Participation of NADPH 4 oxidase in thyroid regulation

Abstract

Different factors are involved in thyroid function and proliferation such as thyrotropin (TSH), insulin, growth factors, iodide, etc. TSH and IGF1/insulin increase proliferation rate and stimulate genes involved in thyroid differentiation. In the present study, we analyze the physiological regulation of NOX4 expression by TSH, insulin and iodine, and the role of NOX4 on thyroid genes expression. Differentiated rat thyroid cells (FRTL-5) were incubated in the presence or absence of TSH/ insulin and TTF2, PAX8, TPO, NIS, NOX4, TGFβ1, FOXO1/3 mRNA levels were examined by Real Time PCR. We showed that TSH and insulin repress NOX4 expression and appears to be inversely correlated with some thyroid genes. SiRNA targeted knockdown of NOX4 increased mRNA levels of TGFβ1, TPO, PAX8, TTF2, FOXO1 and FOXO3. A PI3K inhibitor (LY294002), increases the expression of NIS, TTF2 and FOXO1/3, however PI3K/AKT pathway does not regulate NOX4 expression. We observed that iodine increased NOX4 expression and knockdown of NOX4 reduced ROS and reversed the inhibitory effect of iodine on NIS, TPO, PAX8 and TTF2 expression. Our findings provide strong evidence that NOX4 could be a novel signalling modulator of TSH/insulin pathway and would have a critical role in the autoregulatory mechanism induced by iodine.

Redox Homeostasis in Thyroid Cancer: Implications in Na+/I− Symporter (NIS) Regulation

“…Additionally, NOX4-derived ROS are implicated in cell dedifferentiation and NIS repression in BRAF V600E -driven PTC, as discussed later [ 25 ] ( Figure 1 ). Corroborating these findings, it has been demonstrated that the knockdown of NOX4 in the normal rat thyroid cell line FRTL-5 increases the mRNA expression of thyroid-related genes, including TTF2, TPO, and PAX8 [ 68 ].…”

“…Iodide has been shown to induce an acute increase in mitochondrial superoxide anions (O 2 •− ), which induces PI3K/AKT pathway activation and NIS repression [ 83 ]. Recent data revealed NOX4 as another potential ROS source positively regulated by excess iodide [ 68 ]. Oglio et al showed that I − treatment increased NOX4 expression and induced ROS production, which was eliminated in the presence of the unspecific NADPH oxidase inhibitor DPI or siRNA against NOX4 in the rat thyroid cell line FRTL-5.…”

“…Oglio et al showed that I − treatment increased NOX4 expression and induced ROS production, which was eliminated in the presence of the unspecific NADPH oxidase inhibitor DPI or siRNA against NOX4 in the rat thyroid cell line FRTL-5. NOX4 silencing inhibited iodide-induced NIS mRNA repression, indicating a central role of this NADPH oxidase in thyroid auto-regulation mediated by iodide [ 68 ].…”

H2O2 Metabolism in Normal Thyroid Cells and in Thyroid Tumorigenesis: Focus on NADPH Oxidases

“…One very recent study indicated enhanced NOX4 expression and ROS production as a link between goiter size and NIS regulation in Wistar rats [108]. Oglio et al suggested a potential role for NOX4-derived ROS in iodine-induced autoregulatory mechanisms evidenced by the lack of inhibitory effect of iodine on thyroid-specific genes after NOX4 silencing in differentiated rat thyroid cells in vitro [109]. Taken together, these very recent data indicate the need of further investigations to elucidate the potential role of NOX4 in physiological thyroid hormone synthesis and iodine-related regulation.…”

“…Supporting these data, TSH and insulin suppress NOX4, and elevate the expression levels of TPO and the thyroid-specific transcription factors Pax8 and TTF-2 in differentiated rat thyroid cells in vitro. On the contrary, NOX4 silencing increases expression of these genes [109]. These data indicate that elevated NOX4 transcription and thus, increased NOX4-derived H 2 O 2 production, are linked to dysregulated thyroid differentiation status.…”