The role of miR‐335‐5p in the redifferentiation of BRAF p.V600E thyroid cancers
5 affiliations
- 1Department of Translational and Precision Medicine Sapienza University of Rome Italy
- 2Department for the Promotion of Human Science and Quality of Life San Raffaele Roma University Rome Italy
- 3Department of Computer, Control, and Management Engineering “Antonio Ruberti” Sapienza University of Rome Italy
- 4Department of Oncology Istituto Dermopatico dell'Immacolata IDI‐IRCCS Rome Italy
- 5Department of Health Sciences University “Magna Graecia” of Catanzaro Italy
Abstract
The BRAF p.V600E mutation activates the RAS/BRAF/MEK/ERK pathway, leading to cancer cell dedifferentiation and uncontrolled growth. In radioiodine‐refractory thyroid cancers, MEK and/or BRAF inhibitors can induce redifferentiation, resensitizing tumors to radioiodine. However, compensatory mechanisms limit this efficacy. We used the SWitchMiner software to identify a small pool of regulatory genes, called switch genes, critically associated with drastic changes in cell phenotypes, using TCGA transcriptomic data from BRAF‐mutant papillary thyroid carcinoma and normal thyroid tissues, which highlighted miR‐335‐5p. Restoring miR‐335‐5p in thyroid cancer cell lines harboring the BRAF mutation increased expression of thyroid‐specific genes and proteins, especially in well‐differentiated cell lines, with enhanced sodium‐iodide symporter localization and iodine uptake confirmed in organoids. Due to the connection between thyroid‐specific and EMT‐related genes in the protein–protein interaction network, we examined how miR‐335‐5p overexpression affects EMT pathway genes that modulate thyroid‐specific genes and Kinase Inhibitor (KI) resistance. miR‐335‐5p inhibited the expression of nearly all analyzed genes in less‐differentiated thyroid cell lines. Thus, miR‐335‐5p may be a viable therapeutic target to restore radioiodine avidity in BRAF‐mutant metastatic thyroid cancer and enhance KI treatment redifferentiation.
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BibTeX
@article{pecce2026role,
title = {{The role of miR‐335‐5p in the redifferentiation of BRAF p.V600E thyroid cancers}},
author = {Valeria Pecce and Simone Bini and Marialuisa Sponziello and Giorgio Grani and Giulia Fiscon and Paola Paci and Lorenzo Farina and Rosa Falcone and Valentina Maggisano and Sebastiano Filetti and Cosimo Durante and Antonella Verrienti},
journal = {Molecular Oncology},
year = {2026},
month = jun,
doi = {10.1002/1878-0261.70181},
url = {https://doi.org/10.1002/1878-0261.70181},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The role of miR‐335‐5p in the redifferentiation of BRAF p.V600E thyroid cancers
AU - Valeria Pecce
AU - Simone Bini
AU - Marialuisa Sponziello
AU - Giorgio Grani
AU - Giulia Fiscon
AU - Paola Paci
AU - Lorenzo Farina
AU - Rosa Falcone
AU - Valentina Maggisano
AU - Sebastiano Filetti
AU - Cosimo Durante
AU - Antonella Verrienti
PY - 2026
DA - 2026/06/22
JO - Molecular Oncology
DO - 10.1002/1878-0261.70181
UR - https://doi.org/10.1002/1878-0261.70181
AB - The BRAF p.V600E mutation activates the RAS/BRAF/MEK/ERK pathway, leading to cancer cell dedifferentiation and uncontrolled growth. In radioiodine‐refractory thyroid cancers, MEK and/or BRAF inhibitors can induce redifferentiation, resensitizing tumors to radioiodine. However, compensatory mechanisms limit this efficacy. We used the SWitchMiner software to identify a small pool of regulatory genes, called switch genes, critically associated with drastic changes in cell phenotypes, using TCGA transcriptomic data from BRAF‐mutant papillary thyroid carcinoma and normal thyroid tissues, which highlighted miR‐335‐5p. Restoring miR‐335‐5p in thyroid cancer cell lines harboring the BRAF mutation increased expression of thyroid‐specific genes and proteins, especially in well‐differentiated cell lines, with enhanced sodium‐iodide symporter localization and iodine uptake confirmed in organoids. Due to the connection between thyroid‐specific and EMT‐related genes in the protein–protein interaction network, we examined how miR‐335‐5p overexpression affects EMT pathway genes that modulate thyroid‐specific genes and Kinase Inhibitor (KI) resistance. miR‐335‐5p inhibited the expression of nearly all analyzed genes in less‐differentiated thyroid cell lines. Thus, miR‐335‐5p may be a viable therapeutic target to restore radioiodine avidity in BRAF‐mutant metastatic thyroid cancer and enhance KI treatment redifferentiation.
SN - 1574-7891
SN - 1878-0261
ER -