Poster Sessions

CANCER-36

Changxue Lu

C. Lu, H. Ying, L. Zhao, M. Willingham, S.-Y. Cheng

Mutated Thyroid Hormone Receptor Beta, But Not TSH, Activates p38 MAPK Signaling and Promotes Metastasis in a Mouse Model of Follicular Thyroid Carcinoma

Thyroid stimulating hormone (TSH) controls the development and function of thyroid, but its role in thyroid carcinogenesis is unclear. To understand the role of TSH in thyroid cancers, we used a mouse model of follicular thyroid carcinoma (FTC), the TRbetaPV/PV mouse (PV-mouse). The PV-mouse contains a C-terminal mutation in thyroid hormone receptor (TR), exhibiting high levels of TSH. We inhibited the TSH activity in PV-mice by crossing them with TSH receptor gene knockout (TSHR-/-) mice. For comparison, wild-type (WT) mice were treated with antigoitrogenic propylthiouracil (PTU-mice) to elevate the TSH level for more than a year. Hormone assays indicated that PTU-mice had a 9.1-fold higher TSH level than that in PV-mice. Thyroids from PV-mice deficient in TSHR were atrophic and had no occurrence of FTC. At 11 months of age, thyroids of both PTU-mice and PV-mice were enlarged as compared to WT mice (8-fold and 51-fold, respectively), indicating that thyroids of PTU-mice were 6-fold smaller than those of PV-mice in spite of a higher TSH level. While 100%, 33%, and 60% of PV-mice developed capsular invasion, vascular invasion, and metastasis, respectively, vascular invasion was observed at a lower frequency (12%) in PTU-mice, but importantly without detectable lung metastasis. These findings suggest that TSH is necessary for aberrant thyroid growth, but not sufficient for metastasis to occur. To elucidate the mechanisms underlining metastasis in PV-mice, we investigated altered MAPK signaling pathways. An activated p38 MAPK pathway was evidenced by elevated p-p38 MAPK, p-MKK3/6, and p-ATF-2. In addition, the protein abundance of several key players in cell invasion such as integrins (alphaV, alpha5, beta3, beta1), beta-actin, and ezrin was increased in PV-mice (1.5-3 fold) as compared to WT. The activated integrins could trigger the downstream p38 MAPK pathway and affect the recruitment of cytoskeleton machinery such as beta-actin and ezrin to facilitate the migration of tumor cells in PV-mice. These results indicate that the TR mutant, TRbetaPV, collaborating with the TSH signaling pathway, is essential in transforming the hyperplastic thyrocytes to metastatic tumor cells. The present study demonstrates that TRbetaPV could function as a novel oncogene to promote metastatic spread of thyroid tumors.