Decreased type 1 iodothyronine deiodinase expression might be an early and discrete event in thyroid cell dedifferentation towards papillary carcinoma

Abstract

Type I iodothyronine deiodinase (D1) catalyses the 5' monodeiodination of T4 and is highly expressed in normal human thyroid gland. We have investigated D1 expression in a series of benign and malignant differentiated thyroid neoplasias. Surgically isolated thyroid tumour fragments were used. D1 expression was determined by reverse transcription polymerase chain reaction (RT-PCR) and enzymatic assay. Tumours and adjacent normal tissues were obtained from 28 unselected patients (papillary carcinoma, n = 14; follicular adenoma, n = 7; follicular carcinoma, n = 6; anaplastic carcinoma, n = 1). D1 mRNA levels were determined using specific primers for the human D1 gene and enzymatic assays were performed using T4 as substrate. In papillary thyroid carcinoma (PTC), D1 mRNA and activity levels were decreased compared with the surrounding tissue (0.25 +/- 0.24 vs. 1.09 +/- 0.54 arbitrary units (AU), P < 0.001 and 0.08 +/- 0.07 vs. 0.24 +/- 0.15 pmol T4/min/mg protein, P = 0.045, respectively). Decreased D1 expression was consistent and was observed in all histological subtypes and clinical stages analysed, including microcarcinomas. By contrast, significantly higher D1 mRNA levels and enzyme activity were present in follicular adenoma (1.9 +/- 1.5 vs. 0.83 +/- 0.58 AU, P = 0.028 and 2.67 +/- 1.42 vs. 0.22 +/- 0.06 pmol T4/min/mg protein, P = 0.044, respectively) and in follicular thyroid carcinoma (FTC) than in surrounding normal tissue (1.2 +/- 0.46 vs. 0.67 +/- 0.18 AU, P = 0.038 and 1.20 +/- 0.58 vs. 0.20 +/- 0.10 pmol T4/min/mg protein, P < 0.001, respectively). Type II iodothyronine deiodinase (D2) activity was also significantly higher in metastatic FTC samples than in normal thyroid tissues (5.20 +/- 0.81 vs. 0.30 +/- 0.27 fmol T4/min/mg protein, P < 0.001). These findings suggest that thyroid cell dedifferentiation promotes changes in D1 gene expression by pretranscriptional mechanisms and indicate that decreased D1 expression might be an early and discrete event in thyroid cell dedifferentiation towards papillary thyroid carcinoma.