PSMA和AR在膀胱移行细胞癌中的表达及其相关性研究
摘要
背景与目的：膀胱癌是泌尿系统中最常见的恶性肿瘤。近年来,我国部分城市肿瘤发病率报告显示膀胱癌发病率有增高趋势。正确判断膀胱癌的生物学性质对肿瘤治疗和监控复发具有重要临床意义。多年来,大量研究试图找到一种或几种可用于诊断或监测膀胱癌复发和进展的肿瘤标记物,然而至今尚无满意的特异生物标记物可用。前列腺特异性膜抗原(prostate specific membrane antigen, PSMA)和雄激素受体(androgen receptor,AR)是近些年来发现的可能与多种恶性肿瘤的发生发展有关的标记物,我们采用免疫组织化学方法来检测二者在膀胱移行细胞癌组织中的表达情况,探讨它们在膀胱癌中的生物学行为及其临床意义。
资料与方法：选取天津医科大学第二医院2005年3月-2008年12月手术切除的75例经术后病理证实的膀胱移行细胞癌组织,所有患者均为开放手术,术前均未行放、化疗及免疫治疗。其中男52例,女23例,年龄33-88岁,平均(66.9±11.3)岁。按照TNM分期：Ta-125例；T2-450例；WHO膀胱肿瘤组织学分类标准(1999)分级：G16例,G220例,G349例。另取正常膀胱黏膜15例作为正常对照组,均为前列腺增生症开放性手术时留取,男性,年龄42-75岁,平均(61.6±12.2)岁。采用链霉菌素抗生物素蛋白-过氧化物酶免疫组化法(streptavidin-peroxidase, SP法)进行检测。染色步骤按试剂盒说明书分别进行,选用前列腺癌已知阳性组织切片作阳性对照,用PBS液代替—抗作阴性对照。结果判定以光镜下观察细胞出现黄色颗粒为阳性染色。应用SPSS 17.0统计软件包对所有数据进行统计学分析,P<0.05为差异有统计学意义。
结果：(1)在膀胱移行细胞癌中,PSMA呈阳性表达,其阳性表达率为28%,15例正常膀胱黏膜组织均未见阳性表达,差异具有统计学意义(P<0.05)。PSMA在膀胱移行细胞癌Tis-T,期和T2-T4期中的阳性表达率分别为20%和32%,差别无统计学意义(P>0.05)。PSMA在膀胱移行细胞癌G,、G2、G3级的阳性表达率依次为50%、35%和22.4%,三者之间均无统计学差异(P>0.05)。PSMA的阳性表达率与肿瘤是否复发有关,其在复发性膀胱癌中的表达明显高于初发性膀胱癌,差异具有统计学意义(P<0.01)。PSMA的表达在患者年龄、性别、肿瘤数目及大小等临床病理特征方面无统计学差异(P>0.05)。(2)AR在膀胱移行细胞癌中的阳性表达率为21.3%,在正常膀胱黏膜组织中亦未见阳性表达,两组之间差异具有统计学意义(P<0.05)。AR在膀胱移行细胞癌中的阳性表达随着肿瘤临床分期的增高而降低,其在Tis-T1期、T2-T4期中的阳性表达率分别为36%和14%,差异具有统计学意义(P<0.05)。AR在G1、G2、G3级膀胱移行细胞癌组织中的阳性表达率分别为50%、15%和20.4%,三者之间无统计学差异(P>0.05)。与PSMA不同,AR的表达仅与膀胱移行细胞癌的临床分期有关,而在肿瘤是否复发以及肿瘤大小、数目、患者的年龄、性别等方面差异无统计学意义(P<0.05)。(3)在21例PSMA表达呈阳性的膀胱移行细胞癌组织中,有9例同时存在AR的阳性表达,占42.9%,二者的表达相关联(r=0.328,P<0.01)。
结论：(1)研究结果显示PSMA和AR均在膀胱移行细胞癌组织中存在阳性表达,而在正常膀胱黏膜组织中均未发现阳性表达,两组之间差别具有统计学意义。(2) PSMA在膀胱移行细胞癌中的表达与肿瘤的临床分期和病理分级无明确关系；而与肿瘤是否复发有关。(3)AR在膀胱癌中的阳性表达仅与肿瘤的临床分期有关,与肿瘤的病理分级及是否复发等无关。4.在膀胱移行细胞癌中,PSMA与AR的表达相关联,二者可能通过同一途径协同作用参与膀胱移行细胞癌发生、发展的分子调控过程。
Background and Objective:In china, bladder cancer is the most common malignant neoplasm in rinary system. Many extensive studies have been performed to determine whether particular one or several biomarkers are involved in bladder tumors to identify tumors with a high risk of recurrence and progression. None of these markers, however, is currently available. Prostate specific membrane antigen (PSMA) and androgen receptor (AR) are biomarkers which possibly relate to the development of varieties of malignant tumors. We use immunohistochemical method to detect PSMA and AR in bladder transitional cell carcinoma (BTCC) tissues, and explore their biological behavior and clinical significance.
