富含脯氨酸的蛋白酪氨酸激酶2蛋白在非肌层浸润性膀胱癌中的表达及意义

Pyk2 expression in non-muscle invasive bladder cancer and its clinical significance

目的探讨富含脯氨酸的蛋白酪氨酸激酶2(Pyk2)蛋白在非肌层浸润性膀胱癌(NMIBC)中的表达及其与NMIBC预后的关系。方法收集2013年6月至2018年3月114例经尿道膀胱肿瘤切除术后病理诊断为NMIBC患者的组织标本(NMIBC组),取其中50例标本癌旁0.5 cm正常膀胱黏膜组织作为对照组。男63例(55.3%),女51例(44.7%)。年龄42~87岁,平均(63.6±13.8)岁。肿瘤直径<3 cm 73例,≥3 cm 41例。肿瘤单发83例,多发31例。病理分级:高级别53例,低级别61例。病理分期:Ta期59例,T1期55例。采用免疫组化染色法及蛋白质印迹法检测两组标本中Pyk2蛋白表达情况。分析Pyk2蛋白表达与患者性别、年龄,以及肿瘤大小、数目、病理分级、病理分期的关系。采用Kaplan-Merier法及log-rank检验分析Pyk2蛋白表达与NMIBC患者无复发生存率(RFS)和无进展生存率(PFS)的关系。采用Cox回归模型分析影响NMIBC患者预后的危险因素。结果免疫组化染色检测结果显示,NMIBC组和对照组的Pyk2蛋白阳性表达率分别为66.7%(76/114)和16.0%(8/50),差异有统计学意义(P<0.01)。蛋白质印迹检测结果表明Pyk2蛋白在NMIBC组中的表达水平明显高于对照组(0.571±0.230与0.253±0.152,P<0.01)。Pyk2蛋白在NMIBC组织中的表达与肿瘤分期(P=0.027)、肿瘤分级(P=0.010)有关,与患者性别(P=0.275)、年龄(P=0.419)、肿瘤大小(P=0.317)、肿瘤数目(P=0.208)无关。生存分析结果显示,Pyk2蛋白阳性表达者与阴性表达者的RFS分别为46.1%(35/76)和28.9%(11/38),PFS分别为35.5%(27/76)和10.5%(4/38),差异均有统计学意义(P<0.001,P=0.003)。Cox回归分析结果显示,Pyk2蛋白阳性表达是NMIBC患者复发(HR 0.245,95%CI 0.078~0.768,P=0.016)和进展(HR 0.095,95%CI 0.012~0.764,P=0.027)的独立危险因素。结论Pyk2蛋白在NMIBC组织中呈高表达,并与NMIBC的复发和进展均相关。

Objective To investigate the expression of proline rich tyrosine kinase 2(Pyk2)in non-muscle invasive bladder cancer,and analyze its correlation to clinicopathologic features and prognosis of non-muscle invasive bladder cancer.Methods 114 surgical specimens and 50 normal bladder mucosa specimens were collected from 114 non-muscle invasive bladder cancer patients who underwent TURBT at our hospital,from June 2013 to March 2018.Of the 114 patients,63 were male and 51 were female,aged 42-87 years,average age of(63.6±13.8)years,73 cases of tumor<3 cm,41 cases of tumor≥3 cm,83 cases were single and 31 cases were multiple tumor,53 cases were high grade and 61 cases were low grade,59 cases were Ta and 55 cases were T1 stage.Pyk2 protein expression was detected by immunohistochemistry and western blot.The correlation of the expression of Pyk2 with clinicopathologic features,including gender,age,tumor size,the number of tumors,histological grade and clinical stage were analyzed.Survival analysis was calculated by using the Kaplan-Meier method,and the difference in survival curve was analyzed by using the log-rank test.Association of Pyk2 expression with prognosis of non-muscle invasive bladder cancer analyzed by using the Cox proportional hazards regression model.Results Compared with normal bladder tissues,expression of Pyk2 protein was increased in bladder cancer tissue significantly(0.571±0.230 vs.0.253±0.152,P<0.01).The expression of Pyk2 protein was closely related to clinical stage(P=0.027)and grade(P=0.010),rather than gender(P=0.275),age(P=0.419),tumor size(P=0.317),and tumor number(P=0.208).The recurrence rate in the Pyk2 positive group and negative group were 46.1%(35/76)and 28.9%(11/38)respectively.The progression rate in the Pyk2 positive group and negative group were 35.5%(27/76)and 10.5%(4/38)respectively.Survival analysis suggested expression of Pyk2 in non-muscle invasive bladder cancer had a significant relation to recurrence-free survival rate(P<0.001)and progression-free survival rate(P=0.003).In the multivariable Cox analysis,we found that Pyk2 protein was an independent predictor of recurrence-free survival rate(HR 0.245,95%CI 0.078-0.768,P=0.016)and progression-free survival rate(HR 0.095,95%CI 0.012-0.764,P=0.027).Conclusions The expression of Pyk2 in non-muscle invasive bladder cancer was significantly increased.The expression of Pyk2 has a significant relation to recurrence and progression of non-muscle invasive bladder cancer.High Pyk2 expression is an independent prognostic factor in non-muscle invasive bladder cancer.