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Journal Article Epublish 13 citations

PubMed: 38008717 DOI: 10.1186/s13046-023-02878-9

Upregulated expression of miR-4443 and miR-4488 in drug resistant melanomas promotes migratory and invasive phenotypes through downregulation of intermediate filament nestin.

J Exp Clin Cancer Res 42(1):317

Authors: Vittorio Castaldo, Michele Minopoli, Francesca Di Modugno, Andrea Sacconi, Domenico Liguoro, Rachele Frigerio, Arianna Ortolano, Marta Di Martile, Luisa Gesualdi, Gabriele Madonna, Mariaelena Capone, Roberto Cirombella, Angiolina Catizone, Donatella Del Bufalo, Andrea Vecchione, Maria Vincenza Carriero, Paolo Antonio Ascierto, Rita Mancini, Luigi Fattore, Gennaro Ciliberto

Affiliations

  • Department of Anatomy, Histology, Forensic- Medicine and Orthopedics, Sapienza University of Rome, 00161, Rome, Italy.
  • Preclinical Models of Tumor Progression Unit, Istituto Nazionale Tumori IRCCS 'Fondazione G. Pascale', 80131, Naples, Italy.
  • Tumor Immunology and Immunotherapy Unit, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy.
  • Clinical Trial Center, Biostatistics and Bioinformatics Unit, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy.
  • Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00161, Rome, Italy.
  • SAFU Laboratory, Department of Research, Advanced Diagnostics and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy.
  • Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy.
  • Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS 'Fondazione G. Pascale', 80131, Naples, Italy.
  • Faculty of Medicine and Psychology, Department Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, 00118, Rome, Italy.
  • SAFU Laboratory, Department of Research, Advanced Diagnostics and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy.
  • Scientific Directorate, IRCSS Regina Elena National Cancer Institute, 00144, Rome, Italy.

Abstract

BACKGROUND

BRAF-mutant melanoma patients benefit from the combinatorial treatments with BRAF and MEK inhibitors. However, acquired drug resistance strongly limits the efficacy of these targeted therapies in time. Recently, many findings have underscored the involvement of microRNAs as main drivers of drug resistance. In this context, we previously identified a subset of oncomiRs strongly up-regulated in drug-resistant melanomas. In this work, we shed light on the molecular role of two as yet poorly characterized oncomiRs, miR-4443 and miR-4488.

METHODS

Invasion and migration have been determined by wound healing, transwell migration/invasion assays and Real Time Cell Analysis (RTCA) technology. miR-4488 and miR-4443 have been measured by qRT-PCR. Nestin levels have been tested by western blot, confocal immunofluorescence, immunohistochemical and flow cytometry analyses.

RESULTS

We demonstrate that the two oncomiRs are responsible for the enhanced migratory and invasive phenotypes, that are a hallmark of drug resistant melanoma cells. Moreover, miR-4443 and miR-4488 promote an aberrant cytoskeletal reorganization witnessed by the increased number of stress fibers and cellular protrusions-like cancer cell invadopodia. Mechanistically, we identified the intermediate filament nestin as a molecular target of both oncomiRs. Finally, we have shown that nestin levels are able to predict response to treatments in melanoma patients.

CONCLUSIONS

Altogether these findings have profound translational implications in the attempt i) to develop miRNA-targeting therapies to mitigate the metastatic phenotypes of BRAF-mutant melanomas and ii) to identify novel biomarkers able to guide clinical decisions.

MeSH

Cells, Intermediate Filaments, Pharmaceutical Preparations, Melanoma, Micrornas, Phenotype, Therapeutics, Medical Oncology, Down-Regulation, Nestin, Drug Resistance

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