Differentiated thyroid cancers are the commonest endocrine malignancies, but there are no reliable molecular markers of prognosis. Pituitary tumor transforming gene (PTTG) plays several potential roles in tumour initiation and progression, including regulating mitosis and stimulating expression of fibroblast growth factor-2 (FGF-2). PTTG expression has been identified as a potential prognostic marker in pituitary adenomas and colon carcinomas. We postulated that PTTG and FGF-2 expression may be related to the outcome of thyroid carcinomas. Pre- and post-translational expression of PTTG, its binding factor PBF, FGF-2 and its receptor FGFR-1 were determined in 14 differentiated thyroid cancers and compared with expression in 11 normal thyroids. Gene expression was related to tumour stage at presentation and to recurrence early during follow-up. Expression of PTTG and PBF was studied in primary human thyroid cultures stimulated with increasing doses (0.01-1 milli-Units per milliliter) of thyrotropin (TSH), which is known to have a trophic effect on differentiated thyroid cancer growth. PTTG and FGF-2 were overexpressed in thyroid carcinomas (8.2-fold increase, P=0.013 and 4.4-fold increase, P<0.001, respectively). Increased FGF-2 mRNA expression was independently associated with the findings of lymph node invasion (R2=0.83, P=0.008) and distant metastases (R2=0.78, P=0.016) at tumour presentation, after taking into account known prognostic factors such as age, gender, type and size of tumour. High PTTG expression was independently associated with tumour recurrence (R2=0.70; P=0.04). TSH stimulated a 3-fold increase in PTTG expression (P=0.017) at 1 milli-Unit per milliliter in primary thyroid cultures.
Conclusions: PTTG and FGF-2 expression are novel potential prognostic markers (and perhaps therapeutic targets) in differentiated thyroid cancer. PTTG is regulated by TSH in vitro and this may explain the prognostic significance of TSH suppression by T4 treatment in affecting tumour recurrence.