Retinoic acids (RAs) are essential for many biological processes including proliferation, development, differentiation, carcinogenesis, and apoptosis. These biological effects are mediated through their receptors (RARs). The retinoids, both the natural and synthetic analogs, have been shown to be effective in preventing several cancers in experimental animals and in reversing pre-neoplastic lesions in humans (20, 21). Whether the retinoids could be effective in re-differentiating thyroid cancer cells to be amenable to radioiodide or TSH-suppressive T4 therapy has prompted several investigators to study the expression of RAR in cancer cell lines and tissues. Using Northern blot analysis, del Senno found that the expression of RARa mRNA was lower in thyroid carcinoma cells than in normal thyroid follicular cells. Moreover, del Senno demonstrated that RA reduces the proliferation and function of thyroid follicular cells (22, 23). These findings were confirmed in a larger study. Using immunohistochem-istry and Western blotting, Rochaix et al. compared the expression of RAR|3 in 40 normal/benign tissues, 16 papillary carcinomas, and two follicular carcinomas, immunostaining was detected in the nuclei, but was limited to the normal epithelial thyroid tissue. A dramatic decrease in immunostaining was observed in all 16
papillary carcinomas, but in only one follicular carcinoma (24).
Because the feasibility of retinoid-induced differentiation therapy in thyroid cancer hinges on functional RARs, Schmutzler et al. not only examined the expression of mRNA in several human thyroid carcinoma cell lines and tissues, but also assessed the ligand and DNA binding activities (25). Functional RARs were clearly detectable in the two human thyroid carcinoma cell lines (FTC-133 and FTC-238) and two anaplastic thyroid carcinoma cell lines (HTH74 and C643). Intriguingly, variable levels of mRNA were observed in these cell lines, an observation probably indicative of dysregulation of receptor expression in thyroid cancer (25). These results suggest the heterogeneity in the expression of RARs and the association of the dysregula-tion of the expression of RAR with thyroid carcinogenesis. However, the available expressed functional RAR seems to be able to respond to RA treatment. In a pilot study, patients with advanced thyroid cancer and without the therapeutic options of operation or radioiodide therapy were treated with 13-cis-retinoic acid (1.5 mg/kg body weight daily for 5 weeks). Overall, tumor regression was observed in 19 patients (38%). However, response to retinoid therapy did not always correlate with increased radioiodine uptake (a re-differentiation marker), and so other direct antiproliferative effects could also be involved (26). These encouraging clinical findings warrant additional studies on the RA-based treatment of thyroid cancer. At present, however, little is known about either the molecular mechanisms by which the expression of RAR
is dysregulated during thyroid carcinogenesis or the RA-induced-redifferentiation of follicular cells. Elucidation of these mechanisms should help in the design of an effective treatment of thyroid carcinomas that uses the retinoids.
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