多药耐药性相关蛋白在乳腺癌组织中的表达及其与预后关系

目的:研究多药耐药相关蛋白（Multidrug　resistance-associated　protein　1,MRP1）在乳腺癌组织中的表达,评估其在乳腺癌预后中的作用。方法:采用免疫组织化学方法（IHC）检测47例手术切除的乳腺癌组织中MRP1的表达,并分析其与临床、病理特征的关系及对预后的影响。结果:（1）MRP1在乳腺癌组织中的阳性表达率为85.1％（40/47例）,其中高表达者占53.2％（25/47例）;（2）腋淋巴结阳性者MRP1表达水平明显高于腋淋巴结阴性者（P<0.05）,MRP1表达与月经状况、肿瘤大小、组织分级和激素受体状况均无关（P>0.05）;（3）Kaplan-Meier生存分析结果表明MRP1表达与无病生存期明显相关（P<0.05）,但和总生存期无关（P>0.05）;（4）Cox单因素分析显示肿瘤大小和MRP1表达与无病生存期明显相关（P<0.05）,但仅有肿瘤大小和总生存期明显相关（P<0.05）;而多因素分析却显示只有腋淋巴结转移和无病生存期（P<0.01）和总生存期（P<0.05）明显相关。结论:MRP1在乳腺癌组织中具有较高的表达水平,与乳腺癌患者的无病生存期有关,而与总生存期无关。     

Expression of the multidrug resistance-associated protein (MRP) gene in primary non-small-cell lung cancer

BACKGROUND: One of the major problems in the cure of advanced non-small-celllung cancer (NSCLC) is its lack of re sponse to cytotoxic drugtreatment, and the mechanisms underlying this intrinsic drugresistance are unclear. PATIENTS AND METHODS: We determined the expression of a newly recognised drug resistancegene, the Multidrug Resistance-associated Protein (MRP) gene,in normal lung tissue and in tumour biopsies from 35 surgicallyresected NSCLCs (11 adenocarcinomas, 24 squamous cell carcinomas).MRP mRNA levels were quantitated by RNase protection assay andexpression of the MRP Mr 190,000 glycoprotein was estimatedby immunohistochemistry. RESULTS: Using the MRP-speciflc monoclonal antibody MRPr1, MRP expressionwas detected by immunohistochemistry in epithelial cells liningthe bronchi in normal lung. In NSCLC approximately 35% of thesamples showed elevat ed MRP mRNA levels. Based on MRP-specificimmunohis tochemical staining the tumours were divided into4 groups: 12% were scored as negative (–), 14% showedweak cytoplasmic staining of the tumour cells (±), 40%had a clear cytoplasmic staining (±), and in 34% a strongcytoplasmic as well as membranous staining was observed (++).MRP expression, as estimated by immunohistochemistry, correlatedwith the MRP mRNA levels quantitated by RNase protection assay(correlation coefficient -0.745, p=0.0009), with MRP mRNA levels(mean ± SD) of 3.0 ± 1.0 U, 3.5 ± 0.7 U,7.5 ± 5.9 U, and 19.3 ± 10.7 U, in the (–),(±), (+), and (++) immunohistochemistry expression groups,respectively. Among the squamous cell carcinomas a correlationwas observed between MRP staining and tumour cell differentiation:the strongest MRP staining was predominantly found in the welldifferentiated tumours. CONCLUSIONS: Hyperexpression of MRP is frequently observed in primary NSCLC,especially in the well differentiated squamous cell carcinomas.Further studies are needed to assess the role of MRP in themechanism of clinical drug resistance in NSCLC. MRP, NSCLC, RNase protection assay, immunohistochemistry     

乳腺癌耐药蛋白在乳腺癌组织中的表达及其与预后的关系

目的:研究乳腺癌耐药蛋白(BCRP)在乳腺癌组织中的表达,评估其在乳腺癌预后中的作用。方法:采用免疫组织化学方法(IHC)检测60例手术切除的乳腺癌组织中BCRP的表达,并分析其与临床病理特征的关系及对预后的影响。结果:①BCRP在乳腺癌组织中的阳性表达率为35%(21/60例);②腋淋巴结或激素受体阳性者BCRP表达水平显著高于腋淋巴结阴性者和激素受体阴性者(P<0.05),BCRP表达与年龄、月经状况、肿瘤大小和组织学分级均无关(P>0.05);③Kaplan-Meier生存分析结果表明BCRP表达与无病生存期显著相关(P<0.05),但和总生存期无关(P>0.05);④Cox单因素和多因素分析都显示肿瘤大小、淋巴结转移和雌激素受体(ER)与无病生存期和总生存期显著相关(P<0.05),另外孕激素受体与总生存期(P<0.05)显著相关。结论:BCRP在乳腺癌组织中具有一定的表达水平,与乳腺癌患者的无病生存期有关,而与总生存期无关。     

