临床意义。
方法：收集2005年1月至2011年4月经规范化综合治疗且有完整临床和病理资料的病例50例，其中男性28例，女性22例；Enneking临床分期IIB期41例，III期9例；中位年龄15.5岁（95%CI:15.73-20.93岁）。应用免疫组织化学方法检测骨肉瘤组织及8例瘤旁正常骨组织中MRP4的表达，分析其与骨肉瘤患者临床病理特征及预后的相关性。
结果：本试验检测了50例骨肉瘤组织中MRP4的表达。MRP4在骨肉瘤组织细胞浆中的表达率为40%（20/50），明显高于瘤旁正常骨组织的12.5%（1/8），差异有统计学意义（P=0.022）。它的表达水平与骨肉瘤患者的Enneking临床分期、性别、年龄、肿瘤大小、肿瘤部位等无明显的相关性（P>0.05）。41例IIB期骨肉瘤患者中MRP4高水平表达组患者的无病生存时间与低水平表达/不表达组差异不明显（P=0.23），50例患者（41例IIB期和9例III期）中，MRP4高水平表达组患者的总生存时间较低水平表达/不表达组差异亦不显著（P=0.40），它的表达与IIB期患者的总生存时间无明显相关性（P>0.05）。
结论：MRP4在骨肉瘤患者组织中的表达高于瘤旁正常骨组织，但MRP4在骨肉瘤组织中不同程度的表达与骨肉瘤患者预后无明显相关，MRP4高表达患者与低表达患者预后无显著差异性。
Objective To investigate the expression of MRP4(multidrug resistance associated proteins) in osteosarcoma of extremities, analyze its correlation with clinical and histopathological characteristics, and further discuss its role in the prognosis of osteosarcoma.
Methods Immunohistochemical stainning was performed to investigate the expression of MRP4in50cases of osteosarcoma which had complete follow-up data for more than three years.Among this group of patients,there were28males,22females;41stage ⅡB and9stage Ⅲ; with the median age of15.5(95%CI:15.73-20.93).Furthermore, its correlation with patients' clinical manifestations, histopathological characteristics and its significance in prognosis of osteosarcoma was analyzed basing on the clinical follow-up data.
Results This experiment analyzed the expression of MRP4in50cases of osteosarcoma. Compared with that in normal bone cells,MRP4was over-expressed in osteosarcoma cytoplasm (P=0.012). The expression of this marker has no significant difference in the Enneking clinical staging,gender,age,size and location of tumor(P>0.05). Kaplan-Meier analysis showed that in41cases of stage IIB patients,the disease free survival time in MRP4-over-expression patients was similar to that in low-expression/negative-expression patients (P=0.23),and in50patients(41cases of stage ⅡB and9cases of stage Ⅲ),the overall survival time in MRP4-over-expression patients was also similar to that in low-expression/negative-expression patients(P=0.40). In stage ⅡB patients, there was no significant difference between those who showed MRP4-over-expression and those who did not show MRP4-over-expression in the overall survival time (P>0.05).
Conclusion MRP4expression in patients with osteosarcoma tissues was significantly higher than the normal bone tissue adjacent to the tumor, but MRP4is not a poor prognostic factor in patients with osteosarcoma,and the MRP4high expression in patients didn't associated with disease free survival or overall survival.
方法：收集2005年1月至2011年4月经规范化综合治疗且有完整临床和病理资料的病例50例，其中男性28例，女性22例；Enneking临床分期IIB期41例，III期9例；中位年龄15.5岁（95%CI:15.73-20.93岁）。应用免疫组织化学方法检测骨肉瘤组织及8例瘤旁正常骨组织中MRP4的表达，分析其与骨肉瘤患者临床病理特征及预后的相关性。
结果：本试验检测了50例骨肉瘤组织中MRP4的表达。MRP4在骨肉瘤组织细胞浆中的表达率为40%（20/50），明显高于瘤旁正常骨组织的12.5%（1/8），差异有统计学意义（P=0.022）。它的表达水平与骨肉瘤患者的Enneking临床分期、性别、年龄、肿瘤大小、肿瘤部位等无明显的相关性（P>0.05）。41例IIB期骨肉瘤患者中MRP4高水平表达组患者的无病生存时间与低水平表达/不表达组差异不明显（P=0.23），50例患者（41例IIB期和9例III期）中，MRP4高水平表达组患者的总生存时间较低水平表达/不表达组差异亦不显著（P=0.40），它的表达与IIB期患者的总生存时间无明显相关性（P>0.05）。
结论：MRP4在骨肉瘤患者组织中的表达高于瘤旁正常骨组织，但MRP4在骨肉瘤组织中不同程度的表达与骨肉瘤患者预后无明显相关，MRP4高表达患者与低表达患者预后无显著差异性。
Objective To investigate the expression of MRP4(multidrug resistance associated proteins) in osteosarcoma of extremities, analyze its correlation with clinical and histopathological characteristics, and further discuss its role in the prognosis of osteosarcoma.
