Nakashima Masahiro, Suzuki Keiji, Meirmanov Serik, Naruke Yuki, Matsuu-Matsuyama Mutsumi, Shichijo Kazuko, Saenko Vladimir, Kondo Hisayoshi, Hayashi Tomayoshi, Ito Masahiro, Yamashita Shunichi, Sekine Ichiro
Division of Scientific Data Registry, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Int J Cancer. 2008 Mar 1;122(5):1082-8. doi: 10.1002/ijc.23223.
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.
DNA损伤反应（DDR）缺陷可导致基因组不稳定（GIN）并引发癌症转化。P53结合蛋白1（53BP1）属于进化保守的DDR蛋白家族。由于53BP1分子定位于DNA双链断裂（DSB）位点并迅速形成核灶，53BP1灶的存在可被视为反映GIN的内源性DSB的细胞学标志物。尽管有人提出GIN在甲状腺肿瘤进展中起关键作用，但GIN在甲状腺肿瘤发生过程中的意义仍不清楚，尤其是在患者中。因此，我们分析了40例切除的甲状腺组织中通过53BP1免疫荧光检测到的GIN水平。本研究显示甲状腺癌中有许多核53BP1灶，提示甲状腺癌细胞中DDR的组成性激活。由于滤泡性腺瘤也显示出一些53BP1核灶，GIN可能在甲状腺肿瘤发生的癌前阶段被诱导。此外，高级别甲状腺癌显著表现出53BP1免疫反应性的强烈且异质性核染色，这也在辐射相关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，提示随着癌症进展GIN增加。因此，本研究证明了甲状腺癌发生过程中53BP1染色模式的差异。我们提出，53BP1表达的免疫荧光分析可以成为评估GIN水平以及同时评估人类甲状腺肿瘤恶性潜能的有用工具。
