Droop Johanna, Szarvas Tibor, Schulz Wolfgang A, Niedworok Christian, Niegisch Günter, Scheckenbach Kathrin, Hoffmann Michèle J
Department of Urology, Medical Faculty, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.
Department of Urology, Medical Faculty, University of Duisburg-Essen, Essen, Germany.
PLoS One. 2017 Apr 21;12(4):e0176287. doi: 10.1371/journal.pone.0176287. eCollection 2017.
Many long noncoding RNAs (lncRNAs) are deregulated in cancer and contribute to oncogenesis. In urothelial carcinoma (UC), several lncRNAs have been reported to be overexpressed and proposed as biomarkers. As most reports have not been confirmed independently in large tissue sets, we aimed to validate the diagnostic and prognostic value of lncRNA upregulation in independent cohorts of UC patients. Thus, expression of seven lncRNA candidates (GAS5, H19, linc-UBC1, MALAT1, ncRAN, TUG1, UCA1) was measured by RT-qPCR in cell lines and tissues and correlated to clinicopathological parameters including follow-up data (set 1: N n = 10; T n = 106). Additionally, publicly available TCGA data was investigated for differential expression in UC tissues (set 2: N n = 19; T n = 252,) and correlation to overall survival (OS). All proposed candidates tended to be upregulated in tumour tissues, with the exception of MALAT1, which was rather diminished in cancer tissues of both data sets. However, strong overexpression was generally limited to individual tumour tissues and statistically significant overexpression was only observed for UCA1, TUG1, ncRAN and linc-UBC1 in tissue set 2, but for no candidate in set 1. Altered expression of individual lncRNAs was associated with overall survival, but not consistently between both patient cohorts. Interestingly, lower expression of TUG1 in a subset of UC patients with muscle-invasive tumours was significantly correlated with worse OS in both cohorts. Further analysis revealed that tumours with low TUG1 expression are characterized by a basal-squamous-like subtype signature accounting for the association with poor outcome. In conclusion, our study demonstrates that overexpression of the candidate lncRNAs is found in many UC cases, but does not occur consistently and strongly enough to provide reliable diagnostic or prognostic value as an individual biomarker. Subtype-dependent expression patterns of lncRNAs like TUG1 could become useful to stratify patients by molecular subtype, thus aiding personalized treatments.
许多长链非编码RNA（lncRNA）在癌症中表达失调，并促进肿瘤发生。在尿路上皮癌（UC）中，已有报道称几种lncRNA过表达，并被提议作为生物标志物。由于大多数报告尚未在大型组织样本中得到独立验证，我们旨在验证UC患者独立队列中lncRNA上调的诊断和预后价值。因此，通过RT-qPCR检测了7种lncRNA候选物（GAS5、H19、linc-UBC1、MALAT1、ncRAN、TUG1、UCA1）在细胞系和组织中的表达，并将其与包括随访数据在内的临床病理参数相关联（数据集1：N=10；T=106）。此外，研究了公开可用的TCGA数据中UC组织的差异表达（数据集2：N=19；T=252）以及与总生存期（OS）的相关性。所有提议的候选物在肿瘤组织中均有上调趋势，但MALAT1除外，在两个数据集的癌组织中其表达均有所降低。然而，强烈的过表达通常仅限于个别肿瘤组织，仅在数据集2中观察到UCA1、TUG1、ncRAN和linc-UBC1具有统计学意义的过表达，而在数据集1中未观察到任何候选物有过表达。个别lncRNA的表达改变与总生存期相关，但在两个患者队列中并不一致。有趣的是，在一部分肌肉浸润性肿瘤的UC患者中，TUG1表达较低与两个队列中较差的OS均显著相关。进一步分析表明，TUG1表达低的肿瘤具有基底-鳞状样亚型特征，这解释了其与不良预后的关联。总之，我们的研究表明，在许多UC病例中发现了候选lncRNA的过表达，但这种过表达并不一致且强度不足以作为可靠的个体生物标志物提供诊断或预后价值。像TUG1这样的lncRNA亚型依赖性表达模式可能有助于按分子亚型对患者进行分层，从而有助于个性化治疗。
