Decreased iodide uptake in de-differentiated thyroid carcinomas impedes radioiodide therapy. RTPCR analysis revealed reduced expression of Na+/I- symporter (NIS) mRNA in human thyroid carcinomas as compared to normal thyroid. However, in follicular thyroid carcinoma cell lines FTC-133 and FTC-238, treatment with 1 microM all-trans retinoic acid (RA) markedly increased NIS mRNA levels. Anaplastic thyroid carcinoma cell lines HTh74 and C643 showed basal expression of NIS mRNA, but no RA-stimulation. All four cell lines contained the approximately 80 kD NIS protein as judged by Western blot, although they did not accumulate iodide. In contrast, in nontransformed rat FRTL-5 cells, 1 microM RA downregulated NIS mRNA levels, inhibited the TSH- or forskolin-triggered induction of NIS message after TSH-depletion, and reduced iodide uptake to 38% after 5 d. This divergent RA-responsivity of NIS may provide the means to target radioiodide to thyroid carcinomas by upregulating iodide transport into tumor tissue while simultaneously inhibiting iodide accumulation in normal thyrocytes and may thus re-establish the potential for radioiodide therapy.