Methods Immunohistochemical stainning was performed to investigate the expression of MRP4in50cases of osteosarcoma which had complete follow-up data for more than three years.Among this group of patients,there were28males,22females;41stage ⅡB and9stage Ⅲ; with the median age of15.5(95%CI:15.73-20.93).Furthermore, its correlation with patients' clinical manifestations, histopathological characteristics and its significance in prognosis of osteosarcoma was analyzed basing on the clinical follow-up data.
Results This experiment analyzed the expression of MRP4in50cases of osteosarcoma. Compared with that in normal bone cells,MRP4was over-expressed in osteosarcoma cytoplasm (P=0.012). The expression of this marker has no significant difference in the Enneking clinical staging,gender,age,size and location of tumor(P>0.05). Kaplan-Meier analysis showed that in41cases of stage IIB patients,the disease free survival time in MRP4-over-expression patients was similar to that in low-expression/negative-expression patients (P=0.23),and in50patients(41cases of stage ⅡB and9cases of stage Ⅲ),the overall survival time in MRP4-over-expression patients was also similar to that in low-expression/negative-expression patients(P=0.40). In stage ⅡB patients, there was no significant difference between those who showed MRP4-over-expression and those who did not show MRP4-over-expression in the overall survival time (P>0.05).
Conclusion MRP4expression in patients with osteosarcoma tissues was significantly higher than the normal bone tissue adjacent to the tumor, but MRP4is not a poor prognostic factor in patients with osteosarcoma,and the MRP4high expression in patients didn't associated with disease free survival or overall survival.
引文
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[3]Bacci G, Lari S.Current treatment of high grade osteosarcoma of the extremity: review[J].J Chemother,2001,13(3):235-243.
[4]Bacci G,Ferrari S,Lari S,et al.Osteosarcoma of the limb:amputation or limb salvage in patients treated by neoadjuvant chemotherapy [J].J Bone Joint Surg Br,2002,84(1):88-92.
[5]Muscolo DL, Ayerza MA, Aponte-Tinao LA, et al. Partial epiphyseal preservation and intercalary allograft reconstruction in high-grade metaphyseal osteosarcoma of the knee[J].J Bone Joint Surg Am,2004,86(12):2686-2693.
[6]Bielack SS, Kempf-Bielack B, Delling G, et al.Prognostic factors in high-grade osteosarcoma of the extremities or trunk:an analysis of1,702patients treated on neoadjuvant cooperative osteosarcoma study group protocols[J].J Clin Oncol.2002,20(3):776-790.
[7]Bacci G,Longhi A,Versari M,et al.Prognostic factors for osteosarcoma of the extremity treated with neoadjuvant chemotherapy:15-year experience in789patients treated at a single institution[J].Cancer,2006,106(5):1154-1161.
[8]Bakhshi S, Radhakrishnan V.Prognostic markers in osteosarcoma[J].Expert review of anticancer therapy,2010,10(2):271-287.
[9]da Graca Rocha G, Simoes M, Oliveira RR,et al.Effects of3beta-Acethyl Tormentic Acid (3ATA) on ABCC Proteins Activity. Int J Mol Sci,2012,13(6)757-771.
[10]孙大辉,张德宝,谷贵山,等.差异凝胶电泳筛选人骨肉瘤细胞多药耐药相关蛋 白.中国肿瘤生物治疗杂志,2008,15(5)：440-443.
[11]Debska S, Owecka A, Czernek U, et al.Transmembrane transporters ABCC-structure, function and role in multidrug resistance of cancer cells. Postepy Hig Med Dosw (Online),2011,65(5)52-61.
