Restoration of iodide uptake in dedifferentiated thyroid carcinoma: relationship to human Na+/I-symporter gene methylation status.

Disseminated dedifferentiated thyroid epithelial carcinoma, which cannot sufficiently concentrate therapeutic radioiodide, is a terminal disease without any effective systemic treatment or chemotherapy. This is a likely consequence of loss of human sodium-iodide symporter (hNIS) function. We hypothesized that hNIS transcriptional failure in thyroid carcinoma could be consequent to methylation of DNA in critical regulatory regions and could be reversed with chemical demethylation treatment. Analysis of hNIS messenger ribonucleic acid (mRNA) expression in 23 tumor samples revealed that although loss of this expression corresponded to loss of clinical radioiodide uptake, some thyroid carcinomas with hNIS mRNA expression did not concentrate iodide, suggesting additional posttranscriptional mechanisms for loss of hNIS function. In addition, analysis of DNA methylation in CpG-rich regions of the hNIS promoter extending to the first intron failed to define specific methylation patterns associated with transcriptional failure in human thyroid tumor samples. In seven human thyroid carcinoma cell lines lacking hNIS mRNA, treatment with 5-azacytidine or sodium butyrate was able to restore hNIS mRNA expression in four cell lines and iodide transport in two cell lines. Investigation of methylation patterns in these cell lines revealed that successful restoration of hNIS transcription was associated with demethylation of hNIS DNA in the untranslated region within the first exon. This was also associated with restoration of expression of thyroid transcription factor-1. These results suggest a role for DNA methylation in loss of hNIS expression in thyroid carcinomas as well as a potential application for chemical demethylation therapy in restoring responsiveness to therapeutic radioiodide.

[1]  M. Zeiger,et al.  Overexpression of TTF-1 and PAX-8 restores thyroglobulin gene promoter activity in ARO and WRO cell lines. , 1998, Surgery.

[2]  J. Fagin,et al.  Genetic and epigenetic alterations of the cyclin‐dependent kinase inhibitors p15INK4b and p16INK4a in human thyroid carcinoma cell lines and primary thyroid carcinomas , 1998, Cancer.

[3]  E. Baudin,et al.  Na+/I- symporter distribution in human thyroid tissues: an immunohistochemical study. , 1998, The Journal of clinical endocrinology and metabolism.

[4]  A. Fischer,et al.  An immunohistochemical study of Na+/I- symporter in human thyroid tissues and salivary gland tissues. , 1998, Endocrinology.

[5]  Q. Tong,et al.  Promoter characterization of the human Na+/I- symporter. , 1998, The Journal of clinical endocrinology and metabolism.

[6]  E. Pakos,et al.  Redifferentiation therapy with retinoic acid in follicular thyroid cancer. , 1998, Journal of Nuclear Medicine.

[7]  C. Reiners,et al.  Redifferentiation Therapy with Retinoids: Therapeutic Option for Advanced Follicular and Papillary Thyroid Carcinoma , 1998, World Journal of Surgery.

[8]  J. Herman,et al.  Distinct patterns of E-cadherin CpG island methylation in papillary, follicular, Hurthle's cell, and poorly differentiated human thyroid carcinoma. , 1998, Cancer research.

[9]  M. Ohmori,et al.  A novel thyroid transcription factor is essential for thyrotropin-induced up-regulation of Na+/I- symporter gene expression. , 1998, Molecular endocrinology.

[10]  T. Schmitt,et al.  Cloning of a functional promoter of the human sodium/iodide-symporter gene. , 1998, The Biochemical journal.

[11]  K. Ain.  Rare Forms of Thyroid Cancer , 1998 .

[12]  Q. Tong,et al.  Promoter Characterization of the Human Na 1 / I 2 Symporter * , 1998 .

[13]  J. Herman,et al.  Alterations in DNA methylation: a fundamental aspect of neoplasia. , 1998, Advances in cancer research.

[14]  M. Yatin,et al.  Cloning of the human sodium-iodide symporter promoter and characterization in a differentiated human thyroid cell line, KAT-50. , 1998, Thyroid : official journal of the American Thyroid Association.

[15]  Q. Tong,et al.  Promoter characterization of the rat Na+/I- symporter gene. , 1997, Biochemical and biophysical research communications.

[16]  T. Endo,et al.  Iodide uptake and experimental 131I therapy in transplanted undifferentiated thyroid cancer cells expressing the Na+/I- symporter gene. , 1997, Endocrinology.

[17]  S. Baylin.  Tying It All Together: Epigenetics, Genetics, Cell Cycle, and Cancer , 1997, Science.

