The first evidence that oxidative stress induces EGFR and BER pathways cross-regulation in human thyrocytes.

INTRODUCTION. The main clinical concern about thyroid nodules is their possible hidden malignancy. One of the most interesting aspects of thyroid cells is their physiological production of H2O2 for hormone synthesis, but it can increase DNA lesions, which are repaired by BER. A link between EGFR and BER has been documented, but, their cross-regulation is unclear. This study investigated the effect of oxidative stress on ERBB and BER signalling in a normal thyroid cell model. MATERIALS AND METHODS. Nthy-ori3-1 cells (Nthy), were treated with H2O2, EGF, LY294002 (LY) and PD98059 (PD) alone and combined. Goiter tissues were obtained from patients undergoing thyroidectomy. ERBB and BER were analysed by Western Blot and qRT-PCR; gene expression data were evaluated by bioinformatics tools. RESULTS. BER genes showed the same trend for each treatment in Nthy cells. In particular, MUTYH gene expression clustered with other BER genes under oxidative stress conditions, whereas EGF co-treatment induced its significant correlation with PPARγ and ERBB2, which was lost after LY and PD treatment. Gene cluster analysis suggested a pivotal role for JUN/AP1 transcription factor. In goiters tissues with clinical inflammatory features, gene expression showed MUTYH and OGG1 correlation. While JUN/AP1 gene showed a positive correlation with ERBB2 in not-inflammatory goiters. Finally, OGG1 protein expression, in Nthy cells, decreased under H2O2 treatment, contrary to EGFR phosphorylation/activation, except for co-treatment with EGF. CONCLUSIONS. Our observations present the first experimental evidence that oxidative stress may induce a cross-regulation between EGFR and BER pathways in thyroid cells.