Thyrotropin signaling confers more aggressive features with higher genomic instability on BRAF(V600E)-induced thyroid tumors in a mouse model.
BACKGROUND
The BRAF(V600E) mutation is the most common genetic alteration in papillary thyroid carcinomas (PTCs). Transgenic mice overexpressing BRAF(V600E) 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 BRAF(V600E) in the process of thyroid carcinogenesis.


METHODS
We crossed Tg-BRAF2 mice with TSH receptor knockout (TshR(-/-)) mice. Four genetically distinct mice groups-Braf(wt)/TshR(+/-) (group 1), Braf(wt)/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 BRAF(V600E).


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 BRAF(V600E) expression.


CONCLUSIONS
These data demonstrate that the TSH signaling confers more aggressive features in BRAF(V600E)-induced thyroid tumors in mice. This might be due, in part, to accelerated genomic instability.
1 Department of Radiation Medical Sciences, Nagasaki University , Nagasaki, Japan .
Florence
F
Orim
Andrey
A
Bychkov
Mika
M
Shimamura
Masahiro
M
Nakashima
Masahiro
M
Ito
Michiko
M
Matsuse
Tomomi
T
Kurashige
Keiji
K
Suzuki
Vladimir
V
Saenko
Yuji
Y
Nagayama
Shunichi
S
Yamashita
Norisato
N
Mitsutake
D000818:Animals; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D042822:Genomic Instability; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D011989:Receptors, Thyrotropin / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013972:Thyrotropin / Q000378:metabolism*
D011989:Receptors, Thyrotropin; D013972:Thyrotropin; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf