Alterations in Sod2-induced oxidative stress affect endocrine cancer progression

Although significant advances have been made in understanding the genetics of endocrine tumors, cellular physiology is relatively understudied as a determinant of tumor behavior. Oxidative stress (OS) and reactive oxygen species (ROS) are metabolic factors that may impact tumor behavior, and these are, in part, controlled by MnSod, the mitochondrial superoxide dismutase (encoded by SOD2). Objective In this study, we sought to understand the role of the MnSod in the prognosis of aggressive human endocrine cancers. We also aimed to directly assess the effect of MnSod under- or over- expression on tumor behavior using established mouse thyroid cancer models. Methods We performed transcriptome analysis of human and mouse models of endocrine cancer. In order to address the role of Sod2 in endocrine tumors, we introduced a Sod2 null allele or a transgenic Sod2 overexpression allele into mouse models of benign thyroid follicular neoplasia or aggressive metastatic follicular thyroid cancer (FTC) and monitored phenotypic changes in tumor initiation and progression. Results In the thyroid, SOD2/Sod2 was downregulated in FTC but not papillary thyroid cancer (PTC). Reduced expression of SOD2 was correlated with poorer survival of patients with aggressive thyroid or adrenal cancers. In mice with benign thyroid tumors, Sod2 overexpression increased tumor burden. In contrast, in mice with aggressive FTC, overexpression of Sod2 reduced tumor proliferation and improved mortality, whereas its deficiency enhanced tumor growth. Conclusions Overall, our results indicate that SOD2 has dichotomous roles in cancer progression and acts in a context specific manner.