Oxidative Stress Correlates with More Aggressive Features in Thyroid Cancer

SIMPLE SUMMARY: Several pieces of evidence indicate an impact of oxidative stress (OS) in the pathogenesis and progression of thyroid cancer. The aim of the study was to investigate OS in malignant and benign thyroid lesions and normal tissues, and to correlate the degree of OS with the genetic and expression profile of the tumors and clinico-pathologic features of the patients. The level of OS, considering all malignant and benign lesions, was higher than in normal tissues. In malignant tumors, OS was inversely correlated with tumor differentiation, and directly correlated with the presence of somatic mutations and with the worst tumor presentation and higher tumor aggressiveness. The increased OS status in thyroid tumors warrants further investigation since it may have diagnostic, prognostic and therapeutic relevance. ABSTRACT: Oxidative stress (OS) can have an impact in the pathogenesis and in the progression of thyroid cancer. We investigated the levels of reactive oxygen species (ROS) in 50 malignant and benign thyroid lesions and 41 normal tissues, and correlated them with the thyroid differentiation score-TDS and the clinico-pathologic features. NOX4 expression, GPx activity and the genetic pattern of tumors were evaluated. In malignant and benign lesions, ROS generation and NOX4 protein expression were higher than in normal tissues. Follicular (FTCs) and anaplastic/poorly differentiated cancers had increased OS relative to papillary tumors (PTCs). Moreover, OS in FTCs was higher than in follicular adenomas. Mutated PTCs showed increased OS compared with non-mutated PTCs. In malignant tumors, OS was inversely correlated with TDS, and directly correlated with tumor stage and ATA risk. GPx activity was increased in tumors compared with normal tissues, and inversely correlated to OS. In conclusion, our data indicate that thyroid tumors are exposed to higher OS compared with normal tissues, while showing a compensative increased GPx activity. OS correlates with tumor aggressiveness and mutations in the MEK-ERK pathway in PTC. The inverse correlation between OS and TDS suggests that ROS may repress genes involved in thyroid differentiation.