[12]Cantore M, Capparelli E, Berardi F, et al. Clinical pharmacokinetic and metabolism of PET radiotracers for imaging P-glycoprotein in chemoresistant tumor of colorectal cancer. Curr Drug Metab,2011,12(10)985-988.
[13]Yang AK, Zhou ZW, Wei MQ, et al. Modulators of multidrug resistance associated proteins in the management of anticancer and antimicrobial drug resistance and the treatment of inflammatory diseases. Curr Top Med Chem,2010,10(17)1732-1756.
[14]van de Ven R, de Groot J, Reurs AW, et al. Unimpaired immune functions in the absence of Mrp4(Abcc4). Immunology Letters,2009,124(2)81-87.
[15]Russel FG, Koenderink JB, Masereeuw R. Multidrug resistance protein4(MRP4/ABCC4):a versatile efflux transporter for drugs and signalling molecules. Trends Pharmacol Sci,2008,29(4)200-207.
[16]Keppler D. Multidrug resistance proteins (MRPs, ABCCs):importance for pathophysiology and drug therapy. Handb Exp Pharmacol,2011,201,299-323.
[17]Gradilone A, Pulcinelli FM, Lotti LV, et al. Celecoxib upregulates multidrug resistance proteins in colon cancer:lack of synergy with standard chemotherapy. Curr Cancer Drug Targets,2008,8(5)414-420.
[18]Christine L. Hammond, Rosemarie Marchan, Suzanne M. Krance.Glutathione export during Apoptosis Requires Functional Multidrug Resistance associated Proteins. The Journal of biological chemistry vol282, NO.19, pp.14337-14347, May11,2007.
[19]CStammler, E.W.Pommerenke, J.Mattern and M.Volm. Effects of single doses of irradiation of on the expression of resistance-related proteins in murine NIH3T3and human lung carcinoma cells. Carcinogenesls vol.16no.9pp.2051-2055,1995.
[20]Bramer JA, van Linge JH, Scholten RJ.Prognostic factors in localized extremity osteosarcoma:a systematic review[J].Eur J Surg Oncol.2009,35(10):1030-1036.
[21]Burger H,Foekens JA,Look MP,et al.RNA expression of breast cancer resistance protein,Lung resistance related protein,multidrug resistance associated proteins1and2,and multidrug resistance gene lin breast cancer,correlation with chemotherapeutic response[J].Clin Cancer Res,2003,9:827.
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[2]Mirabello L, Troisi RJ, Savage SA.Osteosarcoma incidence and surviral rates from1973to2004:data from the Surveillance,Epidemiology,and End Results Program.Cancer,2009,115(7):1531-1543.
[3]Bacci G, Lari S.Current treatment of high grade osteosarcoma of the extremity: review[J].J Chemother,2001,13(3):235-243.
[4]Bacci G,Ferrari S,Lari S,et al.Osteosarcoma of the limb:amputation or limb salvage in patients treated by neoadjuvant chemotherapy [J].J Bone Joint Surg Br,2002,84(1):88-92.
[5]Muscolo DL, Ayerza MA, Aponte-Tinao LA, et al. Partial epiphyseal preservation and intercalary allograft reconstruction in high-grade metaphyseal osteosarcoma of the knee[J].J Bone Joint Surg Am,2004,86(12):2686-2693.
[6]Bielack SS, Kempf-Bielack B, Delling G, et al.Prognostic factors in high-grade osteosarcoma of the extremities or trunk:an analysis of1,702patients treated on neoadjuvant cooperative osteosarcoma study group protocols[J].J Clin Oncol.2002,20(3):776-790.
[7]Bacci G,Longhi A,Versari M,et al.Prognostic factors for osteosarcoma of the extremity treated with neoadjuvant chemotherapy:15-year experience in789patients treated at a single institution[J].Cancer,2006,106(5):1154-1161.
[8]Bakhshi S, Radhakrishnan V.Prognostic markers in osteosarcoma[J].Expert review of anticancer therapy,2010,10(2):271-287.
[9]da Graca Rocha G, Simoes M, Oliveira RR,et al.Effects of3beta-Acethyl Tormentic Acid (3ATA) on ABCC Proteins Activity. Int J Mol Sci,2012,13(6)757-771.
