Prohibitin Is Overexpressed in Papillary Thyroid Carcinomas Bearing the BRAFV600EMutation

Abstract

Prohibitin (PHB) is a multifunctional protein that is localized in different intracellular sites. PHB may exert different roles in tumorigenesis, having either a permissive action on tumor growth or an oncosuppressor role, depending on the cellular context. The objective of this study was to evaluate PHB expression in normal thyroid tissues, thyroid follicular adenomas (FAs), and papillary thyroid carcinomas (PTCs). PHB expression was analyzed by immunohistochemistry, Western blot, and quantitative reverse transcription polymerase chain reaction (RT-PCR). Transfections in the BCPAP and TPC-1 thyroid cancer cell lines were used to evaluate the PHB promoter activity. In terms of protein and mRNA levels, normal tissues from patients with serum thyrotropin (TSH) values >0.8mU/L had PHB levels that were significantly reduced compared to specimens from patients with serum TSH values <0.5mU/L, suggesting that TSH exerts an inhibitory effect on PHB expression. Consistent with this was the finding that the presence of TSH was associated with low PHB levels in normal FRTL5 thyroid cells. Immunohistochemical analysis showed relatively low and high PHB expression in FAs and PTCs, respectively. PHB mRNA and protein overexpression, as assessed by quantitative RT-PCR and Western blot, was noted only in PTCs bearing the BRAF(V600E) mutation. Notably, cell transfection experiments suggested that presence of the BRAF(V600E) mutation may be associated to increase of the PHB promoter activity. PHB is overexpressed in PTCs bearing the BRAF(V600E) mutation. We postulate that the presence of the BRAF(V600E) mutation increases PHB promoter activity and therefore potentially mediates effects of this mutation on the behavior of BRAF(V600E) positive PTCs.