Implication of Thyroid Status on Proliferation of T Lymphoma: The Usefulness of Murine Models in the Study of Tumor Progression

STERLE, H.; VALLI, E.; KLECHA, A.; CREMASCHI, G.; BARREIRO ARCOS, M.L.

Congreso; The Virtual Congress on Hematology-Age before beaty- An age adjusted approach towards hematological disorders; 2019

Background: We previously demonstrated that thyroid hormones regulate the growth of T lymphoma lines, but the underlying mechanisms of action have not been elucidated. Murine models have been very useful for the study of numerous diseases. Here, we use murine models of hyperthyroidism and hypothyroidism to analyze the role of thyroid status on tumor development. Objetive: To study the effect of thyroid status on cell cycle regulatory proteins. Methods: Female C57BL/6J mice were treated with placebo, with thyroxine (0.012 mg/ml; 30 days) or with propylthiouracil (0.5 mg/ml; 15 days) and were inoculated subcutaneously with EL-4 T lymphoma cells. Tumor volume was measured daily using calipers. Survival analysis was determined using Kaplan-Meier curves. Proliferation and apoptosis markers were examined by immunohistochemistry. The proliferation kinetics was quantified by CFSE-staining. The expression of cell cycle proteins was analyzed by qPCR and Western blot. Results: Hyperthyroid animals exhibited a higher tumor volume that was correlated with a higher rate of cell division and reduced survival. Tumor tissue from hyperthyroid animals had a higher expression of PCNA and caspase 3. Hypothyroid mice did not differ significantly from the euthyroid controls with respect to these parameters. The levels of cyclins D1 and D3 were increased in the tumors from hyperthyroid mice, while the cell cycle inhibitors p16/INK4A and p27/Kip1 and the tumor suppressor p53 were increased in hypothyroid mice. Conclusions: The thyroid status modulates the growth of EL-4 T lymphoma in vivo by regulating the expression of cyclins, cyclin-dependent kinase inhibitors and the tumor suppressor p53.