Materials and Method:A total of 75 patients (52 males and 23 females)from department of urology, second hospital of Tianjin medical university with BTCC undergoing open surgical resection, no radiotherapy, no chemotherapy and no immunotherapy before surgery, with accession from March 2005 through December 2008, were included in this study. The average age is 66.9 with a range of 33-88 years. According to the TNM stage classification of UICC and the grade classification of WHO, these samples could be classified into Ta-1 25 cases, T2-4 50 cases; G1 6 cases, G2 20 cases, G3 49 cases. In addition, we collected 15 normal bladder tissues from the patients underwent the resection of benign prostatic hyperplasia as negative control. The average age of the control group is 61.6 with a range of 42-75 years. Streptavidin-peroxidase(SP) method was used to detect the expression of PSMA, AR in BTCC and normal bladder tissues. Staining steps were carried out according to kit instructions, and we choose positive prostate cancer histological section as positive control, with PBS replaced the antibody as negative control. The results were observed by light microscope, and buffy particles in cells were considered as positive cases. SPSS 17.0 software application was used for all analysis and statistical significance was defined as P values less than 0.05.
Results:(1) The expression rate of PSMA in BTCC was 28%, and no positive expression was detected in 15 cases of normal bladder mucosa, showing significant difference (P<0.05). The PSMA expression ratios in 75 cases of carcinoma were 20% and 32% in Tis-T1 stage and T2-T4 stage respectively, while no significant difference between the two groups(P>0.05). The expression ratios of PSMA were 50%,35% and 22.4% in G1, G2, and G3 respectively. There was also no significant difference in pathological grade between the three groups (P>0.05). However, the PSMA expression was associated with whether the tumor was recurrent, and the positive rate in recurrent cases were significantly higher than in early-onset cases, with the difference was statistically significant (P<0.05). No demonstrable difference was found in age, sex, the number tumor and the tumor's size. (2) The positive expression rate of AR in BTCC was 21.3%, and also no positive expression was detected in normal bladder mucosa, showing significant difference (P<0.05). The AR expression rate in BTCC were 36% and 14% in Tis-T1 stage and T2-T4 stage respectively, showing significant difference (P<0.05). The positive expression rate of PSMA in BTCC were 50%,15% and 20.4% in G1, G2, and G3, respectively, yet no significant difference between the three groups(P>0.05). In contrast with PSMA, the expression of AR in BTCC was only associated with clinical stages, while no significant difference was detected in the size, number of tumor, age, sex, and so on(P>0.05). (3) In the 21 cases that expressed PSMA positively, there were 9 cases expressed AR, with the percentage was 42.9%. There were statistically significant correlation between the expression of PSMA and AR in BTCC(r=0.328, P<0.01). Conclusion:(1) This study suggests that PSMA and AR are both positive expression in BTCC, while negative expression in normal bladder tissues, showing significant difference between the two groups (P<0.05). (2) The high positive expression of PSMA was associated with whether the tumor was recurrent (P<0.01), but not associated with the clinical stages and pathological grade. (3) The positive expression of AR in BTCC was associated with clinical stage (P<0.05), and not associated with pathological grade and whether the tumor was recurrent. (4) PSMA may have cooperation with AR in the process of molecular regulation of BTCC via synergistic actions, promoting the occurrence and development of bladder cancer.
