Iodinated TG in thyroid follicular lumen regulates TTF-1 and PAX8 expression via TSH/TSHR signaling pathway

Abstract

Our previous study showed that highly iodinated thyroglobulin (TG) inhibited thyroid transcription factor‐1 (TTF‐1) and paired box gene 8 (PAX8) expression, but the potential mechanism remains unclear. In this study, we constructed a thyroid follicle model in vitro to mimic its natural physiological structure and explored how iodinated TG in the follicular lumen tuned TTF‐1 and PAX8 expression. Our data showed that lowly iodinated TG enhanced PKA activity while upregulation of both TTF‐1 and PAX8 expression; and that highly iodinated TG triggered PKC activity while suppression of TTF‐1 and PAX8 expression. Further, PKA agonist alone could increase TTF‐1 and PAX8 expression while PKC agonist decreased TTF‐1 and PAX8 level. If blocking PLC‐PKC pathway using PKC‐specific inhibitor, highly iodinated TG significantly promoted the expressions of TTF‐1 and PAX8, and similarly PKA‐specific blocker moderately inhibited TTF‐1 and PAX8 expression. And opposite tendencies of TTF1 and PAX8 aberrant expression were observed in the condition of low iodinated TG when blocking PLC‐PKC and cAMP‐PKA signaling pathways. Our results indicated that iodinated TG manipulated TTF‐1 and PAX8 expression through PLC‐PKC and cAMP‐PKA pathways, and highly iodinated TG played inhibitory role via PLC‐PKC pathway from the TTF1 and PAX8 perspective while low level of iodinated TG was an activator through cAMP‐PKA pathway. Our findings proved that iodinated TG in thyroid follicular lumen regulated TTF‐1 and PAX8 expression through thyroid stimulating hormone/thyroid stimulating hormone receptor (TSH/TSHR) mediated cAMP‐PKA and PLC‐PKC signaling pathways. J. Cell. Biochem. 118: 3444–3451, 2017. © 2017 Wiley Periodicals, Inc.