1. ¹Division of Hematology and Oncology, Department of Medicine, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA
2. ²Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA
3. ³Department of Pathology, UCLA School of Medicine, Los Angeles, CA, USA
4. ⁴School of Biosciences, University of Birmingham, Birmingham, B15 2TT, UK
5. ⁵Division of Endocrinology, Department of Medicine, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA

Correspondence: Dr T Akagi, Division of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, 8700 Beverly Blvd, Los Angeles, CA 90048, USA. E-mail: tadayuki.akagi@gmail.com.

⁶These authors contributed equally to this work.

Received 14 May 2008; Revised 10 July 2008; Accepted 14 July 2008; Published online 5 August 2008.

Abstract

Thyroid carcinoma cells often do not express thyroid-specific genes including sodium iodide symporter (NIS), thyroperoxidase (TPO), thyroglobulin (TG), and thyrotropin-stimulating hormone receptor (TSHR). Treatment of thyroid carcinoma cells (four papillary and two anaplastic cell lines) with histone deacetylase inhibitors (SAHA or VPA) modestly induced the expression of the NIS gene. The promoter regions of the thyroid-specific genes contained binding sites for hepatocyte nuclear factor 3 (HNF3)/forkhead box A2 (FoxA2), thyroid transcription factor 1 (TTF-1), and CCAAT/enhancer binding protein (C/EBP). Quantitative reverse transcription-polymerase chain reaction (RT–PCR) showed decreased expression of HNF3/FoxA2 and TTF-1 mRNA in papillary thyroid carcinoma cell lines, when compared with normal thyroid cells. Forced expression of these genes in papillary thyroid carcinoma cells inhibited their growth. Furthermore, the CpG island in the promoter region of HNF3/FoxA2 was aberrantly methylated; and treatment with 5-aza-2-deoxycytidine (5-Az) induced its expression. Immunohistochemical staining showed that C/EBP was localised in the nucleus in normal thyroid cells but was detected in the cytoplasm in papillary thyroid carcinoma cells. Subcellular fractionation of papillary thyroid carcinoma cell lines also demonstrated high levels of expression of C/EBP in the cytoplasm, suggesting that a large proportion of C/EBP protein is inappropriately localised in the cytoplasm. In summary, these findings reveal novel abnormalities in thyroid carcinoma cells