These results may explain the paradoxical co-expression of wt-p53 and Gal-3 in these types of tumours and suggest that HIPK2 can be considered as a tumour suppressor gene in thyroid cancers. Ionizing radiation has been known for a number of years to be associated with an increased risk of developing a thyroid carcinoma. Exposure to radiation, either from the environment or as a result of medical treatments, in particular when radiation is applied to the head and neck region, represents the most common cause of thyroid cancer. The reason why thyroid cancer is so sensitive to the effects of radiations is not known. The apoptotic pathway triggered by DNA damage is a relevant major target in thyroid cancer tumourigenesis. We recently identified some of the major components of this pathway. In particular, we demonstrated that DNA damage induced by UV irradiation is 4-Aminomethyltrioxsalen hydrochloride responsible for the activation of HIPK2 and that this event, in turn, stimulates the phosphorylation of specific serine/threonine residues in p53 protein. Finally, phosphorylated p53 protein induces downregulation of the potent anti-apoptotic molecule Gal-3, by repressing its expression Dexrazoxane directly at the promoter level. The decrease in Gal-3 mRNA and protein levels facilitates the occurrence of apoptosis. We then demonstrated that in highly aggressive thyroid tumours, characterized by the occurrence of p53 mutations, this pathway is disregulated. UV-induced damage in cells bearing a mutated p53, in fact, not only is no longer able to repress Gal-3, but it exerts a stimulatory effect on Gal-3 expression. Mutant p53- induced Gal-3 overexpression may explain the aggressive phenotype and chemoresistance, typically encountered in ATCs or PDTCs. Therefore, we proposed a model in which the thyroid cells, exposed to radiations, activate the apoptotic pathway HIPK2/wtp53/Gal-3, which physiologically regulates the fate of damaged cells. However, when a gain-of-function p53 mutation occurs, HIPK2/mutp53/Gal-3 axis is no longer protective against the development of cancer and becomes responsible for the acquisition of new additional tumorigenic properties. The weak and unexplained point of this model relies in the paradoxical behaviour of wt-p53 and Gal-3 in WDTCs.