BCL-2 AND C-MYC, BUT NOT BAX AND P53, ARE EXPRESSED DURING HUMAN MEDULLARY-THYROID TUMORIGENESIS

Medullary thyroid carcinoma (MTC) is a tumor of parafollicular cells o f the thyroid gland. It has served as a useful experimental model for the study of tumor proliferation and differentiation. Although recent studies have identified the gene involved in familial forms of MTC, li ttle is known about the molecular pathogenesis of the sporadic variant s of this tumor. It has become increasingly clear that deregulation of programmed cell death is a critical component in multistep tumorigene sis. The present investigation was undertaken to determine whether sim ilar molecular events occur in human MTC, Eighteen MTCs from 18 patien ts (including 12 sporadic and six familial cases and one metastatic ly mph gland) and a MTC cell line (IT cells) were used in this study for detecting the expression of apoptosis-regulatory genes bcl-2, bar, c-m yc, and p53 Immunohistochemical results showed that all MTC tumor samp les displayed Bcl-2 and c-Myc immunoreactivity, whereas only 4 and 2 t umors showed a minority of cells positive for Bar and p53, respectivel y. Western and Northern blotting showed high levels of 26-kd Bcl-2 pro tein and bcl-2 transcript. The co-expression of Bcl-2 and c-Myc was al so detected in the Tf cells by indirect fluorescence immunohistochemis try and Western blotting. Moreover, Bcl-2 immunoreactivity was also fo und in C-cell hyperplasia from familial patients indicating that expre ssion of this oncogene may represent an early event in the pathogenesi s of MTC. The present study suggests that deregulation of programmed c ell death may be a critical component in multistep tumorigenesis of MT C and that the frequent expression of the Bcl-2 oncoprotein in these t umors may contribute to their pathogenesis. The genetic complementatio n of simultaneously deregulated bcl-2 and c-myc may be implicated in t he multistep tumorigenesis of human MTC.