资料与方法：选取天津医科大学第二医院2005年3月-2008年12月手术切除的75例经术后病理证实的膀胱移行细胞癌组织,所有患者均为开放手术,术前均未行放、化疗及免疫治疗。其中男52例,女23例,年龄33-88岁,平均(66.9±11.3)岁。按照TNM分期：Ta-125例；T2-450例；WHO膀胱肿瘤组织学分类标准(1999)分级：G16例,G220例,G349例。另取正常膀胱黏膜15例作为正常对照组,均为前列腺增生症开放性手术时留取,男性,年龄42-75岁,平均(61.6±12.2)岁。采用链霉菌素抗生物素蛋白-过氧化物酶免疫组化法(streptavidin-peroxidase, SP法)进行检测。染色步骤按试剂盒说明书分别进行,选用前列腺癌已知阳性组织切片作阳性对照,用PBS液代替—抗作阴性对照。结果判定以光镜下观察细胞出现黄色颗粒为阳性染色。应用SPSS 17.0统计软件包对所有数据进行统计学分析,P<0.05为差异有统计学意义。
结果：(1)在膀胱移行细胞癌中,PSMA呈阳性表达,其阳性表达率为28%,15例正常膀胱黏膜组织均未见阳性表达,差异具有统计学意义(P<0.05)。PSMA在膀胱移行细胞癌Tis-T,期和T2-T4期中的阳性表达率分别为20%和32%,差别无统计学意义(P>0.05)。PSMA在膀胱移行细胞癌G,、G2、G3级的阳性表达率依次为50%、35%和22.4%,三者之间均无统计学差异(P>0.05)。PSMA的阳性表达率与肿瘤是否复发有关,其在复发性膀胱癌中的表达明显高于初发性膀胱癌,差异具有统计学意义(P<0.01)。PSMA的表达在患者年龄、性别、肿瘤数目及大小等临床病理特征方面无统计学差异(P>0.05)。(2)AR在膀胱移行细胞癌中的阳性表达率为21.3%,在正常膀胱黏膜组织中亦未见阳性表达,两组之间差异具有统计学意义(P<0.05)。AR在膀胱移行细胞癌中的阳性表达随着肿瘤临床分期的增高而降低,其在Tis-T1期、T2-T4期中的阳性表达率分别为36%和14%,差异具有统计学意义(P<0.05)。AR在G1、G2、G3级膀胱移行细胞癌组织中的阳性表达率分别为50%、15%和20.4%,三者之间无统计学差异(P>0.05)。与PSMA不同,AR的表达仅与膀胱移行细胞癌的临床分期有关,而在肿瘤是否复发以及肿瘤大小、数目、患者的年龄、性别等方面差异无统计学意义(P<0.05)。(3)在21例PSMA表达呈阳性的膀胱移行细胞癌组织中,有9例同时存在AR的阳性表达,占42.9%,二者的表达相关联(r=0.328,P<0.01)。
结论：(1)研究结果显示PSMA和AR均在膀胱移行细胞癌组织中存在阳性表达,而在正常膀胱黏膜组织中均未发现阳性表达,两组之间差别具有统计学意义。(2) PSMA在膀胱移行细胞癌中的表达与肿瘤的临床分期和病理分级无明确关系；而与肿瘤是否复发有关。(3)AR在膀胱癌中的阳性表达仅与肿瘤的临床分期有关,与肿瘤的病理分级及是否复发等无关。4.在膀胱移行细胞癌中,PSMA与AR的表达相关联,二者可能通过同一途径协同作用参与膀胱移行细胞癌发生、发展的分子调控过程。
Background and Objective:In china, bladder cancer is the most common malignant neoplasm in rinary system. Many extensive studies have been performed to determine whether particular one or several biomarkers are involved in bladder tumors to identify tumors with a high risk of recurrence and progression. None of these markers, however, is currently available. Prostate specific membrane antigen (PSMA) and androgen receptor (AR) are biomarkers which possibly relate to the development of varieties of malignant tumors. We use immunohistochemical method to detect PSMA and AR in bladder transitional cell carcinoma (BTCC) tissues, and explore their biological behavior and clinical significance.
