Abstract
NK2 homeobox 1 (NKX2-1) is a thyroid transcription factor essential for proper thyroid formation and maintaining its physiological function. In thyroid cancer, NKX2-1 expression decreases in parallel with declined differentiation. However, the molecular pathways and mechanisms connecting NKX2-1 to thyroid cancer phenotypes are largely unknown. This study aimed to examine the effects of NKX2-1 re-expression on dedifferentiated thyroid cancer cell death and explore the underlying mechanisms. A human papillary thyroid carcinoma cell line lacking NKX2-1 expression was infected with an adenoviral vector containing Nkx2-1. Cell viability decreased after Nkx2-1 transduction and apoptosis and necrosis were detected. Arginase 2 (ARG2), regulator of G protein signaling 4 (RGS4), and RGS5 mRNA expression was greatly increased in Nkx2-1-transducted cells. After suppressing these genes by siRNA, cell death, apoptosis, and necrosis decreased in RGS4 knockdown cells. These findings demonstrated that cell death was induced via apoptosis and necrosis by NKX2-1 re-expression and involves RGS4.
Highlights
Thyroid transcription factors (TTFs), namely NK2 homeobox 1 (NKX2-1, known as TTF1), forkhead box E1 (FOXE1), paired box 8 (PAX8), and hematopoietically expressed homeobox (HHEX), are fundamental for proper thyroid gland formation and maintaining the functional differentiated state of the adult thyroid [1]
To investigate whether AdNKX2-1 causes death in another cell line derived from papillary thyroid carcinoma, BHP7-13 cells (NKX2-1−/PAX8+) were infected with AdNKX2-1 or AdLacZ
NKX2-1 expression decreases in dedifferentiated thyroid carcinoma cells [8]
Summary
Thyroid transcription factors (TTFs), namely NK2 homeobox 1 (NKX2-1, known as TTF1), forkhead box E1 (FOXE1), paired box 8 (PAX8), and hematopoietically expressed homeobox (HHEX), are fundamental for proper thyroid gland formation and maintaining the functional differentiated state of the adult thyroid [1]. NKX2-1, FOXE1, and PAX8 bind to the DNA and regulate thyroid-specific genes that drive thyroid hormone synthesis, such as thyroglobulin (TG), thyroid peroxidase (TPO), thyroid stimulating hormone receptor (TSHR), and sodium iodide symporter (NIS, known as solute carrier family 5 member 5). Simultaneous TTF expression is unique to the thyroid follicular cells, each TTF is expressed in other tissues in adults. NKX2-1 is expressed in the lung and nervous system, and FOXE1 and PAX8 are expressed in several tissues [1].
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