PO.PS01.09 · 人群科学
跨独立队列中与前列腺癌侵袭性相关的肿瘤microRNA表达
Tumor microRNA expressions associated with prostate cancer aggressiveness across independent cohorts
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：肿瘤microRNA（miRNA）在前列腺癌（PCa）生物学中起关键作用，可能作为疾病侵袭性的生物标志物。然而，跨独立数据集稳健地鉴定和验证肿瘤miRNA表达仍具挑战性。本研究旨在利用三个独立队列发现并验证与PCa侵袭性相关的miRNA。
方法：我们分析了来自三个数据集的肿瘤miRNA表达谱：本队列（发现集，268例白人）、TCGA-PRAD（406例白人）及GSE135535（GSE，320例男性）。在本队列中，我们采用单变量logistic模型鉴定出与PCa侵袭性显著相关的前25个miRNA（p < 0.01）。使用这25个miRNA，基于本队列在1000个bootstrap样本中进行逐步选择。在1000次bootstrap运行中被选择超过20%的9个miRNA中，许多miRNA表达高度相关。因此，我们进一步进行逐步选择以鉴定与PCa侵袭性相关的最具信息量的miRNA。随后，将所选miRNA在另外两个验证集中进行检验。
结果：两个肿瘤miRNA表达在本队列中与PCa侵袭性显著相关（hsa-miR-145-5p，p<0.001；hsa-miR-182-5p，p = 0.001，AUC=0.74）。在GSE135535队列中，hsa-miR-145-5p和hsa-miR-182-5p的p值分别为0.003和0.099（AUC=0.621）。在TCGA集中，hsa-miR-145-5p和hsa-miR-182-5p的p值分别为0.024和0.059（AUC=0.591）。因此，这两个miRNA代表不同的生物学簇，提示其在PCa侵袭性中具有互补作用。
结论：我们的多队列分析鉴定并验证了两个与PCa侵袭性相关的miRNA。既往其他研究也支持这两个miRNA的生物学功能。已有研究表明，hsa-miR-145-5p通过负向调控metadherin（MTDH）表达而显著抑制PCa细胞生长和转移，并作为肿瘤抑制因子发挥作用。hsa-miR-182-5p作为致癌性miRNA，促成PCa患者的不良预后。miR-182的上调与PCa风险、进展及治疗反应显著相关。既往研究的功能富集分析揭示，miR-182及其靶基因MITF（黑素细胞诱导转录因子）与上皮-间质转化（EMT）之间存在显著关联。我们的发现支持其作为预后生物标志物的潜在效用，并有待进一步的功能研究以阐明其潜在生物学机制。
查看英文原文 English abstract
Introduction: Tumor microRNAs (miRNAs) play a critical role in prostate cancer (PCa) biology and may serve as biomarkers for disease aggressiveness. However, robust identification and validation of tumor miRNA expressions across independent datasets remain challenging. This study aimed to discover and validate miRNAs associated with PCa aggressiveness using three independent cohorts.
Methods: We analyzed tumor miRNA expression profiles from three datasets: our cohort (discovery set, 268 Whites), TCGA-PRAD (406 Whites), and GSE135535 (GSE, 320 men). In our cohort, we identified the top 25 miRNAs significantly associated with PCa aggressiveness (p < 0.01) using univariate logistic models. Using these 25 miRNAs, stepwise selection was performed in the 1,000 bootstrap samples based on our cohort. Among the 9 miRNAs selected in >20% of 1000 bootstrap runs, many miRNA expressions are highly correlated. Therefore, we further performed stepwise selection to identify the most informative miRNAs associated with PCa aggressiveness. Then, the selected miRNAs were tested in the other two validation sets.
Results: Two tumor miRNA expressions were significantly associated with PCa aggressiveness in our cohort (hsa-miR-145-5p, p<0.001, and hsa-miR-182-5p, p = 0.001, AUC=0.74). In the GSE135535 cohort, the p-values were 0.003 and 0.099 for hsa-miR-145-5p and hsa-miR-182-5p, respectively (AUC=0.621). In the TCGA set, the p-values were 0.024 and 0.059 for hsa-miR-145-5p and hsa-miR-182-5p, respectively (AUC=0.591). Thus, these two miRNAs represent distinct biological clusters, suggesting complementary roles in PCa aggressiveness.
Conclusion: Our multi-cohort analysis identified and validated two miRNAs associated with PCa aggressiveness. Other previous studies have supported the biological function of these two miRNAs. It has been shown that hsa-miR-145-5p significantly inhibits PCa cell growth and metastasis by negatively regulating metadherin (MTDH) expression and acts as a tumor suppressor. hsa-miR-182-5p acts as an oncogenic miRNA to contribute to poor prognosis for PCa patients. Up-regulation of miR-182 is significantly associated with PCa risk, progression, and treatment response. Functional enrichment analysis in previous studies revealed a significant association between miR-182 and its target genes, MITF (melanocyte inducing transcription factor) with epithelial-to-mesenchymal transition (EMT). Our findings support their potential utility as prognostic biomarkers and warrant further functional studies to elucidate underlying biological mechanisms.
利益披露 Disclosure
H. Lin, None..
M. Mannan, None.