Materials and Method:A total of 75 patients (52 males and 23 females)from department of urology, second hospital of Tianjin medical university with BTCC undergoing open surgical resection, no radiotherapy, no chemotherapy and no immunotherapy before surgery, with accession from March 2005 through December 2008, were included in this study. The average age is 66.9 with a range of 33-88 years. According to the TNM stage classification of UICC and the grade classification of WHO, these samples could be classified into Ta-1 25 cases, T2-4 50 cases; G1 6 cases, G2 20 cases, G3 49 cases. In addition, we collected 15 normal bladder tissues from the patients underwent the resection of benign prostatic hyperplasia as negative control. The average age of the control group is 61.6 with a range of 42-75 years. Streptavidin-peroxidase(SP) method was used to detect the expression of PSMA, AR in BTCC and normal bladder tissues. Staining steps were carried out according to kit instructions, and we choose positive prostate cancer histological section as positive control, with PBS replaced the antibody as negative control. The results were observed by light microscope, and buffy particles in cells were considered as positive cases. SPSS 17.0 software application was used for all analysis and statistical significance was defined as P values less than 0.05.
Results:(1) The expression rate of PSMA in BTCC was 28%, and no positive expression was detected in 15 cases of normal bladder mucosa, showing significant difference (P<0.05). The PSMA expression ratios in 75 cases of carcinoma were 20% and 32% in Tis-T1 stage and T2-T4 stage respectively, while no significant difference between the two groups(P>0.05). The expression ratios of PSMA were 50%,35% and 22.4% in G1, G2, and G3 respectively. There was also no significant difference in pathological grade between the three groups (P>0.05). However, the PSMA expression was associated with whether the tumor was recurrent, and the positive rate in recurrent cases were significantly higher than in early-onset cases, with the difference was statistically significant (P<0.05). No demonstrable difference was found in age, sex, the number tumor and the tumor's size. (2) The positive expression rate of AR in BTCC was 21.3%, and also no positive expression was detected in normal bladder mucosa, showing significant difference (P<0.05). The AR expression rate in BTCC were 36% and 14% in Tis-T1 stage and T2-T4 stage respectively, showing significant difference (P<0.05). The positive expression rate of PSMA in BTCC were 50%,15% and 20.4% in G1, G2, and G3, respectively, yet no significant difference between the three groups(P>0.05). In contrast with PSMA, the expression of AR in BTCC was only associated with clinical stages, while no significant difference was detected in the size, number of tumor, age, sex, and so on(P>0.05). (3) In the 21 cases that expressed PSMA positively, there were 9 cases expressed AR, with the percentage was 42.9%. There were statistically significant correlation between the expression of PSMA and AR in BTCC(r=0.328, P<0.01). Conclusion:(1) This study suggests that PSMA and AR are both positive expression in BTCC, while negative expression in normal bladder tissues, showing significant difference between the two groups (P<0.05). (2) The high positive expression of PSMA was associated with whether the tumor was recurrent (P<0.01), but not associated with the clinical stages and pathological grade. (3) The positive expression of AR in BTCC was associated with clinical stage (P<0.05), and not associated with pathological grade and whether the tumor was recurrent. (4) PSMA may have cooperation with AR in the process of molecular regulation of BTCC via synergistic actions, promoting the occurrence and development of bladder cancer.
引文
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