Wang D G, Liu W H, Johnston C F, Sloan J M, Buchanan K D
Department of Medicine, School of Clinical Medicine, Queen's University of Belfast, United Kingdom.
Am J Pathol. 1998 Jun;152(6):1407-13.
Medullary thyroid carcinoma (MTC) is a tumor of parafollicular cells of 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, little is known about the molecular pathogenesis of the sporadic variants of this tumor. It has become increasingly clear that deregulation of programmed cell death is a critical component in multistep tumorigenesis. The present investigation was undertaken to determine whether similar molecular events occur in human MTC. Eighteen MTCs from 18 patients (including 12 sporadic and six familial cases and one metastatic lymph gland) and a MTC cell line (TT cells) were used in this study for detecting the expression of apoptosis-regulatory genes bcl-2, bax, c-myc, and p53. Immunohistochemical results showed that all MTC tumor samples displayed Bcl-2 and c-Myc immunoreactivity, whereas only 4 and 2 tumors showed a minority of cells positive for Bax and p53, respectively. Western and Northern blotting showed high levels of 26-kd Bcl-2 protein and bcl-2 transcript. The co-expression of Bcl-2 and c-Myc was also detected in the TT cells by indirect fluorescence immunohistochemistry and Western blotting. Moreover, Bcl-2 immunoreactivity was also found in C-cell hyperplasia from familial patients indicating that expression of this oncogene may represent an early event in the pathogenesis of MTC. The present study suggests that deregulation of programmed cell death may be a critical component in multistep tumorigenesis of MTC and that the frequent expression of the Bcl-2 oncoprotein in these tumors may contribute to their pathogenesis. The genetic complementation of simultaneously deregulated bcl-2 and c-myc may be implicated in the multistep tumorigenesis of human MTC.
甲状腺髓样癌（MTC）是一种起源于甲状腺滤泡旁细胞的肿瘤。它已成为研究肿瘤增殖和分化的有用实验模型。尽管最近的研究已经确定了与家族性MTC相关的基因，但对于这种肿瘤散发性变体的分子发病机制知之甚少。越来越清楚的是，程序性细胞死亡的失调是多步骤肿瘤发生的关键组成部分。本研究旨在确定人类MTC中是否发生类似的分子事件。本研究使用了来自18例患者的18个MTC样本（包括12例散发性和6例家族性病例以及1个转移性淋巴结）和一个MTC细胞系（TT细胞）来检测凋亡调节基因bcl-2、bax、c-myc和p53的表达。免疫组织化学结果显示，所有MTC肿瘤样本均显示Bcl-2和c-Myc免疫反应性，而分别只有4个和2个肿瘤显示少数细胞Bax和p53呈阳性。蛋白质免疫印迹法和Northern印迹法显示26-kd Bcl-2蛋白和bcl-2转录本水平较高。通过间接荧光免疫组织化学和蛋白质免疫印迹法在TT细胞中也检测到了Bcl-2和c-Myc的共表达。此外，在家族性患者的C细胞增生中也发现了Bcl-2免疫反应性，表明该癌基因的表达可能代表MTC发病机制中的早期事件。本研究表明，程序性细胞死亡的失调可能是MTC多步骤肿瘤发生的关键组成部分，并且这些肿瘤中Bcl-2癌蛋白的频繁表达可能有助于其发病机制。同时失调的bcl-2和c-myc的基因互补可能与人类MTC的多步骤肿瘤发生有关。
