Zedan Ahmed Hussein, Blavnsfeldt Søren Garm, Hansen Torben Frøstrup, Nielsen Boye Schnack, Marcussen Niels, Pleckaitis Mindaugas, Osther Palle Jörn Sloth, Sørensen Flemming Brandt
Urological Research Center, Department of Urology, Vejle Hospital, Vejle, Denmark.
Department of Oncology, Vejle Hospital, Vejle, Denmark.
PLoS One. 2017 Jun 19;12(6):e0179113. doi: 10.1371/journal.pone.0179113. eCollection 2017.
In the last decade microRNAs (miRNAs) have been widely investigated in prostate cancer (PCa) and have shown to be promising biomarkers in diagnostic, prognostic and predictive settings. However, tumor heterogeneity may influence miRNA expression. The aims of this study were to assess the impact of tumor heterogeneity, as demonstrated by a panel of selected miRNAs in PCa, and to correlate miRNA expression with risk profile and patient outcome.
Prostatectomy specimens and matched, preoperative needle biopsies from a retrospective cohort of 49 patients, who underwent curatively intended surgery for localized PCa, were investigated with a panel of 6 miRNAs (miRNA-21, miRNA-34a, miRNA-125b, miRNA-126, miRNA-143, and miRNA-145) using tissue micro-array (TMA) and in situ hybridization (ISH). Inter- and intra-patient variation was assessed using intra-class correlation (ICC).
Four miRNAs (miRNA-21, miRNA-34a, miRNA-125, and miRNA-126) were significantly upregulated in PCa compared to benign prostatic hyperplasia (BPH), and except for miRNA-21 these miRNAs documented a positive correlation between the expression level in PCa cores and their matched BPH cores, (r > 0.72). The ICC varied from 0.451 to 0.764, with miRNA-34a showing an intra-tumoral heterogeneity accounting for less than 50% of the total variation. Regarding clinicopathological outcomes, only miRNA-143 showed potential as a prognostic marker with a higher expression correlating with longer relapse-free survival (p = 0.016).
The present study documents significant upregulation of the expression of miRNA-21, miRNA-34a, miRNA-125, and miRNA-126 in PCa compared to BPH and suggests a possible prognostic value associated with the expression of miRNA-143. The results, however, document intra-tumoral heterogeneity in the expression of various miRNAs calling for caution when using these tumor tissue biomarkers in prognostic and predictive settings.
在过去十年中，微小RNA（miRNA）已在前列腺癌（PCa）中得到广泛研究，并已证明在诊断、预后和预测方面是有前景的生物标志物。然而，肿瘤异质性可能会影响miRNA表达。本研究的目的是评估肿瘤异质性的影响，如通过一组选定的miRNA在PCa中所显示的那样，并将miRNA表达与风险特征和患者预后相关联。
对49例接受局限性PCa根治性手术的患者的回顾性队列中的前列腺切除术标本和匹配的术前穿刺活检组织，使用组织微阵列（TMA）和原位杂交（ISH），用一组6种miRNA（miRNA-21、miRNA-34a、miRNA-125b、miRNA-126、miRNA-143和miRNA-145）进行研究。使用组内相关系数（ICC）评估患者间和患者内的变异。
与良性前列腺增生（BPH）相比，四种miRNA（miRNA-21、miRNA-34a、miRNA-125和miRNA-126）在PCa中显著上调，除miRNA-21外，这些miRNA显示PCa核心组织与其匹配的BPH核心组织中的表达水平呈正相关（r>0.72）。ICC从0.451到0.764不等，miRNA-34a显示肿瘤内异质性占总变异的比例不到50%。关于临床病理结果，只有miRNA-143显示出作为预后标志物的潜力，其较高表达与较长的无复发生存期相关（p=0.016）。
本研究证明与BPH相比，PCa中miRNA-21、miRNA-34a、miRNA-125和miRNA-126的表达显著上调，并提示与miRNA-143的表达相关的可能预后价值。然而，结果证明各种miRNA表达存在肿瘤内异质性，这在预后和预测环境中使用这些肿瘤组织生物标志物时需要谨慎。
