尿路上皮非肌层浸润性膀胱癌中失调的微小RNA：从分子特征到临床应用

Dysregulated MicroRNAs in Urinary Non-Muscle-Invasive Bladder Cancer: From Molecular Characterization to Clinical Applicability.

作者信息

Setti Boubaker Nouha, Gurtner Aymone, Boussetta Sami, Manni Isabella, Saadi Ahmed, Ayed Haroun, Ronchetti Livia, Blel Ahlem, Chakroun Marouene, Mokadem Seif, Naimi Zeineb, Bedoui Mohamed Ali, Bel Haj Kacem Linda, Meddeb Khedija, Rammeh Soumaya, Ben Slama Mohamed Riadh, Ouerhani Slah, Piaggio Giulia

机构信息

UOSD SAFU Unit, Department of Research, Diagnosis and Innovative Technologies, IRCCS-Regina Elena National Cancer Institute, 00144 Rome, Italy.

Urology Department, Charles Nicolle Hospital, Faculty of Medicine, University of Tunis El Manar, Boulevard 9 Avril 1938, Tunis 1006, Tunisia.

出版信息

Cancers (Basel). 2025 Aug 25;17(17):2768. doi: 10.3390/cancers17172768.

DOI:10.3390/cancers17172768

PMID:40940866

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12427307/

Abstract

BACKGROUND

Despite clinical and pathological risk tools, predicting outcomes in non-muscle-invasive bladder cancer (NMIBC), particularly high-grade (HG) cases, remains challenging due to its unpredictable recurrence and progression. There is an urgent need for molecular biomarkers to enhance risk stratification and guide treatment.

METHODS

We assessed the prognostic potential of eight miRNAs (miR-9, miR-143, miR-182, miR-205, miR-27a, miR-369, let-7c, and let-7g) in a cohort of ninety patients with primary bladder cancer. Expression data were retrieved from our previously published studies. Kaplan-Meier's and Cox's regression analyses were used to evaluate the associations with overall survival (OS), metastasis-free survival (MFS), and clinical outcomes. Principal component analysis (PCA) was performed to identify informative miRNA combinations. Target gene prediction, pathway enrichment (DAVID), and drug-gene interaction mapping (DGIdb) were conducted in silico.

RESULTS

A high expression of let-7g and miR-9 was significantly associated with better OS in HG NMIBC and MIBC, respectively ( = 0.013 and = 0.000). MiR-9 downregulation correlated with metastasis in MIBC ( = 0.018). Among all combinations, miR-205 and miR-27a best predicted intermediate-risk NMIBC progression and recurrence (r = 0.982, = 0.000). A functional analysis revealed that these miRNAs regulate key cancer-related pathways (MAPK, mTOR, and p53) through genes such as TP53, PTEN, and CDKN1A. Drug interaction mapping identified nine target genes (e.g., DAPK1, ATR, and MTR) associated with eight FDA-approved bladder cancer therapies, including cisplatin and gemcitabine.

CONCLUSIONS

Let-7g, miR-9, miR-143, miR-182, and miR-205 emerged as promising biomarkers for outcome prediction in NMIBC. Their integration into liquid biopsy platforms could support non-invasive monitoring and personalized treatment strategies. These findings warrant validation in larger, prospective studies and through functional assays.

摘要

背景

尽管有临床和病理风险评估工具，但由于非肌肉浸润性膀胱癌（NMIBC），尤其是高级别（HG）病例的复发和进展不可预测，预测其预后仍然具有挑战性。迫切需要分子生物标志物来加强风险分层并指导治疗。

方法

我们评估了8种微小RNA（miR-9、miR-143、miR-182、miR-205、miR-27a、miR-369、let-7c和let-7g）在90例原发性膀胱癌患者队列中的预后潜力。表达数据取自我们之前发表的研究。采用Kaplan-Meier法和Cox回归分析来评估与总生存期（OS）、无转移生存期（MFS）和临床结局的相关性。进行主成分分析（PCA）以识别有信息价值的微小RNA组合。通过计算机模拟进行靶基因预测、通路富集分析（DAVID）和药物-基因相互作用图谱分析（DGIdb）。

结果

let-7g和miR-9的高表达分别与HG NMIBC和MIBC患者更好的OS显著相关（P = 0.013和P = 0.000）。miR-9的下调与MIBC的转移相关（P = 0.018）。在所有组合中，miR-205和miR-27a对中危NMIBC进展和复发的预测效果最佳（r = 0.982，P = 0.000）。功能分析表明，这些微小RNA通过TP53、PTEN和CDKN1A等基因调控关键的癌症相关通路（MAPK、mTOR和p53）。药物相互作用图谱分析确定了9个与8种美国食品药品监督管理局（FDA）批准的膀胱癌治疗药物（包括顺铂和吉西他滨）相关的靶基因（如DAPK1、ATR和MTR）。