Endocrine Abstracts

We have previously shown PTTG binding factor (PBF) to be a transforming gene both in vitro and in vivo, forming colonies in soft agar and tumours in nude mice. We have found that along with PTTG, PBF is upregulated in thyroid cancer and is also a prognostic indicator for recurrence. As our cohort of thyroid cancers showed significantly reduced sodium iodide symporter (NIS) expression compared to normal thyroid (47% reduction, N=27, P=0.005), which was negatively correlated with PBF (R²=0.15, P=0.002), we examined whether PBF could influence NIS expression and function. In primary human thyrocytes, PBF and PTTG significantly reduced NIS mRNA expression (95% (N=6, P<0.001) and 86% (N=15, P<0.001) respectively compared to vector only), and co-transfection of PBF and PTTG resulted in an enhanced repression compared to PTTG alone (96%, N=6, P=0.05 compared to PTTG). Further, PBF and PTTG both significantly reduced ¹²⁵I uptake into primary thyrocytes (68% (N=6, P<0.001) and 59% (N=6, P<0.001) respectively) as assessed by iodide uptake assays. As PTTG upregulates basic fibroblast growth factor (FGF-2), which has been shown to repress NIS, we next investigated whether FGF-2 mediated PTTG's effect on NIS. An FGF-2 antibody was used to deplete secreted FGF-2 back to basal levels, as verified by ELISA. Iodide uptake was then reassessed and whereas the suppression of NIS by PTTG could be reversed (PTTG + Ig: 306 plus/minus 26cpm; PTTG + FGF-2 Ab: 554 plus/minus 41cpm; N=12; P<0.001) in the presence of the blocking antibody this was not the case for PBF (PBF + Ig: 303 plus/minus 21 cpm; PBF + Ab; 341 plus/minus 38; N=12; P=0.42). We propose that PBF, as well as PTTG, inhibits NIS expression and iodide uptake resulting in a de-differentiated phenotype observed in thyroid cancers. Furthermore, PBF is able to repress NIS activity by an FGF-2 independent mechanism.