Endocrine Abstracts

Objectives: The oncogene UHRF1 (Ubiquitin-like with PHD and RING Finger domains 1) codifies for a nuclear protein which primarily acts as epigenetic regulator during the replication phase, but also as cycle cell regulator upon DNA damage. The over-expression of this oncogene has been documented in several human cancers, including thyroid cancers (TCs), and correlates with both tumour aggressiveness and response to treatment. Regarding TC, scanty data are available on limited series showing that UHRF1 is overexpressed in tumours with respect to normal tissues and seems to associate with the degree of differentiation, while no data are available for benign thyroid tumours and non-invasive follicular thyroid neoplasms with papillary- like nuclear features (NIFTPs). Interestingly, in hepatocarcinoma cell lines UHRF1 was found to be downregulated after Lenvatinib (LENV) treatment, a multi tyrosine kinase inhibitor also used in patients harbouring advanced radioiodine refractory TCs. Moreover, it is known that the expression of UHRF1 is downregulated by functional p53. Since we demonstrated that TP53 mutations are associated to the resistance of LENV in patients with advanced TC, we aimed to evaluate UHRF1 expression levels in a larger series of malignant and benign tumours as well as in TC cell lines. Moreover, we explored the possible association of UHRF1 mRNA levels with TP53 mutational status and the response to LENV in both patients and in vitro models.

Methods: The expression analysis of UHRF1 gene was done by qRT-PCR in 45 malignant and 12 benign TCs, 17 metastases, 26 normal thyroid tissues, as well as in 4 TC cell lines. Increasing doses of LENV were used to treat two TC cell lines, known to be TP53 mutated and resistant to LENV (B-CPAP and SW1736), and two TC cell lines TP53 wild type and sensitive to LENV treatment (TPC-1 and IHH-4). The expression of UHRF1 mRNA was evaluated after 72 hours treatment.

Results: A significant increase in UHRF1 mRNA levels was observed with increasing tumour aggressiveness and progression in both TC tissues and cell lines. Moreover, UHRF1 resulted to be over-expressed in TC tissues of patients harbouring TP53 mutations or developing LENV resistance. in vitro models showed that the treatment with increasing dose of LENV induced a significant reduction of UHRF1 levels only in TPC-1 cell line with functional p53.

Conclusions: Our study showed a significant association between UHRF1 expression levels and TC aggressiveness and progression. UHRF1 expression resulted to be also associated with the presence of TP53 mutations and to LENV resistance. Overall, these data indicating UHRF1 as a possible new diagnostic and prognostic biomarker for TC. Future studies will investigate targets of UHRF1, that might be involved in the mechanism of resistance to LENV