乳腺癌组织中四种耐药相关蛋白的表达及其临床意义

目的:研究包括P-糖蛋白(P-glycoprotein,PGP)、多药耐药相关蛋白-1(Multidrug resistance-associated protein1,MRP1)、肺耐药相关蛋白(Lung resistance-related protein,LRP)和乳腺癌耐药蛋白(Breast cancer resistance protein,BCRP)在乳腺癌组织中的表达,并评估其在乳腺癌预后中的作用。方法:采用免疫组织化学方法检测50例经手术切除的乳腺癌组织中PGP、MRP1、LRP和BCRP的表达,并分析其与临床、病理特征的关系及其对预后的影响。结果:(1)各种耐药蛋白在乳腺癌组织中均有不同程度的表达,PGP、MRP1、LRP和BCRP的表达率分别为82·0%(41/50)、86·0%(43/50)、80·0%(40/50)和58·0%(29/50);(2)除MRP1表达与淋巴结转移状况有关以及BCRP表达与激素受体有关外(P<0·05),PGP、MRP1、LRP和BCRP表达与月经状况、肿瘤大小、淋巴结转移、组织分级和激素受体状况均无关(P>0·05);(3)Kaplan-Meier生存分析结果表明PGP、MRP1、LRP和BCRP表达均与无病生存期明显相关(P<0·05),但只有PGP表达与总生存期显著相关(P<0·01),而MRP1、LRP和BCRP表达与总生存期无关(P>0·05);(4)Cox多因素分析中,肿瘤大小和腋淋巴结转移与无病生存期和总生存期明显相关(P<0·05),但PGP表达仅与总生存期明显相关(P<0·05)。结论:乳腺癌组织中具有多种耐药蛋白的过度表达,其中PGP有可能成为判断乳腺癌患者预后的独立指标。     

乳腺癌耐药蛋白在乳腺癌组织中的表达及与预后关系

目的研究乳腺癌耐药蛋白（Breast cancer resistance protein,BCRP）在乳腺癌组织中的表达,评估其在乳腺癌预后中的作用。方法采用免疫组织化学方法（Immunohistochemistry,IHC）检测47例手术切除的乳腺癌组织中BCRP的表达,并分析其与临床、病理特征的关系及对预后的影响。结果（1）BCRP在乳腺癌组织中的阳性表达率为55．3％（26／47例）,其中高表达者13例（27．7％）;（2）激素受体阳性者BCRP表达水平明显高于激素受体阴性者（P〈0．05）,BCRP表达与月经状况、肿瘤大小、腋淋巴结转移和组织分级均无关（P〉0．05）;（3）Kaplan—Meier生存分析结果表明BCRP和无病生存期相关（P〈0．05）,但和总生存期无关（P〉0．05）;（4）Cox单因素分析显示肿瘤大小和BCRP表达与无病生存期明显相关（P〈0．05）,而肿瘤大小和总生存期也明显相关（P〈0．05）;在多因素分析中BCRP表达仅和无病生存期明显相关,此外腋淋巴结转移与无病生存期和总生存期均明显相关（P〈0．05）。结论BCRP在乳腺癌组织中具有较高的表达水平,但与乳腺癌患者预后无关。     

Expression of the multidrug resistance-associated protein (MRP) gene in urothelial carcinomas

The intrinsic or acquired resistance of urothelial cancer to chemotherapy is one major obstacle to successful treatment. Generally, the expression level of P-glycoprotein in urothelial cancer is low, so we accordingly investigated the expression of multidrug resistance-associated protein (MRP). We examined the expression of MRP mRNA by means of slot-blotting samples of 11 renal pelvic and/or ureteral tumors, 33 bladder tumors, one lung metastasis from a ureter tumor, 7 non-cancerous urothelia from patients with transitional-cell carcinoma (TCC) and one urothelium from a patient with renal-cell carcinoma (RCC). We also estimated, by Southern blotting, whether or not the MRP gene was amplified in clinical specimens that overexpressed MRP mRNA. MRP was detected immunohistochemically using a polyclonal antibody against MRP. In all, 5 of 11 renal pelvic and/or ureter tumors (45.5%), 17 of 33 bladder tumors (51.5%) and 4 of 7 non-cancerous urothelia of TCC patients (57.1%) expressed more than 2-fold the MRP mRNA levels of drug-sensitive human KB cells. There was no significant difference in the MRP mRNA level between primary and recurrent tumors. Low-grade urothelial carcinomas (G1 and G2 TCCs) expressed significantly higher levels of MRP mRNA than the high-grade G3 TCC. The MRP gene was not amplified in urothelial carcinomas, irrespective of their expression levels of MRP mRNA. Immunohistochemically, MRP was located mainly on the plasma membrane, but also detected on the cytoplasm of cancer cells. MRP may be one mechanism responsible for intrinsic drug resistance in low-grade urothelial cancer. © 1996 Wiley-Liss, Inc.     

