Switching from MAPK-dependent to MAPK-independent repression of the sodium-iodide symporter in 2D and 3D cultured normal thyroid cells

Area of Science:

• Endocrinology
• Molecular Biology
• Cancer Research

Background:

• Loss of sodium-iodide symporter (NIS) expression in thyroid tumors, often due to MAPK pathway activation, is resistant to MAPK inhibitors.
• Rebound signaling and alternative pathways are proposed mechanisms for this resistance.

Purpose of the Study:

• To investigate if the failure to recover down-regulated NIS by MEK inhibition is specific to tumor cells.
• To explore the role of morphogenetic signals and serum in modulating NIS expression and response to MEK inhibition.

Main Methods:

• Primary thyroid cells and 3D thyroid follicles were treated with TSH, EGF, and the MEK inhibitor U0126.
• NIS mRNA levels, iodide transport, iodination, and thyroglobulin synthesis were assessed.
• Experiments were conducted in the presence and absence of fetal bovine serum.

Main Results:

• NIS mRNA remained repressed in TSH-stimulated primary thyroid cells co-treated with EGF and U0126, irrespective of serum presence.
• Inhibited iodide transport and iodination were observed under these conditions.
• U0126 restored thyroglobulin synthesis in EGF-treated cells, but only blocked NIS down-regulation in serum-starved cells with a diminished TSH response.

Conclusions:

• The failure to recover NIS expression via MEK inhibition is not limited to tumor cells.
• Morphogenetic signals, such as EGF and serum, significantly influence NIS expression and the cellular response to MEK inhibition.
• These findings suggest complex regulatory mechanisms for NIS expression in thyroid cells beyond simple MAPK pathway activation.