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Submitted on May 21, 2004
Accepted on December 21, 2004
mRNA EXPRESSING THYROID CANCER CELL LINES BUT DOES NOT RE-INDUCE THE EXPRESSION OF THYROID SPECIFIC GENES
Department of Endocrinology and Metabolism, Section of Endocrinology, (R.E., A.V., L.A., R.C., E.M., P.P., C.R., A.P.); Department of Oncology, Division of Pathology III, (P.F., F.B.), Division of Pathology I, (A.C., P.C.), Department of Surgery (P.M.). University of Pisa, 56124 Pisa, Italy. Department of Internal Medicine, Endocrinology and Metabolism and Biochemistry, University of Siena, 53100 Siena, Italy (F.P.); AMBISEN Center, High Technology Center for the Study of the Environmental Damage of the Endocrine and Nervous Systems, University of Pisa, 56100, Pisa, Italy (A.P.)
* To whom correspondence should be addressed. E-mail: relisei{at}endoc.med.unipi.it.
Conventional chemoteraphy and radiotherapy are ineffective for the treatment of advanced thyroid tumors like poorly differentiated papillary (PTC), anaplastic (ATC) and medullary thyroid cancer (MTC). In the attempt to evaluate the possibility of using retinoic acid (RA) in the treatment of thyroid cancer refractory to conventional therapy, we studied the effect of all-trans RA treatment on five human thyroid cancer cell lines. We found that WRO and NPA, derived from follicular and poorly differentiated human thyroid carcinoma respectively, showed a growth inhibition after 21 and 25 days of RA treatment. The involvement of both apoptosis and decrease in DNA synthesis were observed as mechanisms of growth inhibition. In NPA cell line also a retard of the progression of the cell cycle has been observed.
On the contrary, we did not observe any recovery of mRNA expression of thyroid specific genes and in particular of the sodium iodide symporter (NIS) gene. The lack of recovery of radioiodide uptake after all-trans RA treatment confirmed the inability to re-express NIS mRNA.
The main difference between the all-trans RA responding cells (WRO and NPA) and the non responding cells (ARO, FRO [derived from human anaplastic thyroid tumors] and TT [derived from human medullary thyroid tumor]) was the basal and all-trans RA induced RAR
mRNA expression. Interestingly, 14 thyroid tumors (10 papillary and 4 anaplastic) showed a significant lower expression of RAR mRNA when compared with normal thyroid tissues. In agreement with this result, only 30% of papillary thyroid carcinomas analyzed were positive for RAR protein expression with a degree of expression that was much lower than that found in normal thyroid tissue.
In conclusion we found that all-trans RA treatment can determine a significant "in vitro" growth inhibition especially in differentiated thyroid tumors derived cell lines but it seems unable to re-induce the expression of thyroid specific genes and in particular to re-induce the ability to take up iodine. The growth inhibition is likely due to apoptosis in an early phase and to a decrease of DNA synthesis later. In some cases also a retard of the cell cycle progression may be responsible for the growth inhibition. The finding of a basal and RA-induced RAR mRNA expression only in cell lines responding to all-trans RA suggests that the growth inhibition might be mediated by RAR.
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