Induction of iodide-metabolizing genes expression in anaplastic thyroid cancer

Objectives Anaplatic thyroid cancer lostes the ability of uptaking radioiodine by aberrant silencing of iodide-metabolizing genes. There is no effective strategy to treat anaplastic thyroid cancer at present. Both the MAPK and PI3K/Akt pathways play an important role in the pathogenesis of anaplastic thyroid cancer. This study was conducted to induce iodide-metabolizing genes expression in anaplastic thyroid cancer ARO cell through suppressing over-activated MAPK and PI3K/Akt pathways and demethylation to restore the ability of uptaking radioiodine.

Methods The MEK inhibitor U0126, the Akt inhibitor AktiIV, the demethylase 5-Aza-2'-deoxycytidine and TSH were tested separately and in different combinations on iodide-metabolizing genes expression and radioiodine uptake in ARO cell.

Results Phosphorylation of ERK and Akt were inhibited by U0126 and AktiIV, respectively. The expression of sodium/iodide symporter, thyroglobulin, thyroperoxidase and TSH receptor genes could be restored in ARO cell. Quantitative PCR demonstrated that expressions of these genes were restored to various extents by these agents. The effect was particularly robust and synergistic when combinations containing U0126 were used. Radioiodine uptake by ARO cell was correspondingly induced under these conditions.

Conclusions Inhibitors targeting MAPK and PI3K/Akt pathways combine demethylation and TSH could restore iodide-metabolizing genes expression in ARO cell. Futher studies are warranted to test the therapeutic potential of radioiodine for effective ablation treatment.

Research Support This work was supported by the National Natural Science Fund of China (grant 81071184) and Sector Funds of Ministry of Health of China (grant 201002002).