The role of miR ‐335‐5p in the redifferentiation of BRAF p. V600E thyroid cancers

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.