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Thyrotropin Signaling Confers More Aggressive Features with Higher Genomic Instability on BRAFV600E-Induced Thyroid Tumors in a Mouse Model


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Title: Thyrotropin Signaling Confers More Aggressive Features with Higher Genomic Instability on BRAFV600E-Induced Thyroid Tumors in a Mouse Model
Authors: Orim, Florence / Bychkov, Andrey / Shimamura, Mika / Nakashima, Masahiro / Ito, Masahiro / Matsuse, Michiko / Kurashige, Tomomi / Suzuki, Keiji / Saenko, Vladimir / Nagayama, Yuji / Yamashita, Shunichi / Mitsutake, Norisato
Issue Date: 1-Mar-2014
Publisher: Mary Ann Liebert Inc.
Citation: Thyroid, 24(3), pp.502-510; 2014
Abstract: 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.
URI: http://hdl.handle.net/10069/34386
ISSN: 10507256
DOI: 10.1089/thy.2013.0038
Rights: This is a copy of an article published in the Thyroid © 2014, Mary Ann Liebert, Inc.; Thyroid is available online at: http://online.liebertpub.com.
Type: Journal Article
Text Version: publisher
Appears in Collections:Articles in academic journal

Citable URI : http://hdl.handle.net/10069/34386

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