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Down-regulation of the Sodium/Iodide Symporter Explains ¹³¹I-Induced Thyroid Stunning

¹ Department of Medical Chemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy at Göteborg University; ² Department of Radiation Physics, Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden

Requests for reprints: Madeleine M. Nordén, Institute of Biomedicine, The Sahlgrenska Academy at Göteborg University, Box 440, SE-405 30 Göteborg, Sweden. Phone: 46-31-786-3140; Fax: 46-31-786-3322; E-mail: madeleine.norden{at}anatcell.gu.se.

¹³¹I radiation therapy of differentiated thyroid cancer may be compromised by thyroid stunning (i.e., a paradoxical inhibition of radioiodine uptake caused by radiation from a pretherapeutic diagnostic examination). The stunning mechanism is yet uncharacterized at the molecular level. We therefore investigated whether the expression of the sodium/iodide symporter (NIS) gene is changed by irradiation using ¹³¹I. Confluent porcine thyroid cells on filter were stimulated with thyroid-stimulating hormone (TSH; 1 milliunit/mL) or insulin-like growth factor-I (IGF-I; 10 ng/mL) and simultaneously exposed to ¹³¹I in the culture medium for 48 h, porcine NIS mRNA was quantified by real-time reverse transcription-PCR using 18S as reference, and transepithelial iodide transport was monitored using ¹²⁵I^– as tracer. TSH increased the NIS expression >100-fold after 48 h and 5- to 20-fold after prolonged stimulation. IGF-I enhanced the NIS transcription at most 15-fold but not until 5 to 7 days. ¹³¹I irradiation (7.5 Gy) decreased both TSH-stimulated and IGF-I–stimulated NIS transcription by 60% to 90% at all investigated time points. TSH and IGF-I stimulated NIS synergistically 15- to 60-fold after 5 days. NIS expression was reduced by ¹³¹I also in costimulated cells, but the transcription level remained higher than in nonirradiated cells stimulated with TSH alone. Changes in NIS mRNA always correlated with altered ¹²⁵I^– transport in cultures with corresponding treatments. It is concluded that down-regulation of NIS is the likely explanation of ¹³¹I-induced thyroid stunning. Enhanced NIS expression by synergistically acting agents (TSH and IGF-I) partly prevents the loss of iodide transport expected from a given absorbed dose, suggesting that thyroid stunning might be pharmacologically treatable. [Cancer Res 2007;67(15):7512–17]