Extracellular superoxide dismutase is a thyroid differentiation marker down-regulated in cancer

Abstract

Reactive oxygen species, specifically hydrogen peroxide (H 2 O 2 ), have a significant role in hormone production in thyroid tissue. Although recent studies have demonstrated that dual oxidases are responsible for the H 2 O 2 synthesis needed in thyroid hormone production, our data suggest a pivotal role for superoxide dismutase 3 (SOD3) as a major H 2 O 2 -producing enzyme. According to our results, Sod3 is highly expressed in normal thyroid, and becomes even more abundant in rat goiter models. We showed TSH-stimulated expression of Sod3 via phospholipase C-Ca 2C and cAMP-protein kinase A, a pathway that might be disrupted in thyroid cancer. In line with this finding, we demonstrated an oncogene-dependent decrease in Sod3 mRNA expression synthesis in thyroid cancer cell models that corresponded to a similar decrease in clinical patient samples, suggesting that SOD3 could be used as a differentiation marker in thyroid cancer. Finally, the functional analysis in thyroid models indicated a moderate role for SOD3 in regulating normal thyroid cell proliferation being in line with our previous observations.

Changes in Expression of the Antioxidant Enzyme SOD3 Occur Upon Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells In Vitro

“…The functional role of differential changes in SOD3 levels during differentiation is unclear. Recently SOD3 expression has been suggested as a cellular differentiation marker [64], and it is possible that SOD3 may also be marker of MSC differentiation down adipogenic, chondrogenic, and osteogenic cell lineages. Site-specific adipogenic and chondrogenic differentiation have been reported following transplantation of bone marrow-derived hMSCs [65].…”

Extracellular superoxide dismutase and its role in cancer

“…Expression levels of EcSOD have been shown to be slightly increased in a benign thyroid tumor goiter model but gradually downregulated in cell lines that model advanced papillary and anaplastic thyroid cancers correlating with the level of Ras oncogene activation [139 140]. Although growth promoting effects of EcSOD at lower levels have been shown in a thyroid cancer cell line, PCCL3 [141 142], inhibitory effects of this antioxidant in cells harboring p53 mutations resulted in reductions in cell growth, invasion, and soft agar colony formation [143 144].…”

“…Although growth promoting effects of EcSOD at lower levels have been shown in a thyroid cancer cell line, PCCL3 [141 142], inhibitory effects of this antioxidant in cells harboring p53 mutations resulted in reductions in cell growth, invasion, and soft agar colony formation [143 144]. Thus, EcSOD may have biphasic effects on tumor progression switching from a tumor promoter during tumorigenesis to a tumor suppresser shortly after transformation.…”

“…HDAC3 is up-regulated in many solid cancers, such as lung, breast, pancreatic, liver, and colon, indicating another potential mechanism of EcSOD silencing in cancer [181–185]. Although, HDAC inhibition may also indirectly increase EcSOD expression via loss of thyroid stimulating hormone autocrine signaling [140 142], these studies indicate that decreased histone acetylation can contribute to silencing of EcSOD in cancer.…”

RET-mediated modulation of tumor microenvironment and immune response in multiple endocrine neoplasia type 2 (MEN2)

“…It has been recently proposed that focal tumor hypoxia could trigger the remodeling of the ECM and increase the ability of cancer cells to invade lymphatic vessels (Koperek et al 2011); moreover, the switch of superoxide dismutase 3 expression from cancer cells to cancer mesenchymal stromal cells has been suggested to modulate cancer growth and migration (Laatikainen et al 2010, Parascandolo et al 2017. Interestingly, PTC with mutations in the RET/PTC-RAS-BRAF pathway has been described to show high expression of CAF-related proteins (Sun et al 2016).…”