The Splicing Factor PTBP1 Promotes Expression of Oncogenic Splice Variants and Predicts Poor Prognosis in Patients with Non-muscle-Invasive Bladder Cancer
The Splicing Factor PTBP1 Promotes Expression of Oncogenic Splice Variants and Predicts Poor Prognosis in Patients with Non-muscle-Invasive Bladder Cancer
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DOI：
10.1158/1078-0432.ccr-17-3850
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发表时间：
2018-11-01
影响因子：
11.5
通讯作者：
Sette, Claudio
中科院分区：
文献类型：
--
作者：
Bielli, Pamela;Panzeri, Valentina;Sette, Claudio
目的：非肌层浸润性膀胱癌（NMIBC）是一种高度异质性的恶性疾病，其特征在于基因表达和选择性剪接（AS）谱失调。可能与膀胱癌进展相关的剪接因子的生物信息学分析鉴定了异质核核糖核蛋白I（即，PTBP 1）作为候选人。本研究旨在调查PTBP 1表达是否与NMIBC.Experimental Design患者的临床结局相关：纳入了152例原发性NMIBC（pTa-pT 1）患者的队列。通过IHC评估原代NMIBC的PTBP 1表达，并使用Kaplan-Meier曲线和考克斯回归分析将结果与临床数据相关联。进行细胞增殖和存活测定以评估PTBP 1的功能。此外，PTBP 1对特定膀胱癌相关基因的AS模式的影响进行了调查，在癌细胞系和患者的samples.Results：公共查询数据集突出了PTBP 1表达和NMIBC进展之间的正相关性，然后通过IHC分析证实。PTBP 1高表达与NMIBC患者肿瘤复发率和生存率方面的临床结局较差相关。有趣的是，膀胱癌细胞系中PTBP 1的下调影响了促生存特征。因此，PTBP 1调制AS膀胱癌相关基因的细胞系和patient's samples.Conclusions：PTBP 1的表达与疾病进展，预后不良，更糟糕的生存NMIBC患者。PTBP 1表达的下调影响膀胱癌细胞的促生存特征，并调节与膀胱癌相关的基因的AS，表明其在这种疾病中作为结果预测因子的作用。(C)2018年AACR。
Purpose: Non-muscle-invasive bladder cancer (NMIBC) is a malignant disease characterized by high heterogeneity, which corresponds to dysregulated gene expression and alternative splicing (AS) profiles. Bioinformatics analyses of splicing factors potentially linked to bladder cancer progression identified the heterogeneous nuclear ribonucleoprotein I (i.e., PTBP1) as candidate. This study aimed at investigating whether PTBP1 expression associates with clinical outcome in patients with NMIBC.Experimental Design: A cohort of 152 patients presenting with primary NMIBC (pTa-pT1) was enrolled. Primary NMIBCs were assessed for PTBP1 expression by IHC, and the results were correlated with clinical data using Kaplan-Meier curves and Cox regression analyses. Cell proliferation and survival assays were performed to assess the function of PTBP1. Furthermore, the impact of PTBP1 on the AS pattern of specific bladder cancer-related genes was investigated in cancer cell lines and in patients' specimens.Results: Public datasets querying highlighted a positive correlation between PTBP1 expression and NMIBC progression, which was then confirmed by IHC analysis. High PTBP1 expression was associated with worse clinical outcome in terms of incidence of tumor relapse and survival in patients with NMIBC. Interestingly, downregulation of PTBP1 in bladder cancer cell lines affected prosurvival features. Accordingly, PTBP1 modulated AS of bladder cancer-related genes in cell lines and patient's specimens.Conclusions: PTBP1 expression correlates with disease progression, poor prognosis, and worse survival in patients with NMIBC. Downregulation of PTBP1 expression affects prosurvival features of bladder cancer cells and modulates AS of genes with relevance for bladder cancer, suggesting its role as an outcome-predictor in this disease. (C) 2018 AACR.