This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Elisei, R. Articles by Pinchera, A. Search for Related Content PubMed PubMed Citation Articles by Elisei, R. Articles by Pinchera, A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Thyroid Cancer Hazardous Substances DB TRANS-RETINOIC ACID Related Collections Thyroid Endocrine Oncology

All-Trans-Retinoic Acid Treatment Inhibits the Growth of Retinoic Acid Receptor ß Messenger Ribonucleic Acid Expressing Thyroid Cancer Cell Lines but Does Not Reinduce 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.), and Department of Surgery (P.M.), University of Pisa, 56124 Pisa, Italy; Department of Internal Medicine, Endocrinology and Metabolism and Biochemistry (F.P.), University of Siena, 53100 Siena, Italy; AmbiSEN Center (A.P.), High Technology Center for the Study of the Environmental Damage of the Endocrine and Nervous Systems, University of Pisa, 56100 Pisa, Italy

Address all correspondence and requests for reprints to: Rossella Elisei, M.D., Department of Endocrinology and Metabolism, University of Pisa, via Paradisa n° 2, 56124 Pisa, Italy. 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, anaplastic, and medullary thyroid cancer. 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 25 and 21 d of RA treatment. Both apoptosis and a decrease in DNA synthesis were observed as mechanisms of growth inhibition. In the NPA cell line, a delay of cell-cycle progression has also 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 gene. The lack of recovery of radioiodide uptake after all-trans-RA treatment confirmed the inability to reexpress sodium iodide symporter mRNA.

The main difference between the all-trans-RA responding cells (WRO and NPA) and the nonresponding 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 RA receptor (RAR)ß mRNA expression. Interestingly, 14 thyroid tumors (10 papillary and four anaplastic) showed a significant lower expression of RARß mRNA when compared with normal thyroid tissues. In agreement with this result, only 30% of papillary thyroid carcinomas analyzed were positive for RARß 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 tumor-derived cell lines but it seems unable to reinduce the expression of thyroid-specific genes and in particular to reinduce 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, a delay of the cell-cycle progression also may be responsible for the growth inhibition. The finding of a basal and RA-induced RARß mRNA expression only in cell lines responding to all-trans-RA suggests that the growth inhibition might be mediated by RARß.

This article has been cited by other articles:

				H. C Hoftijzer, Y. Y Liu, H. Morreau, T. van Wezel, A. M Pereira, E. P M Corssmit, J. A Romijn, and J. W A Smit Retinoic acid receptor and retinoid X receptor subtype expression for the differential diagnosis of thyroid neoplasms Eur. J. Endocrinol., April 1, 2009; 160(4): 631 - 638. [Abstract] [Full Text] [PDF]

				R. Elisei, A. Vivaldi, R. Ciampi, P. Faviana, F. Basolo, F. Santini, C. Traino, F. Pacini, and A. Pinchera Treatment with Drugs Able to Reduce Iodine Efflux Significantly Increases the Intracellular Retention Time in Thyroid Cancer Cells Stably Transfected with Sodium Iodide Symporter Complementary Deoxyribonucleic Acid J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2389 - 2395. [Abstract] [Full Text] [PDF]

				M. C. Zatelli, D. Piccin, F. Tagliati, A. Bottoni, A. Luchin, C. Vignali, A. Margutti, M. Bondanelli, G. C. Pansini, M. R. Pelizzo, et al. Selective Activation of Somatostatin Receptor Subtypes Differentially Modulates Secretion and Viability in Human Medullary Thyroid Carcinoma Primary Cultures: Potential Clinical Perspectives J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2218 - 2224. [Abstract] [Full Text] [PDF]

				Y. Y Liu, M. P Stokkel, A. M Pereira, E. P Corssmit, H. A Morreau, J. A Romijn, and J. W A Smit Bexarotene increases uptake of radioiodide in metastases of differentiated thyroid carcinoma. Eur. J. Endocrinol., April 1, 2006; 154(4): 525 - 531. [Abstract] [Full Text] [PDF]

				A. S. Rao, P. E. Goretzki, J. Kohrle, and G. Brabant Letter re: Id1 Gene Expression in Hyperplastic and Neoplastic Thyroid Tissues J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5906 - 5906. [Full Text] [PDF]

				T. Kogai, Y. Kanamoto, A. I. Li, L. H. Che, E. Ohashi, K. Taki, R. A. Chandraratna, T. Saito, and G. A. Brent Differential Regulation of Sodium/Iodide Symporter Gene Expression by Nuclear Receptor Ligands in MCF-7 Breast Cancer Cells Endocrinology, July 1, 2005; 146(7): 3059 - 3069. [Abstract] [Full Text] [PDF]