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Effects of Pax8 and TTF-1 Thyroid Transcription Factor Gene Transfer in Hepatoma Cells: Imaging of Functional Protein–Protein Interaction and Iodide Uptake

¹ Clinical Cooperation Unit of Nuclear Medicine, German Cancer Research Center, Heidelberg, Germany
² Department of Nuclear Medicine, University of Heidelberg, Heidelberg, Germany
³ Department of Medical Physics in Radiology, German Cancer Research Center, Heidelberg, Germany
⁴ Department of Radiochemistry and Radiopharmacology, German Cancer Research Center, Heidelberg, Germany

The thyroid transcription factors TTF-1 and Pax8 cooperate in the transcriptional activation of thyroid-specific genes such as thyroglobulin (Tg), thyroperoxidase (TPO), and sodium/iodide symporter (NIS). Methods: Dog TTF-1 (dTTF-1) and the human Pax8 (hPax8) gene were transfected in Morris hepatoma (MH3924A) cells to investigate (a) the possible visualization of functional protein–protein interaction and (b) the induction of thyroid-specific gene expression. In MH3924A cell lines expressing dTTF-1, hPax8, or both, the activation of human Tg (hTg), human TPO (hTPO), or rat NIS (rNIS) promoter/enhancer was measured using firefly luciferase reporter constructs. Furthermore, the possible induction of thyroid-specific genes was investigated in iodide uptake and reverse transcription polymerase chain reaction (RT-PCR) experiments. Results: Low transcriptional activation of these constructs was observed in cells expressing either hPax8 or dTTF-1 alone. In contrast, the hTg and hTPO and, to a lesser extent, the rNIS regulatory region were significantly activated in cell lines expressing both transcription factors. Imaging the transcriptional activation of the thyroid-specific regulatory regions by Pax8 and TTF-1 was possible in nude mice implanted with MHhPax8dTTF-1 cells using a cooled charge-coupled device camera. Na¹²⁵I uptake experiments and RT-PCR showed no effect of hPax8 and dTTF-1 on endogenous thyroid-specific gene expression in genetically modified cells. Conclusion: The activation of thyroid-specific promoter/enhancer elements in Morris hepatoma cells depends on the functional interaction of hPax8 and dTTF-1. The cooperation of these 2 transcription factors can be visualized in vitro as well as in vivo. With regard to a possible application for radioiodine therapy, further modifications are required.

Key Words: thyroid transcription • thyroid transcription factors human Pax8 and dog TTF-1 • protein–protein interaction • bioluminescence imaging

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