Nakashima Masahiro, Meirmanov Serik, Naruke Yuki, Kondo Hisayoshi, Saenko Vladimir, Rogounovitch Tatiana, Shimizu-Yoshida Yuki, Takamura Noboru, Namba Hiroyuki, Ito Masahiro, Abrosimov Aleksander, Lushnikov Eugeny, Roumiantsev Pavel, Tsyb Anatoly, Yamashita Shunichi, Sekine Ichiro
Tissue and Histopathology Section, Division of Scientific Data Registry, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Sakamoto, Nagasaki, Japan.
J Pathol. 2004 Apr;202(4):446-55. doi: 10.1002/path.1534.
Cyclin D1 is a target molecule transcriptionally activated by aberrant beta-catenin in Wnt signalling, while prolyl isomerase Pin1 promotes cyclin D1 overexpression directly or through accumulation of beta-catenin in cancer cells. This study aimed to elucidate whether Pin1 was involved in cyclin D1 overexpression and aberrant beta-catenin in thyroid tumourigenesis by examining 14 follicular adenomas (FAa) and 14 papillary thyroid carcinomas (PTCs). All PTCs displayed cyclin D1 overexpression and strong cytoplasmic beta-catenin and/or decreased membrane beta-catenin expression by immunohistochemistry. Overexpression of cyclin D1 mRNA was observed in 45.5% of FAs and 54.5% of PTCs by TaqMan real-time PCR. Pin1 expression was observed in PTC by immunostaining and was confirmed by reverse transcriptase-PCR. There was a strong correlation between cyclin D1 and Pin1/cytoplasmic/membrane beta-catenin expression (p < 0.001), and between Pin1 and cytoplasmic (p < 0.001)/membrane (p = 0.002) beta-catenin expression in thyroid tumours. Mutation of the beta-catenin gene could not be detected in PTC. Western blot analysis demonstrated high levels of cyclin D1 and beta-catenin as well as Pin1 expression in a human PTC cell line possessing wild-type beta-catenin and APC genes. This study suggests that both cyclin D1 overexpression and aberrant beta-catenin expression are of significance in thyroid tumours. Pin1 expression appears to correlate closely with the level of cyclin D1 and aberrant beta-catenin expression in thyroid tumours such as FA and PTC. Pin1 may be an important factor in regulating cyclin D1 and beta-catenin expression during thyroid carcinogenesis.
细胞周期蛋白D1是Wnt信号通路中由异常β-连环蛋白转录激活的靶分子，而脯氨酰异构酶Pin1直接或通过癌细胞中β-连环蛋白的积累促进细胞周期蛋白D1的过表达。本研究旨在通过检测14例滤泡性腺瘤（FAa）和14例甲状腺乳头状癌（PTC），阐明Pin1是否参与甲状腺肿瘤发生过程中的细胞周期蛋白D1过表达和异常β-连环蛋白表达。通过免疫组织化学，所有PTC均显示细胞周期蛋白D1过表达以及强烈的细胞质β-连环蛋白和/或膜β-连环蛋白表达降低。通过TaqMan实时PCR在45.5%的FA和54.5%的PTC中观察到细胞周期蛋白D1 mRNA的过表达。通过免疫染色在PTC中观察到Pin1表达，并通过逆转录酶PCR得到证实。在甲状腺肿瘤中，细胞周期蛋白D1与Pin1/细胞质/膜β-连环蛋白表达之间存在强相关性（p < 0.001），Pin1与细胞质（p < 0.001）/膜（p = 0.00）β-连环蛋白表达之间也存在强相关性。在PTC中未检测到β-连环蛋白基因的突变。蛋白质印迹分析显示，在具有野生型β-连环蛋白和APC基因的人PTC细胞系中，细胞周期蛋白D1、β-连环蛋白以及Pin1表达水平较高。本研究表明，细胞周期蛋白D1过表达和异常β-连环蛋白表达在甲状腺肿瘤中均具有重要意义。Pin1表达似乎与甲状腺肿瘤如FA和PTC中的细胞周期蛋白D1水平以及异常β-连环蛋白表达密切相关。Pin1可能是甲状腺癌发生过程中调节细胞周期蛋白D1和β-连环蛋白表达的重要因素。
