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Modulation of Sodium/Iodide Symporter Expression and Function in Thyroid

Liu, Yu-Yu
http://rave.ohiolink.edu/etdc/view?acc_num=osu1293691026

Abstract Details

2011, Doctor of Philosophy, Ohio State University, Biochemistry Program, Ohio State.
Na+/I- Symporter (NIS) is a membrane glycoprotein that mediates active iodide uptake into the thyroid gland for thyroid hormone synthesis. NIS-mediated iodide uptake and iodide organification is the basis for the post-operative use of radioiodide in detection and targeted ablation of differentiated thyroid cancer. However, about 20-30% patients with metastatic thyroid cancer do not benefit from radioiodine therapy due to reduced or absent NIS expression/function. Thus, it is of clinical importance to investigate the underlying mechanism of NIS modulation such that strategies to selectively upregulate NIS expression and/or functional activity can be devised. Micro-SPECT was used to examine and quantify temporal thyroidal and salivary radioiodine accumulation in both wild type and Tg-PTC1 mice treated with triiodothyronine (T3), bTSH and/or 17-AAG. The extent of thyroidal radioiodine accumulation stimulated by a single dose of exogenous bTSH in T3-supplemented endogenous TSH suppressed mice was much less than that in non-treated mice. Furthermore, the extent and duration of radioiodine accumulation stimulated by bTSH was reduced in thyroid tumor-bearing thyroid glands of Tg-PTC1 thyroid cancer mouse model compared to the thyroids in wild type mice. Lastly, the effect of 17-AAG on increasing thyroidal, but not salivary, radioiodine accumulation was validated in WT mice and in Tg-PTC1 thyroid cancer mouse model. We also aimed to understand the mechanism underlying regulation of NIS in vitro. In PC Cl3 rat thyroid cells, inhibition of PI3K by LY294002 increased NIS-mediated RAIU activity through upregulation of NIS expression. On the other hand, inhibition of mTORC1 by Rapamycin decreased NIS-mediated RAIU activity yet increased NIS protein levels. The discordance between NIS protein and NIS-mediated RAIU activity by Rapamycin is due to its effect on activating pERK and pAkt levels. The effect of Akt inhibition on NIS expression/function was further examined showing that Akti-1/2 markedly increased NIS-mediated RAIU activity by decreasing iodide efflux rate and increasing iodide transport rate and iodide affinity of NIS. The effect of Akti-1/2 on increasing NIS-mediated RAIU activity is restricted to thyroid cells encourages the use of Akt pharmacological inhibitors to selectively increase thyroidal radioiodine accumulation and decrease radioiodine accumulation in non-thyroid tissues.
Sissy Jhiang, PhD (Advisor)
Lawrence S. Kirschner (Other)
Jiayuh Lin (Other)
Chenglong Li (Other)
Endocrinology
thyroidal iodide accumulation; NIS; SPECT; 17-AAG; Akt; PI3K; mTOR; MEK

Recommended Citations

Citations

  • Liu, Y.-Y. (2011). Modulation of Sodium/Iodide Symporter Expression and Function in Thyroid [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1293691026

    APA Style (7th edition)

  • Liu, Yu-Yu. Modulation of Sodium/Iodide Symporter Expression and Function in Thyroid. 2011. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1293691026.

    MLA Style (8th edition)

  • Liu, Yu-Yu. "Modulation of Sodium/Iodide Symporter Expression and Function in Thyroid." Doctoral dissertation, Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1293691026

    Chicago Manual of Style (17th edition)

osu1293691026
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This open access ETD is published by The Ohio State University and OhioLINK.