Helix-loop transcription factor, Id1, is overexpressed in medullary thyroid cancer

Abstract

Abstract Background The helix-loop transcription factor (Id1) protein inhibits differentiation, enhances cell proliferation and is required for cell-cycle progression. Id1 is highly expressed in a variety of tumour-derived cell lines, increases following mitogenic stimuli and is overexpressed in some human neoplasms. It was therefore reasoned that the Id1 gene may play a role in medullary thyroid carcinogenesis. Methods Id1 protein expression in human medullary thyroid cancer (MTC) and corresponding normal thyroid tissue was determined by Id1 immunohistochemistry. Calcitonin immunohistochemistry was used to determine the cellular localization of Id1 immunostaining. In a well characterized human MTC cell line (TT), the effects of growth stimulation (with serum) and redifferentiation (with phorbol esters) on Id1 expression were determined by Northern blot analysis. Results Id1 immunostaining intensity in MTC (n = 9; six sporadic MTCs, two familial MTCs and one multiple endocrine neoplasia type 2A MTC) was moderate to strong whereas in the corresponding normal thyroid tissues (n = 9) it was absent or faint in the C cells and follicular cells. Id1 immunostaining was significantly higher in MTC than the corresponding normal thyroid tissue based on the percentage of positive cells and immunostaining intensity (P = 0·002, rank sum test). The 1·2-kilobase Id1 transcript was expressed in the TT cell line under basal culture conditions. Interestingly, Id1 messenger RNA (mRNA) expression was markedly upregulated (4·0 fold) following growth stimulation with 10 per cent fetal bovine serum. In addition, phorbol ester (which is known to induce redifferentiation of the TT cell line) downregulated Id1 mRNA expression in the TT cell line. Conclusion Id1 is overexpressed in MTC. Furthermore, increased Id1 expression is associated with an enhanced proliferative potential in MTC. The inappropriate proliferation and dedifferentiation of the C cells that lead to MTC, at least in part, may be regulated by the Id1 gene.