TYPE 3 DEIODINASE EXPRESSION IN PAPILLARY THYROID CARCINOMA IS ASSOCIATED WITH TUMOR AGRESSIVENESS AND MODULATED BY BRAFV600E MUTATION Romitti M, Zennig N, Bueno AL, Meyer ELS, Wajner SM, Maia AL Thyroid Section, Endocrine Division, Hospital de Clínicas de Porto Alegre, UFRGS, Porto Alegre, RS, Brasil.
Introduction: Thyroid hormone regulates a wide range of cellular activities, including the balance between cell proliferation and differentiation. The type 3 deiodinases (D3) catalyzes thyroid hormone inactivation and recent studies have showed that D3 can be reactivated in human neoplasias.
Objective: To evaluate DIO3 expression in papillary thyroid carcinoma (PTC) to explore the signaling pathways involved in D3 regulation, as well as the potential implications on disease presentation.
Methods: Twenty-six PTC samples and adjacent thyroid tissues were obtained from patients attending our Institution. DIO3 mRNA was measured by Real-Time PCR and D3 activity by paper descendent chromatography. BRAFV600E mutation was identified in DNA from paraffin blocks by direct sequencing. The human PTC cell line (K1) was used to study D3 regulation.
Results: DIO3 transcripts were detected in all samples analyzed. We observed a paralleled increase in DIO3 mRNA (~5 fold) and activity in PTC samples. Remarkable, DIO3 mRNA and activity were significantly higher in BRAFV600E mutated samples (P=0.003). Increased D3 activity was associated with tumor size (r=0.68, P=0.003), lymph node (P=0.03) and distant metastasis (P=0.006). As expected, in K1 cells, D3 activity was increased by SeO4, cAMP or T3 and abolished by iopanoic acid. Interestingly, TGF-β, which has been implicated on tumor progression, induced a 4-fold increase in DIO3 mRNA levels in PTC cell line.
Conclusions: The results demonstrate that increased DIO3 expression in PTC is associated with tumor size and aggressiveness. These findings support the concept that increased thyroid hormone inactivation might be associated with dedifferentiation and proliferative activity in tumoral cells.