Increased oxidative stress has been linked to thyroid
carcinogenesis. In this paper, we investigate whether oxidative DNA damage and DNA repair differ in
follicular adenoma (FA) and
follicular thyroid carcinoma (
FTC).
7,8-Dihydro-8-oxoguanine (8-OxoG) formation was analysed by immunohistochemistry in 46 FAs, 52 FTCs and 18 normal thyroid tissues (NTs).
mRNA expression of DNA repair genes OGG1, Mut Y homologue (MUTYH) and
endonuclease III (NTHL1) was analysed by real-time PCR in 19 FAs, 25 FTCs and 19 NTs. Induction and repair of oxidative DNA damage were studied in rat FRTL-5 cells after u.v. irradiation. Moreover, activation of DNA damage checkpoints (
ataxia telangiectasia mutated (ATM) and H2A
histone family, member X (H2AFX (H2AFX))) and proliferation index (MIB-1) were quantified in 28 non-oxyphilic and 24 oxyphilic FTCs. Increased nuclear and cytosolic 8-OxoG formation was detected in
FTC compared with
follicular adenoma, whereby cytosolic 8-OxoG formation was found to reflect
RNA oxidation. Significant downregulation of
DNA repair enzymes was detected in
FTC compared with FA. In vitro experiments mirrored the findings in
FTC with oxidative stress-induced
DNA checkpoint activation and downregulation of OGG1, MUTYH and NTHL1 in FRTL-5 cells, an effect that, however, was reversible after 24 h. Further analysis of
FTC variants showed decreased oxidative DNA damage, sustained checkpoint activation and decreased proliferation in oxyphilic vs non-oxyphilic
FTC. Our data suggest a pathophysiological scenario of accumulating unrepaired
DNA/
RNA damage in
FTC vs counterbalanced
DNA/
RNA damage and repair in FA. Furthermore, this study provides the first evidence for differences in oxidative stress defence in
FTC variants with possible implications for therapeutic response and prognostic outcome.