Urinary expression of let-7c cluster as non-invasive tool to assess the risk of disease progression in patients with high grade non-muscle invasive bladder Cancer: A pilot study

Manuela Spagnuolo, Manuela Costantini, Mariaconsiglia Ferriero, Marco Varmi, Isabella Sperduti, Giulia Regazzo, Lucia Cicchillitti, Ana Belén Díaz Méndez, Giovanni Cigliana, Vincenzo Pompeo, Andrea Russo, Valentina Laquintana, Riccardo Mastroianni, Giulia Piaggio, Umberto Anceschi, Aldo Brassetti, Alfredo Bove, Gabriele Tuderti, Rocco Simone Flammia, Michele GallucciGiuseppe Simone, Maria Giulia Rizzo

Research output: Contribution to journalArticlepeer-review


Background: High grade non-muscle-invasive bladder cancer (HG-NMIBC) is a heterogeneous disease with variable risk of progression. Urinary microRNAs are promising biomarkers for BC detection and surveillance. Let-7c-5p miRNA, clustered with miR-99a-5p and -125b-5p, is deregulated in cancer, including BC. The aim of this study is to evaluate urinary let-7c cluster expression in Ta/T1 HG-NMIBC patients and its impact on progression-free survival (PFS). Methods: Quantitative Real-Time-Polymerase-Chain-Reaction (qRT-PCR) was used to analyze the let-7c cluster expression in 57 urine and 49 neoplastic paired tissue samples prospectively collected from transurethral resection (TUR) HG-NMIBC patients. Twenty urine and 10 bladder tissue samples were collected and analyzed as normal controls. QRT-PCR was also used to detect intra-/extra-cellular let-7c cluster in BC cells. Receiver Operating Characteristic (ROC) curves were used to identify urinary miRNAs cut-off values predicting T-stage and PFS. Uni/multivariable Cox regression was performed to identify predictors of PFS. A nomogram predicting progression risk and a decision curve analysis (DCA) were performed. Results: Urinary let-7c was significantly up-regulated in patients compared with controls, while the whole cluster was down-regulated in tumor tissues. Supporting these findings, in vitro comparison of extra-/intra-cellular ratios of cluster levels between BC cells, showed a higher ratio for let-7c in HG-NMIBC versus low-grade cells. Urinary let-7c cluster expression was increased in higher T-stage and was an independent predictor of progression. Lower EORTC-score and downregulation of urinary cluster were predictors of higher PFS on univariable Cox regression, while on multivariable analysis only cluster expression was an independent progression predictor. On DCA, a benefit was evident for patients with a PFS probability > 20%. Conclusions: Urinary let-7c cluster evaluation may improve prognosis, identifying patients at risk of progression and addressing early radical treatment.

Original languageEnglish
Article number68
JournalJournal of Experimental and Clinical Cancer Research
Issue number1
Publication statusPublished - Apr 17 2020


  • Let-7c cluster, urinary biomarkers, progression free survival
  • microRNA
  • Non-muscle-invasive bladder cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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