Cho J Y, Sagartz J E, Capen C C, Mazzaferri E L, Jhiang S M
Department of Physiology, The Ohio State University, Columbus 43210, USA.
Oncogene. 1999 Jun 17;18(24):3659-65. doi: 10.1038/sj.onc.1202709.
The RET/PTC1 oncogene, a rearranged form of the RET proto-oncogene, has been reported to be associated with human papillary thyroid carcinomas. We have shown that targeted expression of RET/PTC1 in the thyroid gland leads to the development of thyroid carcinomas in transgenic mice with histologic and cytologic similarities to human papillary thyroid carcinoma. To further investigate how RET/PTC1 expression contributes to the pathogenesis of papillary thyroid tumor, the time of tumor onset and the early phenotypic consequences of RET/PTC1 expression in thyrocytes were determined. All high copy transgenic mice developed bilateral thyroid tumors as early as 4 days of age. At embryological days 16-18, increased proliferation rate, distorted thyroid follicle formation and reduced radioiodide concentrating activity were identified in transgenic embryos. The reduced radioiodide concentrating activity was attributed to decreased expression of the sodium-iodide symporter. Our study showed that RET/PTC1 not only increased proliferation of thyrocytes, it also altered morphogenesis and differentiation. These findings provide a model for the role of RET/PTC1 in the formation of abnormal follicles with reduced iodide uptake ability observed in human papillary thyroid carcinoma.
RET/PTC1致癌基因是RET原癌基因的一种重排形式，据报道与人类甲状腺乳头状癌相关。我们已经表明，在甲状腺中靶向表达RET/PTC1会导致转基因小鼠发生甲状腺癌，其组织学和细胞学特征与人类甲状腺乳头状癌相似。为了进一步研究RET/PTC1表达如何促进甲状腺乳头状肿瘤的发病机制，我们确定了肿瘤发生的时间以及RET/PTC1在甲状腺细胞中表达的早期表型后果。所有高拷贝转基因小鼠在4日龄时就早早出现了双侧甲状腺肿瘤。在胚胎第16 - 18天，转基因胚胎中出现增殖率增加、甲状腺滤泡形成异常以及放射性碘摄取活性降低。放射性碘摄取活性降低归因于钠碘同向转运体表达减少。我们的研究表明，RET/PTC1不仅增加了甲状腺细胞的增殖，还改变了形态发生和分化。这些发现为RET/PTC1在人类甲状腺乳头状癌中观察到的碘摄取能力降低的异常滤泡形成中的作用提供了一个模型。
