Network based approach identifies miR ‐145‐3p as a central regulatory hub associated to the progression from localized to metastatic medullary thyroid carcinoma
10 affiliations
- 1Department of Life Science, Health, and Health Professions Link Campus University Rome Italy
- 2Department of Computer, Control and Management Engineering Sapienza University of Rome Rome Italy
- 3Department of Experimental Medicine Sapienza University of Rome Rome Italy
- 4Laboratory of Preclinical and Translational Research, Centro di Riferimento Oncologico della Basilicata, (IRCCS‐CROB) Rionero in Vulture (Potenza) Italy
- 5Department of Radiological Sciences, Oncology and Pathology Sapienza University of Rome Rome Italy
- 6Department of Translational and Precision Medicine Sapienza University of Rome Rome Italy
- 7Endocrine Unit, Department of Clinical and Experimental Medicine University of Pisa Pisa Italy
- 8Department of Medical, Surgical and Neurological Sciences University of Siena Siena Italy
- 9Department of Medicine, Surgery and Dentistry, ‘Scuola Medica Salernitana’ University of Salerno Baronissi Italy
- 10Clinica Sanatrix SPA – Napoli e Pineta Grande Hospital SPA ‐ Castel Volturno Caserta Italy
Abstract
Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor originating from calcitonin producing C‐cells and accounts for 1–5% of thyroid cancers. Total thyroidectomy is curative in localized disease (N0), whereas lymph node metastases (N1) are associated with poorer prognosis. However, the molecular mechanisms driving the metastatic shift remain poorly understood. This study aimed to identify miRNA features linked to metastatic spread in MTC, focusing on the transition from N0 to N1. Co‐expression networks were constructed for N0 and N1 tumors, and differential connectivity analysis was used to identify key miRNAs acting as regulatory hubs. Functional annotation of their target genes was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Reactome pathway analyses. Validation experiments were carried out in MTC cells to evaluate the effects of selected miRNAs on cell proliferation, survival, and MAPK pathway activation. Network analysis revealed distinct miRNA co‐expression patterns between N0 and N1 tumors. Differential network analysis highlighted miR‐145‐3p as a central regulatory hub, exhibiting 29 altered co‐expression changes and a marked loss of connectivity in N1. Target enrichment identified 59 validated genes, including key oncogenic drivers such as MYC, PTEN, BCL2, PIK3CA, AKT1, and MAPK7. In MTC cells, simultaneous inhibition of miR‐145‐3p together with its top co‐expressed miRNAs increased proliferation and survival, and enhanced ERK phosphorylation, indicating MAPK pathway activation and a shift toward a more aggressive phenotype. In conclusion, this study identifies a miRNA regulatory hub centered on miR‐145‐3p that is associated with metastatic progression and highlights the value of network‐based approaches in uncovering mechanisms of cancer dissemination. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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BibTeX
@article{citarella2026network,
title = {{Network based approach identifies miR ‐145‐3p as a central regulatory hub associated to the progression from localized to metastatic medullary thyroid carcinoma}},
author = {Anna Citarella and Manuela Petti and Zein Mersini Besharat and Caterina Alfano and Elena Splendiani and Sofia Trocchianesi and Sara Cassandro and Martina Chiacchiarini and Claudia Sabato and Francesca Gianno and Tanja Milena Autilio and Martina Brunetti and Giuseppina Catanzaro and Antonella Verrienti and Rossella Elisei and Raffaele Ciampi and Cristina Romei and Maria Grazia Castagna and Silvia Cantara and Vincenzo Marotta and Luciano Pezzullo and Lorenzo Farina and Cosimo Durante and Agnese Po and Elisabetta Ferretti},
journal = {The Journal of Pathology},
year = {2026},
month = sep,
doi = {10.1002/path.70116},
url = {https://doi.org/10.1002/path.70116},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Network based approach identifies miR ‐145‐3p as a central regulatory hub associated to the progression from localized to metastatic medullary thyroid carcinoma
AU - Anna Citarella
AU - Manuela Petti
AU - Zein Mersini Besharat
AU - Caterina Alfano
AU - Elena Splendiani
AU - Sofia Trocchianesi
AU - Sara Cassandro
AU - Martina Chiacchiarini
AU - Claudia Sabato
AU - Francesca Gianno
AU - Tanja Milena Autilio
AU - Martina Brunetti
AU - Giuseppina Catanzaro
AU - Antonella Verrienti
AU - Rossella Elisei
AU - Raffaele Ciampi
AU - Cristina Romei
AU - Maria Grazia Castagna
AU - Silvia Cantara
AU - Vincenzo Marotta
AU - Luciano Pezzullo
AU - Lorenzo Farina
AU - Cosimo Durante
AU - Agnese Po
AU - Elisabetta Ferretti
PY - 2026
DA - 2026/09/09
JO - The Journal of Pathology
DO - 10.1002/path.70116
UR - https://doi.org/10.1002/path.70116
AB - Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor originating from calcitonin producing C‐cells and accounts for 1–5% of thyroid cancers. Total thyroidectomy is curative in localized disease (N0), whereas lymph node metastases (N1) are associated with poorer prognosis. However, the molecular mechanisms driving the metastatic shift remain poorly understood. This study aimed to identify miRNA features linked to metastatic spread in MTC, focusing on the transition from N0 to N1. Co‐expression networks were constructed for N0 and N1 tumors, and differential connectivity analysis was used to identify key miRNAs acting as regulatory hubs. Functional annotation of their target genes was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Reactome pathway analyses. Validation experiments were carried out in MTC cells to evaluate the effects of selected miRNAs on cell proliferation, survival, and MAPK pathway activation. Network analysis revealed distinct miRNA co‐expression patterns between N0 and N1 tumors. Differential network analysis highlighted miR‐145‐3p as a central regulatory hub, exhibiting 29 altered co‐expression changes and a marked loss of connectivity in N1. Target enrichment identified 59 validated genes, including key oncogenic drivers such as MYC, PTEN, BCL2, PIK3CA, AKT1, and MAPK7. In MTC cells, simultaneous inhibition of miR‐145‐3p together with its top co‐expressed miRNAs increased proliferation and survival, and enhanced ERK phosphorylation, indicating MAPK pathway activation and a shift toward a more aggressive phenotype. In conclusion, this study identifies a miRNA regulatory hub centered on miR‐145‐3p that is associated with metastatic progression and highlights the value of network‐based approaches in uncovering mechanisms of cancer dissemination. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
SN - 0022-3417
SN - 1096-9896
ER -