Department of Radiation Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Thyroid. 2013 Jul;23(7):817-28. doi: 10.1089/thy.2012.0466. Epub 2013 Jun 21.
FOXE1, a thyroid-specific transcription factor also known as TTF-2, was recently identified as a major genetic risk factor for papillary thyroid carcinoma (PTC). Its role in thyroid carcinogenesis, however, remains unknown. The purpose of the present study was to assess the relationship between the FOXE1 immunohistochemical features and the clinical and genetic characteristics of PTC.
Immunohistochemical staining of FOXE1 was performed in 48 PTC cases. Two single nucleotide polymorphisms immediately inside (rs1867277) or in the vicinity (rs965513) of the FOXE1 gene were genotyped by direct sequencing. Histopathological, clinical, and genetic data were included in statistical analyses.
FOXE1 exhibited cytoplasmic overexpression in tumor tissue compared to the normal counterpart (p<0.001). Both cancer and normal thyroid cells demonstrated the highest FOXE1 scores in the areas closest to the tumor border (<300 μm) compared with more distant areas (p<0.001). No differences in FOXE1 staining distributions were found between microcarcinomas and PTC of larger size, between different histopathological variants of PTC, and encapsulated and nonencapsulated tumors. Multivariate regression analysis revealed that nuclear FOXE1 expression in neoplastic cells in the vicinity of the tumor border independently associated with the genotype at rs1867277 (the dominant model of inheritance, p=0.037) and tumor multifocality (p=0.032), and with marginal significance with capsular invasion (p=0.051).
FOXE1 overexpression and translocation to the cytoplasm are phenotypic hallmarks of tumor cells suggesting that FOXE1 is involved in the pathogenesis of PTC. Nuclear FOXE1 expression in tumor cells in the vicinity of the PTC border is associated with the presence of a risk allele of rs1867277 (c.-238G>A) in the 5' untranslated region of the FOXE1 gene, as well as with pathological characteristics of PTC, suggesting possible FOXE1 involvement in the facilitation of tumor development beginning at an early stage.
FOXE1 是一种甲状腺特异性转录因子，也称为 TTF-2，最近被确定为甲状腺乳头状癌 (PTC) 的主要遗传风险因素。然而，其在甲状腺癌发生中的作用尚不清楚。本研究的目的是评估 FOXE1 免疫组织化学特征与 PTC 的临床和遗传特征之间的关系。
对 48 例 PTC 病例进行 FOXE1 免疫组织化学染色。通过直接测序对 FOXE1 基因内（rs1867277）或附近（rs965513）的两个单核苷酸多态性进行基因分型。将组织病理学、临床和遗传数据纳入统计分析。
与正常对照相比，肿瘤组织中 FOXE1 表现出细胞质过表达（p<0.001）。与更远的区域相比，癌组织和正常甲状腺细胞在靠近肿瘤边界（<300μm）的区域表现出最高的 FOXE1 评分（p<0.001）。微癌和较大大小的 PTC 之间、PTC 的不同组织学变体之间以及包膜和非包膜肿瘤之间，FOXE1 染色分布无差异。多变量回归分析显示，肿瘤边界附近肿瘤细胞的核 FOXE1 表达与 rs1867277 基因型（显性遗传模式，p=0.037）和肿瘤多灶性（p=0.032）独立相关，与包膜侵犯具有边缘显著性（p=0.051）。
FOXE1 的过表达和转位到细胞质是肿瘤细胞的表型特征，表明 FOXE1 参与了 PTC 的发病机制。PTC 边界附近肿瘤细胞的核 FOXE1 表达与 FOXE1 基因 5'非翻译区 rs1867277 （c.-238G>A）风险等位基因的存在以及 PTC 的病理特征相关，提示 FOXE1 可能参与促进早期肿瘤的发展。
