膀胱移行细胞癌Mta-1表达及与ER、u-PA/PAI-1、MVD的相关性研究

Study on the correlation between Mta-1 expression and ER,u-PA/PAI-1,MVD in bladder transitional cell carcinoma

目的研究膀胱移行细胞癌(BTCC)中转移相关基因(Mta-1)表达,分析其与BTCC临床分期、病理分级、转移及复发的关系,探求其可能的分子作用机制。方法免疫组化方法检测42例BTCC组织Mta-1、雌激素受体(ER)、尿激酶型纤溶酶原激活物(u-PA)、I型纤溶酶原激活物抑制物(PAI-1)的表达；CD34标记血管内皮细胞,计数肿瘤组织微血管密度(MVD)；分析Mta-1与BTCC的侵袭转移、血管生成及复发间的关系及Mta-1表达与ER、u-PA、PAI-1表达及MVD的相关性。结果BTCC Mta-1蛋白表达阳性率为73.8%(31/42),正常膀胱组织无一例阳性表达,P＜0.01；Mta-1蛋白表达阳性率随BTCC临床分期及病理分级的升高而增加,肿瘤复发组(100.0%,15/15)高于无复发组(59.3%,16/27),肿瘤转移组(100.0%,14/14)高于无转移组(60.7%,17/28)(P＜0.05)。BTCC组织中ER表达阳性率随肿瘤临床分期和组织学分级的升高而降低；有转移者14例均无表达(0.0%),28例未转移者中13例有表达(53.6%)(P＜0.05)；复发组15例中仅1例表达(6.7%),未复发组27例中12例表达(44.4%)(P＜0.05)。BTCC中ER与Mta-1蛋白表达呈负相关(r= -0.739,P＜0.01)。BTCC组织和正常膀胱组织中u-PA表达阳性率分别为59.5%(25/42)和16.7% (2/12),BTCC组明显高于对照组(P＜0.05)。BTCC中u-PA蛋白表达与Mta-1蛋白表达呈正相关(r=0.875),而与PAI-1蛋白表达呈负相关(r=-0.535)。PAI-1表达阳性率对照组(50.0%,6/12)明显高于BTCC组(19.0%,8/42)(P＜0.05)。PAI-1蛋白表达与Mta-1蛋白表达呈负相关(r= -0.706)。BTCC中MVD与Mta-1蛋白表达呈正相关(r=0.683)。结论Mta-1在BTCC中高度表达,并随肿瘤临床分期和病理分级的升高而增加,与肿瘤的转移及复发密切相关。Mta-1参与BTCC的侵袭、转移,可能与上调u-PA蛋白、下调PAI-1蛋白的表达,促进血管生成有关。Mta-1在BTCC侵袭和转移中的作用亦与ER的负调节机制有关。

Objective To investigate the expression of Mta-1 in bladder transitional cell carcinoma （BTCC） and to analyze its correlation with the clinical staging, pathologic grading, metastasis and recurrence, and to explore the possible molecular mechanisms. Methods Samples of 42 cases of BTCC and 12 normal bladder mucosa tissues were examined with immunohistochemical analysis for the expression of Mta-1,ER,u-PA and PAI-1. Endothelial cells were stained by anti-CD34, and microvascular density （MVD） of carcinoma tissue was calculated. The correlation of Mta-1 expression with the invasion, metastasis, angiogenesis and recurrence of BTCCs was analyzed; and the correlation of Mta-1 expression with ER,u-PA, PAI-1 ,and MVD was also analyzed. Results The positive rate of Mta-1 expression in BTCCs was 73.8% （31/42） ,while it was O. 0% in normal bladder mucosa tissues （ P 〈 0.01 ）. The expression level of Mta-1 increased with the higher clinical stages and pathologic grades of BTCCs ;it was higher in recurrence group （100.0% , 15/15） than in non-recurrence group （ 59.3% , 16/27 ） , and high in metastasis group （ 100.0% , 14/14） than in non-metastasis group （60.7% , 17/28 ） （ P 〈 0.05 ）. The expression level of ER increased with the lower clinical stages and pathologic grades of BTCCs;the positive rate of ER expression was 0.0% in 14 cases with metastasis and was 53.6% in 13 of 28 cases without metastasis （ P 〈 0.05 ） ;and the rate was 6.7% in 1 of 15 cases with recurrence and 44.4% in 12 of 27 cases without recurrence （P 〈 0.05）. Negative correlation was found between Mta-1 and ER expression （ r = - 0. 739 ,P 〈 0.01 ）. The positive rate of u-PA expression （59.5% ,25/42） was significantly higher in BTCCs than that in normal bladder mucosa tissues （16.7% , 2/12 ） （ P 〈 0.05 ）. Positive correlation was found between u-PA and Mta-1 expression （ r = 0. 875） ,while negative correlation was found between u-PA and PAI-1 expression （r = -0. 535 ）. The positive rate of PAI-1 expression in normal bladder mucosa tissues （50.0% ,6/12） was significantly higher than that in BTCCs （ 19.0% , 8/42） （ P 〈 0.05 ）. In addition,negative correlation was found between PAI-1 and Mta-1 expression （ r = - 0. 706）. And positive correlation was found between MVD in BTCCs marked by anti-CD34 and Mta-1 expression （r = 0. 683）. Conclusions Mta-1 is highly expressed in BTCCs, and it correlates closely with tumor pathologic grades,clinical stages, recurrence and metastasis. Mta-1 up-regulates the expression of u-PA and down-regulates that of PAI-1, which is associated with invasion and metastasis and acts as an angiogenic mediator in BTCCs. A negative correlation is found between Mta-I and ER in invasion and metastasis of BTCCs.