多药耐药相关蛋白2及其在肿瘤耐药中的研究进展

肿瘤对化疗药物多药耐药是肿瘤治疗失败的重要原因之一.多药耐药的主要原因是由PgP、多药耐药相关蛋白(MRP)、肺耐药相关蛋白(LRP)、乳腺癌耐药相关蛋白(BCRP)等转运蛋白表达异常增高所致.MRP包含9个成员:MRP1-MRP9.多药耐药相关蛋白2(MRP2)是三磷酸腺苷(ATP)结合盒运载体蛋白家族成员之一,本文就MRP2基因的特性及其在肿瘤耐药中的作用作一综述.     

Alterations in expression of the multidrug resistance-associated protein (MRP) gene in high-grade transitional cell carcinoma of the bladder.

Expression of the MRP gene has been demonstrated in vitro to be a casual factor in non-P-glycoprotein-mediated multidrug resistance, and is implicated in resistance to a number of the chemotherapeutic agents currently used in the treatment of high-grade transitional cell carcinoma (TCC) of the bladder (doxorubicin, epirubicin and vinblastine). Using a sensitive RT-PCR-based technique, we have quantified MRP mRNA levels in a series of untreated TCC (n=24), normal bladder (n=5) and control tissue and cell line samples. MRP mRNA was widely expressed and detectable in all samples analysed, with considerable (up to 190-fold) variation observed between individual tumour samples. MRP mRNA levels found in TCC samples were lower than those determined for normal peripheral mononucleocyte (2.3-fold) and testis (4.1-fold) samples, previously reported to be high-expressing tissues, and varied over a similar range to that observed in normal bladder samples. Results indicate that MRP mRNA levels in a greater proportion of high-grade (G3) bladder tumours (55%, 6/11) are significantly reduced (P=0.018) compared with low- and moderate-grade (G1/2) bladder tumours (8%, 1/13), and suggest that MRP mRNA levels frequently become reduced as a consequence of tumour progression to advanced, poorly differentiated disease. No correlation was apparent between MRP and MDR1 mRNA levels, thus providing no evidence to suggest common regulation of the two genes. In a limited number of patients, no evidence was found to support a role for MRP mRNA levels as a determinant of response to chemotherapy in patients being uniformly treated with either cisplatin-methotrexate-vinblastine (n=6) or epirubicin-cisplatin-methotrexate (n=4) regimens. Similarly, no overall pattern of altered MRP mRNA expression was observed following chemotherapy in four patients from whom post chemotherapy biopsies were taken. This study provides a useful pilot investigation regarding the level, variation and pattern of MRP mRNA expression in TCC of the bladder, and suggests that further studies to establish the clinical significance of these variations are required.     

食管鳞癌多药耐药相关蛋白表达的研究

目的:观察24例食管癌组织及食道正常组织MRP的表达.方法:采用RT-PCR方法.结果:75. 0%的食管癌组织表达MRP,29.2%的食管正常组织表达MRP,两者有明显差异(P=0.0039),分析24例食管癌MRP的表达情况,可以看到:MRP的表达与临床分期、癌细胞的分化程度无明显关系.结论:大多数食管癌组织表达MRP,MRP的表达可能与食管癌的先天耐药有关.     

The expression and significance of P-glycoprotein,lung resistance protein and multidrug resistance-associated protein in gastric cancer

Background

To detect the expression of multidrug resistance molecules P-glycoprotein (P-gp), Lung resistnce protein (LRP) and Multidrug resistance-associated protein (MRP) and analyze the relationship between them and the clinico-pathological features.

Methods

The expressions of P-gp, LRP and MRP in formalin-fixed paraffin-embedded tissue sections from 59 gastric cancer patients were determined by a labbelled Streptavidin-Peroxidase (SP) immunohistochemical technique, and the results were analyzed in correlation with clinicopathological data. None of these patients received chemotherapy prior to surgery.

Results

The positive rates of P-gp, LRP, MRP were 86.4%, 84.7% and 27.1%, respectively. The difference between the positive rate of P-gp and MRP was significant statistically, as well as the difference between the expression of MRP and LRP. No significant difference was observed between P-gp and LRP, but the positively correlation between the expression of P-gp and LRP had been found. No significant correlation between the expression of P-gp, LRP, MRP and the grade of differentiation were observed. The expression of P-gp was correlated with clinical stages positively (r = 0.742), but the difference with the expression of P-gp in different stages was not significant.

