甲状腺刺激ホルモンシグナルは、BRAFV600E甲状腺癌マウスモデルにおけるゲノム不安定性を伴った高度悪性化に関与している

Background: The BRAFV600E mutation is the most common genetic alteration in papillary thyroid carcinomas (PTCs). Transgenic mice overexpressing BRAFV600E in their thyroids under control of the thyroglobulin promoter (Tg-BRAF2 mice) developed invasive PTCs with high penetrance. However, these mice showed elevated thyrotropin (TSH) levels, which also stimulate the proliferation of thyrocytes and tumorigenesis. The purpose of the present study was to investigate how TSH signaling cooperates with BRAFV600E in the process of thyroid carcinogenesis. Methods: We crossed Tg-BRAF2 mice with TSH receptor knockout (TshR-/-) mice. Four genetically distinct mice groups - Brafwt/TshR+/- (group 1), Brafwt/TshR-/- (group 2), Tg-BRAF2/TshR+/- (group 3), and Tg-BRAF2/TshR-/- (group 4) - were sacrificed at 12 and 24 weeks of age. We performed histopathological analysis. Genomic instability was evaluated by immunofluorescence for p53-binding protein 1 (53BP1) and γH2AX. Invasiveness and genomic instability were also evaluated using thyroid PCCL3 cells expressing BRAFV600E. Results: Groups 3 and 4 developed distinct neoplasias comparable to human PTCs. Group 3 developed typically larger, more aggressive, invasive tumors compared to group 4. The frequency of 53BP1 and γH2AX foci - indicators of genomic instability - in group 3 was higher than that in group 4. TSH also enhanced invasiveness and genomic instability in PCCL3 cells with BRAFV600E expression. Conclusions: These data demonstrate that the TSH signaling confers more aggressive features in BRAFV600E-induced thyroid tumors in mice. This might be due, in part, to accelerated genomic instability.長崎大学学位論文 学位記番号:博(医歯薬)甲第636号 学位授与年月日:平成25年10月2日Author: Orim Florence, Bychkov Andrey, Shimamura Mika, Nakashima Masahiro, Ito Masahiro, Matsuse Michiko, Kurashige Tomomi, Suzuki Keiji, Saenko Vladimir, Nagayama Yuji, Yamashita Shunichi, Mitsutake NorisatoCitation: Thyroid, 24(3), pp.502-510; 2014Nagasaki University (長崎大学)課程博