Redox Homeostasis in Thyroid Cancer: Implications in Na+/I- Symporter (NIS) Regulation

Abstract

Radioiodine therapy (RAI) is a standard and effective therapeutic approach for differentiated thyroid cancers (DTCs) based on the unique capacity for iodide uptake and accumulation of the thyroid gland through the Na⁺/I^- symporter (NIS). However, around 5-15% of DTC patients may become refractory to radioiodine, which is associated with a worse prognosis. The loss of RAI avidity due to thyroid cancers is attributed to cell dedifferentiation, resulting in NIS repression by transcriptional and post-transcriptional mechanisms. Targeting the signaling pathways potentially involved in this process to induce de novo iodide uptake in refractory tumors is the rationale of "redifferentiation strategies". Oxidative stress (OS) results from the imbalance between ROS production and depuration that favors a pro-oxidative environment, resulting from increased ROS production, decreased antioxidant defenses, or both. NIS expression and function are regulated by the cellular redox state in cancer and non-cancer contexts. In addition, OS has been implicated in thyroid tumorigenesis and thyroid cancer cell dedifferentiation. Here, we review the main aspects of redox homeostasis in thyrocytes and discuss potential ROS-dependent mechanisms involved in NIS repression in thyroid cancer.

Keywords: NIS; radioiodine therapy; reactive oxygen species; thyroid cancer.

Figure 1

The role of oxidative stress in thyroid carcinogenesis. A pro-oxidant environment is associated with thyroid tumorigenesis, and NADPH oxidases have been described as important ROS sources. Ionizing radiation, a risk factor for thyroid cancer, induces DUOX1-dependent H₂O₂ production, resulting in DNA damage and potentially genomic instability. NOX4 is upregulated in PTCs and is positively regulated by the oncogenes BRAF^V600E and HRAS^V12. Increased NOX4 has been implicated in thyroid cancer dedifferentiation and genomic instability. DUOX2 is the source of H₂O₂ for thyroid hormone biosynthesis in the apical membrane of thyrocytes, but its role in thyroid carcinogenesis is unclear.

Figure 2

Mechanisms hypothetically involved in NIS redox regulation: (1) PAX8 oxidation results in reduced PAX8 DNA binding activity and the repression of NIS transcription; (2) ROS might mediate alterations of epigenetic events also promoting NIS transcriptional repression; (3) ROS might directly oxidize NIS protein or indirectly change the phosphorylation pattern of NIS protein, resulting in decreased NIS activity; (4) ROS might activate pathways involved in NIS endocytosis and autophagy, promoting NIS internalization and degradation.