Backgrounds

It has been reported that papillary carcinoma develops in a mouse model with a thyroid-stimulating hormone (TSH) receptor gene mutation, suggesting that enhanced signaling downstream of the TSH receptor plays a significant role in tumorigenesis. However, the upregulation of TSH in normal mice is achievable only through compensatory TSH elevation induced by antithyroid drugs, so it remains unclear what effect TSH overexpression has on the thyroid tumorigenesis in normal mice.

Objectives

This study aims to investigate the effects of TSH overexpression on the thyroid tumorigenesis using a newly developed mouse model.

Methods

We created a new model of acquired TSH overexpression in normal mice by administering a TSH expression vector every 12 weeks using a hydrodynamic method. The mice were observed for up to 48 weeks post-administration. Measurements of thyroid function and tissue evaluations (HE staining and immunohistochemistry) were performed.

Results

The TSH group exhibited persistently elevated TSH levels compared to the control group, although free T4 levels were only transiently elevated, returning to normal 8 weeks post-treatment. Tumor formations resembling adenomatous goiter were observed in some mice 18 weeks post-administration, with almost all mice showing these changes by 24 weeks. Immunostaining indicated that the tumor areas were hyperactivated in the PI3K-Akt-mTOR and MAPK pathways.

Conclusions

Benign tumor formation was observed in a mouse model of TSH overexpression. This model is well suited for studying TSH signaling-induced thyroid changes and the process of tumorigenesis. In addition, it has the potential to provide additional insights when combined with transgenic mouse models of thyroid tumors.