Talk abstracts

Talk on Wednesday 10:15-10:30am submitted by Daphne Pringle

Thyroid specific ablation of the Carney Complex gene, PRKAR1A, results in hyperthyroidism and follicular thyroid cancer

Daphne R. Pringle (Molecular Virology, Immunology, & Medical Genetics, The Ohio State University), Zhirong Yin, Audrey A. Lee, Parmeet K. Manchanda (Molecular Virology, Immunology, & Medical Genetics, The Ohio State University), Linabo Yu, David Jarjoura (Center for Biostatistics, The Ohio State University), Alfred. F. Parlow (National Hormone and Peptide Program, Harbor-UCLA Medical Center), Krista M. D. LaPerle (Department of Veterinary Biosciences, The Ohio State University), Lawrence S. Kirschner (Molecular Virology, Immunology, & Medical Genetics; Division of Endocrinology, Diabetes, & Metabolism, The Ohio State University)

Abstract:
Carney Complex (CNC) is a dominantly inherited tumor syndrome characterized by spotty skin pigmentation and endocrine overactivity. CNC is caused by inactivating mutations in PRKAR1A which encodes the type 1a regulatory subunit of the cyclic-AMP dependent kinase (Protein Kinase A, PKA). A defining feature of CNC is the presence of thyroid nodules and/or cancer, which are observed in approximately 25% and 5% of patients, respectively. Mutations in PRKAR1A have also been identified in patients with sporadic thyroid cancer, indicating a central role for PKA in thyroid tumorgenesis. To elucidate the mechanism by which overactive PKA elicits tumor formation in the thyroid, we have generated a novel mouse model harboring a thyroid specific deletion of Prkar1a. At one year of age, the thyroids of these animals are grossly enlarged; pathologically, all animals exhibit follicular thyroid adenomas, with 43% of animals developing follicular thyroid carcinoma (FTC). We have also observed, via ultrasound imaging, that the thyroids of these animals are enlarged beginning as early as 3 months of age. Serum analyses showed that these animals are hyperthyroid, indicating that these tumors are secretory. Interestingly, these tumors do not show ctivation of the PI3K/AKT or ERK pathways, but do exhibit an increase in phosphorylated Stat3, suggesting that the mechanisms of thyroid tumorgenesis in the context of dysregulated PKA are distinct from that in previously described models of FTC. In vitro experiments with primary cultures of these tumor cells indicate that suppression of Stat3 inhibits cell growth, highlighting the potential importance of the JAK/STAT pathway. This study demonstrates that loss of Prkar1a in the murine thyroid leads to hyperthyroidism and FTC. Our model adds to the understanding of the molecular mechanisms involved in FTC development and may guide the development of therapies for not only the rare CNC patients, but also for those patients with sporadic thyroid cancer.

Keywords: thyroid cancer, PKA