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Open Access 01-12-2024 | Biomarkers | Research

A MiR181/Sirtuin1 regulatory circuit modulates drug response in biliary cancers

Authors: Anna Barbato, Fabiola Piscopo, Massimiliano Salati, Carla Pollastro, Lorenzo Evangelista, Luigi Ferrante, Davide Limongello, Simona Brillante, Antonella Iuliano, Luca Reggiani-Bonetti, Maria Salatiello, Antonino Iaccarino, Pasquale Pisapia, Umberto Malapelle, Giancarlo Troncone, Alessia Indrieri, Massimo Dominici, Brunella Franco, Pietro Carotenuto

Published in: Clinical and Experimental Medicine | Issue 1/2024

Abstract

Despite recent advances, biliary tract cancer (BTC) remains one of the most lethal tumor worldwide due to late diagnosis, limited therapeutic strategies and resistance to conventional therapies. In recent years, high-throughput technologies have enabled extensive genome, and transcriptome sequencing unveiling, among others, the regulatory potential of microRNAs (miRNAs). Compelling evidence shown that miRNA are attractive therapeutic targets and promising candidates as biomarkers for various therapy-resistant tumors. The analysis of miRNA profile successfully identified miR-181c and -181d as significantly downregulated in BTC patients. Low miR-181c and -181d expression levels were correlated with worse prognosis and poor treatment efficacy. In fact, progression-free survival analysis indicated poor survival rates in miR-181c and -181d low expressing patients. The expression profile of miR-181c and -181d in BTC cell lines revealed that both miRNAs were dysregulated. Functional in vitro experiments in BTC cell lines showed that overexpression of miR-181c and -181d affected cell viability and increased sensitivity to chemotherapy compared to controls. In addition, by using bioinformatic tools we showed that the miR-181c/d functional role is determined by binding to their target SIRT1 (Sirtuin 1). Moreover, BTC patients expressing high levels of miR-181 and low SIRT1 shown an improved survival and treatment response. An integrative network analysis demonstrated that, miR-181/SIRT1 circuit had a regulatory effect on several important metabolic tumor-related processes. Our study demonstrated that miR-181c and -181d act as tumor suppressor miRNA in BTC, suggesting the potential use as therapeutic strategy in resistant cancers and as predictive biomarker in the precision medicine of BTC.

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Title: A MiR181/Sirtuin1 regulatory circuit modulates drug response in biliary cancers
Authors: Anna Barbato
Fabiola Piscopo
Massimiliano Salati
Carla Pollastro
Lorenzo Evangelista
Luigi Ferrante
Davide Limongello
Simona Brillante
Antonella Iuliano
Luca Reggiani-Bonetti
Maria Salatiello
Antonino Iaccarino
Pasquale Pisapia
Umberto Malapelle
Giancarlo Troncone
Alessia Indrieri
Massimo Dominici
Brunella Franco
Pietro Carotenuto
Publication date: 01-12-2024
Publisher: Springer International Publishing
Keyword: Biomarkers
Published in: Clinical and Experimental Medicine / Issue 1/2024
Print ISSN: 1591-8890
Electronic ISSN: 1591-9528
DOI: https://doi.org/10.1007/s10238-024-01332-0

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