[18]  T. Brent,et al.  Methylation hot spots in the 5' flanking region denote silencing of the O6-methylguanine-DNA methyltransferase gene. , 1997, Cancer research.

[19]  S. Jhiang,et al.  Expression, exon-intron organization, and chromosome mapping of the human sodium iodide symporter. , 1997, Endocrinology.

[20]  S. Clark,et al.  Extensive DNA methylation spanning the Rb promoter in retinoblastoma tumors. , 1997, Cancer research.

[21]  M. Arnone,et al.  TTF‐2, a new forkhead protein, shows a temporal expression in the developing thyroid which is consistent with a role in controlling the onset of differentiation , 1997, The EMBO journal.

[22]  K. Ain,et al.  Somatostatin receptor subtype expression in human thyroid and thyroid carcinoma cell lines. , 1997, The Journal of clinical endocrinology and metabolism.

[23]  B. Chadwick,et al.  FKHL15, a new human member of the forkhead gene family located on chromosome 9q22. , 1997, Genomics.

[24]  J. Köhrle,et al.  Redifferentiation therapy of differentiated thyroid carcinoma with retinoic acid: basics and first clinical results. , 2009, Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association.

[25]  Qing-Rong Liu,et al.  Cloning of the human sodium lodide symporter. , 1996, Biochemical and biophysical research communications.

[26]  J. Herman,et al.  Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[27]  J. Konishi,et al.  Tumoricidal cytokines enhance radioiodine uptake in cultured thyroid cancer cells. , 1996, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[28]  K. Ain.  Papillary thyroid carcinoma : etiology, assessment and therapy , 1995 .

[29]  G. Johnston,et al.  Radioiodine therapy for thyroid cancer. , 1995, Endocrinology and metabolism clinics of North America.

[30]  K. Ain,et al.  Somatostatin analogs affect proliferation of human thyroid carcinoma cell lines in vitro. , 1994, The Journal of clinical endocrinology and metabolism.

[31]  T. Brent,et al.  Effect of 5-azacytidine on expression of the human DNA repair enzyme O6-methylguanine-DNA methyltransferase. , 1994, Carcinogenesis.

[32]  A. Levine.  The origins of the small DNA tumor viruses. , 1994, Advances in cancer research.

[33]  N. Carrasco,et al.  Iodide transport in the thyroid gland. , 1993, Biochimica et biophysica acta.

[34]  S. Mundlos,et al.  PAX8, a human paired box gene: isolation and expression in developing thyroid, kidney and Wilms' tumors. , 1992, Development.

[35]  D. Samid,et al.  Induction of erythroid differentiation and fetal hemoglobin production in human leukemic cells treated with phenylacetate. , 1992, Blood.

[36]  P. Kelly,et al.  Transcriptional regulation of prolactin receptor gene expression by sodium butyrate in MCF-7 human breast cancer cells. , 1992, Endocrinology.

[37]  T. Akamizu,et al.  Characterization of the 5'-flanking region of the rat thyrotropin receptor gene. , 1992, Molecular endocrinology.

[38]  J. Robbins,et al.  Thyroid cancer: a lethal endocrine neoplasm. , 1991, Annals of internal medicine.

[39]  M. Ueffing,et al.  Reversible inhibition of a thyroid-specific trans-acting factor by Ras. , 1991, Genes & development.

[40]  A. V. Van Herle,et al.  Effects of 13 cis-retinoic acid on growth and differentiation of human follicular carcinoma cells (UCLA R0 82 W-1) in vitro. , 1990, The Journal of clinical endocrinology and metabolism.

[41]  M. Parmentier,et al.  Tissue-specific expression and methylation of a thyroglobulin-chloramphenicol acetyltransferase fusion gene in transgenic mice. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[42]  A. Musti,et al.  Reactivation of thyroglobulin gene expression in transformed thyroid cells by 5-azacytidine , 1989, Cell.

[43]  V. R. McCready,et al.  Radiation dose assessments in radioiodine (131I) therapy. 1. The necessity for in vivo quantitation and dosimetry in the treatment of carcinoma of the thyroid. , 1989, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[44]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[45]  E. Gaitan,et al.  Frontiers in Thyroidology , 1986, Springer US.

[46]  T. Mosmann.  Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. , 1983, Journal of immunological methods.

[47]  M. Ehrlich,et al.  Comparison of bisulfite modification of 5-methyldeoxycytidine and deoxycytidine residues. , 1980, Nucleic acids research.

[48]  W. Kao,et al.  Proline analogue removes fibroblasts from cultured mixed cell populations , 1977, Nature.

[49]  S. Gilbert,et al.  D-valine as a selective agent for normal human and rodent epithelial cells in culture , 1975, Cell.