[10]孙大辉,张德宝,谷贵山,等.差异凝胶电泳筛选人骨肉瘤细胞多药耐药相关蛋 白.中国肿瘤生物治疗杂志,2008,15(5)：440-443.
[11]Debska S, Owecka A, Czernek U, et al.Transmembrane transporters ABCC-structure, function and role in multidrug resistance of cancer cells. Postepy Hig Med Dosw (Online),2011,65(5)52-61.
[12]Cantore M, Capparelli E, Berardi F, et al. Clinical pharmacokinetic and metabolism of PET radiotracers for imaging P-glycoprotein in chemoresistant tumor of colorectal cancer. Curr Drug Metab,2011,12(10)985-988.
[13]Yang AK, Zhou ZW, Wei MQ, et al. Modulators of multidrug resistance associated proteins in the management of anticancer and antimicrobial drug resistance and the treatment of inflammatory diseases. Curr Top Med Chem,2010,10(17)1732-1756.
[14]van de Ven R, de Groot J, Reurs AW, et al. Unimpaired immune functions in the absence of Mrp4(Abcc4). Immunology Letters,2009,124(2)81-87.
[15]Russel FG, Koenderink JB, Masereeuw R. Multidrug resistance protein4(MRP4/ABCC4):a versatile efflux transporter for drugs and signalling molecules. Trends Pharmacol Sci,2008,29(4)200-207.
[16]Keppler D. Multidrug resistance proteins (MRPs, ABCCs):importance for pathophysiology and drug therapy. Handb Exp Pharmacol,2011,201,299-323.
[17]Gradilone A, Pulcinelli FM, Lotti LV, et al. Celecoxib upregulates multidrug resistance proteins in colon cancer:lack of synergy with standard chemotherapy. Curr Cancer Drug Targets,2008,8(5)414-420.
[18]Christine L. Hammond, Rosemarie Marchan, Suzanne M. Krance.Glutathione export during Apoptosis Requires Functional Multidrug Resistance associated Proteins. The Journal of biological chemistry vol282, NO.19, pp.14337-14347, May11,2007.
[19]CStammler, E.W.Pommerenke, J.Mattern and M.Volm. Effects of single doses of irradiation of on the expression of resistance-related proteins in murine NIH3T3and human lung carcinoma cells. Carcinogenesls vol.16no.9pp.2051-2055,1995.
[20]Bramer JA, van Linge JH, Scholten RJ.Prognostic factors in localized extremity osteosarcoma:a systematic review[J].Eur J Surg Oncol.2009,35(10):1030-1036.
[21]Burger H,Foekens JA,Look MP,et al.RNA expression of breast cancer resistance protein,Lung resistance related protein,multidrug resistance associated proteins1and2,and multidrug resistance gene lin breast cancer,correlation with chemotherapeutic response[J].Clin Cancer Res,2003,9:827.
[1]Pallis M, Russell N. Strategies for overcoming p-glycoprotein-mediated drug resistance in acute myeloblastic leukaemia. Leukemia,2004,18(12):1927-1930.
[2]Johnstone RW, Cretney E, Smyth MJ. P-Glycoprotein Protects Leukemia Cells Against Caspase-Dependent, but not Caspase-Independent, Cell Death. Blood,1999,93(3):1075-1085.
[3]Breuninger LM, Paul S, Gaughan K, Miki T, Chan A, Aaronson SA, Kruh GD. Expression of Multidrug Resistance-associated Protein in NIH/3T3Cells Confers Multidrug Resistance Associated with Increased Drug Efflux and Altered Intracellular Drug Distribution. Cancer Research,1995,55(22):5342-5347.
[4]刘忠民,毕维民,王明玉,陈廷武,寿楠海,姜希宏,徐克森.多药耐药相关蛋白在胃癌中的表达及其临床意义.山东医药,2000(03)：3-4.
[5]Dietrich CG, de Waart DR, Ottenhoff R, Bootsma AH, van Gennip AH, Elferink RPJO. Mrp2-deficiency in the rat impairs biliary and intestinal excretion and influences metabolism and disposition of the food-derived carcinogen2-amino-l-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Carcinogenesis,2001,22(5):805-811.
[6]Konig J, Rost D, Cui Y, Keppler D. Characterization of the human multidrug resistance protein isoform MRP3localized to the basolateral hepatocyte membrane. Hepatology,1999,29(4):1156-1163.
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