Advances in molecular mechanisms of iodine-131 therapy resistance in thyroid carcinoma

Abstract

Thyroid cancer is the most common malignant tumor of the endocrine system, with differentiated thyroid carcinoma (DTC) accounting for over 90%. Most DTC patients have a good prognosis after systematic treatment, but a few develop dedifferentiation of primary tumor site or metastases, progressing to radioiodine-refractory DTC (RAIR-DTC), leading to significantly worse prognosis, which is a major cause of thyroid carcinoma-related mortality. Dysregulation of sodium iodide symporter (NIS) expression and function is the main reason for iodine-131 therapy resistance in thyroid carcinoma, influenced by genetic changes, epigenetic changes, tumor microenvironment, autophagy, and other factors. Genetic alterations such as the BRAFV600E mutation and RET/PTC chromosomal rearrangements activate oncogenic signaling pathways, directly or indirectly affecting NIS expression and its normal localization on the cell membrane. Epigenetic regulation modulates specific gene expression patterns, regulating NIS gene expression levels, thereby affecting the radioiodine uptake function of thyroid cells. Components in the tumor microenvironment, including immune cells, cytokines, and extracellular matrix, may also disrupt iodine uptake by reducing the expression levels of NIS and/or disrupting its normal function on the cell membrane. Additionally, autophagy, as an intracellular metabolic regulatory mechanism, can also modulate NIS expression and its intracellular distribution, thus impacting the radioiodine uptake and the sensitivity to iodine-131 therapy. Reviewing the roles of these factors in thyroid carcinoma dedifferentiation comprehensively can provide a more thorough understanding of the occurrence and progression of RAIR-DTC, aiding in the exploration of new therapeutic targets, improving prognosis, and providing more effective personalized treatment strategies for patients.

Keywords

• differentiated thyroid carcinoma
• dedifferentiation
• radioiodine
• sodium iodide symporter