Foci formation of P53-binding protein 1 in thyroid tumors: Activation of genomic instability during thyroid carcinogenesis
Foci formation of P53-binding protein 1 in thyroid tumors: Activation of genomic instability during thyroid carcinogenesis
复制标题
DOI：
10.1002/ijc.23223
复制
发表时间：
2008-03-01
影响因子：
6.4
通讯作者：
Sekine, Ichiro
中科院分区：
文献类型：
--
作者：
Nakashima, Masahiro;Suzuki, Keiji;Sekine, Ichiro
缺陷性DNA损伤反应（DDR）可导致基因组不稳定性（GIN）并导致转化为癌症。P53结合蛋白1（53 BP 1）属于进化上保守的DDR蛋白家族。由于53 BP 1分子定位于DNA双链断裂（DSB）位点并迅速形成核灶，因此53 BP 1灶的存在可被认为是反映GIN的内源性DSB的细胞学标记。虽然已经提出GIN在甲状腺肿瘤的进展中具有关键作用，但GIN在甲状腺肿瘤发生过程中的意义仍不清楚，特别是在患者中。因此，我们分析了40例切除的甲状腺组织中GIN的水平，用53 BP 1的免疫荧光法检测。这项研究表明，在甲状腺癌细胞核53 BP 1灶的数量，表明在甲状腺癌细胞中的DDR的组成性激活。由于滤泡性腺瘤也显示出一些53 BP 1核灶，GIN可能在甲状腺肿瘤发生的癌前阶段被诱导。此外，高级别甲状腺癌突出地表现出强烈的和不均匀的53 BP 1免疫反应性核染色，这也在辐射相关的癌症和小鼠结肠隐窝中观察到，作为对高剂量电离辐射的延迟反应，表明随着癌症的进展GIN增加。因此，本研究证明了在甲状腺癌发生过程中53 BP 1的染色模式的差异。我们建议，53 BP 1表达的免疫荧光分析可以是一个有用的工具来估计GIN的水平，同时，人类甲状腺肿瘤的恶性潜能。(c)2007 Wiley-Liss，Inc.
Defective DNA damage response (DDR) can result in genomic instability (GIN) and lead to the transformation into cancer. P53-binding protein 1 (53BP1) belongs to a family of evolutionarily conserved DDR proteins. Because 53BP1 molecules localize at the sites of DNA double strand breaks (DSBs) and rapidly form nuclear foci, the presence of 53BP1 foci can be considered as a cytologic marker for endogenous DSBs reflecting GIN. Although it has been proposed that GIN has a crucial role in the progression of thyroid neoplasms, the significance of GIN during thyroid tumorigenesis remains unclear, particularly in patients. We analyzed, therefore, the level of GIN, as detected with immunofluorescence of 53BP1, in 40 cases of resected thyroid tissues. This study demonstrated a number of nuclear 53BP1 foci in thyroid cancers, suggesting a constitutive activation of DDR in thyroid cancer cells. Because follicular adenoma also showed a few 53BP1 nuclear foci, GIN might be induced at a precancerous stage of thyroid tumorigenesis. Furthermore, high-grade thyroid cancers prominently exhibited an intense and heterogeneous nuclear staining of 53BP1 immunoreactivity, which was also observed in radiation-associated cancers and in mouse colonic crypts as a delayed response to a high dose ionizing radiation, suggesting increased GIN with progression of cancer. Thus, the present study demonstrated a difference in the staining pattern of 53BP1 during thyroid carcinogenesis. We propose that immunofluorescence analysis of 53BP1 expression can be a useful tool to estimate the level of GIN and, simultaneously, the malignant potency of human thyroid tumors. (c) 2007 Wiley-Liss, Inc.