Conclusion

The expressions of P-gp, LRP and MRP in patients with gastric cancer without prior chemotherapy are high, indicating that innate drug resistance may exist in gastric cancer.     

多药耐药相关蛋白基因在非小细胞肺癌表达的临床意义

目的 探索多药耐药相关蛋白（ＭＲＰ）在非小细胞肺癌（ＮＳＣＬＣ）的表达,以及与病理类型、病期及预后的关系。方法 以原位杂交法检测冰冻ＮＳＣＬＣ组织。结果 全组５８例ＮＳＣＬＣ、ＭＲＰＭＲＮＡ总表达率为７４．１％,鳞癌为７２．０％,腺癌为７３．３％。ＭＲＰ的表达与病理类型、ＴＮＭ发期及分化程度无关。４７例接受化疗的ＮＳＣＬＣ中,３５例ＭＲＰ表达者生存率明显低于ＭＲＰ表达者,中位生存期分别为８．７个月     

多药耐药相关蛋白及肺耐药蛋白在人直肠癌组织中的表达及临床 …

目的 检测多药耐药相关蛋白（ＭＲＰ）及肺耐药蛋白（ＬＲＰ）在人直肠癌组织中的表达,探讨其与临床分期、分化程度及预后的关系。方法 采用免疫组织化学技术法检测５７例人直肠癌组织中ＭＲＰ及ＬＲＰ的表达。结果 ５７例人直肠癌组织中可检测到ＭＲＰ表达者２８例,占４９．１％;ＬＲＰ表达者２４例,占４２．１％;二者同时表达者１０例,占１７．５％;有ＭＲＰ或ＬＲＰ表达者４２例,占７３．７％;两蛋白表达阳性率与肿瘤     

Multidrug resistance-associated protein (MRP) expression is correlated with expression of aberrant p53 protein in colorectal cancer

Multidrug resistance-associated protein (MRP) is one of the major factors responsible for non-P-glycoprotein (Pgp)-mediated multidrug resistance of human tumour cells. In this study, we examined MRP and aberrant p53 expression in 54 colorectal cancers (CRC), 35 carcinoma in adenomas (CIA) and 40 adenomatous polyps by immunohistochemical procedures. 38 of 54 (70%) CRCs, 16 of 35 (46%) CIAs and 3 of 40 (8%) adenomatous polyps were MRP positive (χ² test, P<0.0001). 36/54 (67%) CRCs, 10/35 (29%) CIAs and 0/40 adenomatous polyps were p53 positive. 30 of the 36 p53-positive CRCs were also MRP positive and 8/10 CIAs were both p53 and MRP positive. MRP overexpression correlated with aberrant p53 accumulation in CRCs and CIAs (χ² test, P≤0.01). Coexpression of MRP and p53 in the same cells was confirmed in the CRCs and CIAs by double staining procedures. These results suggested that MRP overexpression is related to aberrant p53 expression in CRC.     

EXPRESSION OF MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN （MRP） AND ITS RELATIONSHIP WITH CLINICOPATHOLOGICAL FACTORS IN NON-SMALL CELL LUNG CANCER

Atpresentchemotherapyisstilloneofthemainmethodsforcontrollingtherecurrentandmetastasisofmalignanttumors.Butmultidrugresistance(MDR)isamajorobstacleinthesuccessfultreatmentofcancerbychemotherapy.Therelationshipbetweenmultidrugresistance-associatedprotein(MRP)andchemotherapyresistancehasattractedmuchattention[1].ColeseparatedakindofoverexpressingmRNAfromthemultidrugresistancehum ansmallcelllungcancer(SCLC)celllineH69ARwhichhadnooverexpressionofp-gp,andcloneditscDNA.Theproteincodedbelonge…     

原位分子杂交检测肺癌组织MRP基因表达及意义

目的　研究多药耐药性相关蛋白基因 MRP基因 (multi drugresistanceassociatedproteingene ,MRPgene)对肺癌患者预后的影响。方法　应用地高辛抗体标记探针原位分子杂交结合免疫组化技术 ,检测 47例非小细胞肺癌 (NSCLC)根治术后石蜡组织标本中肺癌细胞MRP基因mRNA表达 ,并回顾性随访。结果　 47例组织标本中 ,肺癌细胞均有不同程度MRP基因mRNA过度表达 ,其表达水平与患者术后生存期、化疗疗效、复发及转移密切相关 ,与病理类型、肿瘤大小、淋巴结转移、病理分期、癌细胞分化程度、年龄、性别无明显相关性。结论　MRP基因与肺癌患者预后有密切相关性 ,检测MRP基因mRNA表达水平可作为预测肺癌患者预后、确定化疗方案的手段之一。