Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, K4/436 Clinical Science Center, Madison, WI, USA.
Mod Pathol. 2013 Jan;26(1):54-61. doi: 10.1038/modpathol.2012.137. Epub 2012 Aug 17.
Epithelial-mesenchymal transition is an important mechanism of epithelial tumor progression, local invasion and metastasis. The E-cadherin (CDH1) repressor SLUG (SNAI2) and the basic helix-loop-helix transcription factor TWIST1 inhibit CDH1 expression in poorly differentiated malignancies as inducers of epithelial-mesenchymal transition. Epithelial-mesenchymal transition has been implicated in progression from well to poorly differentiated/anaplastic thyroid carcinoma but the expression of SNAI2 and TWIST1 proteins and their phenotypic association in human thyroid cancers has not been extensively studied. We examined the expression of SNAI2, TWIST1 and CDH1 by immunohistochemistry in a panel of well-differentiated and anaplastic thyroid cancers and by qRT-PCR in thyroid cell lines. Ten normal thyroids, 33 follicular adenomas, 56 papillary thyroid carcinomas including 28 follicular variants, 27 follicular carcinomas and 10 anaplastic thyroid carcinomas were assembled on a tissue microarray and immunostained for SNAI2, TWIST1 and CDH1. Most (8/10) anaplastic thyroid carcinomas demonstrated strong nuclear immunoreactivity for SNAI2 with associated absence of CDH1 in 6/8 cases (75%). TWIST1 was expressed in 5/10 anaplastic thyroid carcinomas with absence of CDH1 in 3/5 (60%) cases. These findings were confirmed in whole sections of all anaplastic thyroid carcinomas and in a separate validation set of 10 additional anaplastic thyroid carcinomas. All normal thyroids, follicular adenomas, papillary and follicular thyroid carcinomas were negative for SNAI2 and TWIST1 (P<0.0001) and all showed strong diffuse immunoreactivity for CDH1 (P=0.026). Expression of SNAI2, TWIST1 and CDH1 mRNA varied in a normal thyroid, papillary carcinoma and two anaplastic thyroid carcinoma cell lines tested, but the highest levels of CDH1 mRNA were detected in the normal thyroid cell line while the anaplastic thyroid carcinoma cell line demonstrated the highest levels of SNAI2 and TWIST1 mRNA. Our findings support the role of epithelial-mesenchymal transition in the development of anaplastic thyroid carcinoma.
上皮-间充质转化是上皮性肿瘤进展、局部侵袭和转移的重要机制。E-钙黏蛋白 (CDH1) 抑制因子 SLUG（SNAI2）和碱性螺旋-环-螺旋转录因子 TWIST1 在低分化恶性肿瘤中抑制 CDH1 的表达，作为上皮-间充质转化的诱导因子。上皮-间充质转化已被牵涉到从高分化到低分化/间变性甲状腺癌的进展中，但 SNAI2 和 TWIST1 蛋白的表达及其在人类甲状腺癌中的表型关联尚未得到广泛研究。我们通过免疫组织化学法在一组分化良好和间变性甲状腺癌中检测了 SNAI2、TWIST1 和 CDH1 的表达，并通过 qRT-PCR 在甲状腺细胞系中进行了检测。在组织微阵列上组装了 10 个正常甲状腺、33 个滤泡性腺瘤、56 个乳头状甲状腺癌（包括 28 个滤泡变体）、27 个滤泡癌和 10 个间变性甲状腺癌，并对 SNAI2、TWIST1 和 CDH1 进行免疫染色。大多数（8/10）间变性甲状腺癌表现出强烈的核免疫反应性 SNAI2，6/8 例（75%）伴有 CDH1 的缺失。TWIST1 在 5/10 例间变性甲状腺癌中表达，3/5 例（60%）伴有 CDH1 的缺失。这些发现在所有间变性甲状腺癌的全切片中以及在另外 10 例间变性甲状腺癌的独立验证集中得到了证实。所有正常甲状腺、滤泡性腺瘤、乳头状和滤泡性甲状腺癌均为 SNAI2 和 TWIST1 阴性（P<0.0001），并且均显示出 CDH1 的强烈弥漫性免疫反应性（P=0.026）。在测试的正常甲状腺、乳头状癌和 2 种间变性甲状腺癌细胞系中，SNAI2、TWIST1 和 CDH1 mRNA 的表达各不相同，但在正常甲状腺细胞系中检测到最高水平的 CDH1 mRNA，而间变性甲状腺癌细胞系则显示出最高水平的 SNAI2 和 TWIST1 mRNA。我们的发现支持上皮-间充质转化在间变性甲状腺癌发展中的作用。
