Association of MMP-2, RB and PAI-1 with decreased recurrence-free survival and overall survival in bladder cancer patients.

We previously reported an accurate urine-based bladder cancer (BCa)-associated diagnostic signature that can be used to non-invasively detect BCa. In this study, we investigated whether a component of this signature could risk stratify patients with BCa. Utilizing immunohistochemistry, we investigated angiogenin, MMP-2, p53, RB and PAI-1 expression from 939 patients with BCa. The expression levels were scored by assigning a proportion score and an intensity score to yield a total staining score for each protein. The expressions of each protein individually and as an aggregate were then correlated with progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). Differential expressions of these markers were noted in BCa. With multivariate analysis in non-muscle invasive bladder cancer (NMIBC) age, tumor grade portended a worse PFS, while age, tumor grade, nodal status, MMP2, RB and PAI-1 expression portended a worse OS. As for multivariate analysis in muscle invasive bladder cancer (MIBC), age MMP-2 and RB were associated with a worse PFS, while age, nodal status, MMP-2, RB and PAI-1 were associated with a worse OS. Using Kaplan-Meier survival analysis, we noted a significant reduction in OS as more of the five biomarkers were expressed in a tumor. Thus, overall, high expressions of MMP-2, RB and/or PAI-1 in bladder tumors were markers of poor prognosis. Individually, MMP-2, RB and PAI-1, as well as in aggregate correlated with poor survival in patients with BCa. Thus, patients whose bladder tumors express these biomarkers may benefit from early radical treatment and/or neoadjuvant or adjuvant therapies.

我们先前报道了一种准确的基于尿液的膀胱癌（BCa）相关诊断特征，可用于无创检测膀胱癌。在本研究中，我们探讨了该特征的一个组成部分是否能够对膀胱癌患者进行风险分层。 利用免疫组织化学方法，我们研究了939例膀胱癌患者中血管生成素、基质金属蛋白酶 - 2（MMP - 2）、p53、视网膜母细胞瘤蛋白（RB）和纤溶酶原激活物抑制剂 - 1（PAI - 1）的表达情况。通过赋予比例评分和强度评分来对表达水平进行评分，从而得出每种蛋白质的总染色评分。然后将每种蛋白质单独以及总体的表达情况与无进展生存期（PFS）、癌症特异性生存期（CSS）和总生存期（OS）相关联。 在膀胱癌中注意到这些标志物的差异表达。在非肌层浸润性膀胱癌（NMIBC）的多变量分析中，年龄、肿瘤分级预示着更差的PFS，而年龄、肿瘤分级、淋巴结状态、MMP - 2、RB和PAI - 1的表达预示着更差的OS。对于肌层浸润性膀胱癌（MIBC）的多变量分析，年龄、MMP - 2和RB与更差的PFS相关，而年龄、淋巴结状态、MMP - 2、RB和PAI - 1与更差的OS相关。通过卡普兰 - 梅尔生存分析，我们注意到当肿瘤中表达这五种生物标志物越多时，OS显著降低。因此，总体而言，膀胱肿瘤中MMP - 2、RB和/或PAI - 1的高表达是预后不良的标志。 单独来看，MMP - 2、RB和PAI - 1以及总体上都与膀胱癌患者的不良生存相关。因此，膀胱肿瘤表达这些生物标志物的患者可能受益于早期根治性治疗和/或新辅助或辅助疗法。