Mouse models of sporadic thyroid cancer derived from BRAFV600E alone or in combination with PTEN haploinsufficiency under physiologic TSH levels.
Mouse models of sporadic thyroid cancer derived from BRAFV600E alone or in combination with PTEN haploinsufficiency under physiologic TSH levels.
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DOI：
10.1371/journal.pone.0201365
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Nagayama Y
中科院分区：
文献类型：
--
作者：
Shimamura M;Shibusawa N;Kurashige T;Mussazhanova Z;Matsuzaki H;Nakashima M;Yamada M;Nagayama Y
BRAFV600E突变是散发性乳头状甲状腺癌（PTC）最常见的驱动突变。先前的研究表明，在TSH水平升高的情况下，BRAFV600E的产前或产后表达可在几种基因工程小鼠模型中诱导甲状腺癌。相比之下，我们发现在生理TSH水平下，出生后表达BRAFV600E的条件转基因Tg（LNL-BrafV600E）小鼠在甲状腺注射了在甲状腺球蛋白启动子（Ad-TgP-Cre）控制下表达Cre的腺病毒后，未能发生甲状腺癌。在本研究中，我们首先证明了携带BrafV600E的re激活等位基因的BrafCA/+小鼠与TPO-Cre小鼠杂交时，比Tg（LNL-BrafV600E）小鼠表现出更高的转化效率。结果，大多数BrafCA/+小鼠注射Ad-TgP-Cre后1年内发生甲状腺癌。组织学检查显示滤泡或筛网样结构，TG和PAX染色阳性，未见胶体形成。部分肿瘤还存在乳头状结构成分，TG表达较低。BrafCA/+注射伴PTEN单倍体不足Ptenf/+小鼠诱导的肿瘤主要表现为乳头状结构，偶尔表现为未分化的实体形态，PAX表达正常至低，TG表达低至不存在。典型的人类PTC核特征和甲状腺外侵袭主要发生在后者小鼠身上。后者的pERK阳性、Ki67阳性和tunel阳性细胞比例均较高。总之，我们建立了新的甲状腺癌小鼠模型，在生理性TSH水平下，出生后仅表达BRAFV600E可诱导PTC。同时PTEN单倍体不足会促进肿瘤生长和去分化。
The BRAFV600E mutation is the most prevalent driver mutation of sporadic papillary thyroid cancers (PTC). It was previously shown that prenatal or postnatal expression of BRAFV600E under elevated TSH levels induced thyroid cancers in several genetically engineered mouse models. In contrast, we found that postnatal expression of BRAFV600E under physiologic TSH levels failed to develop thyroid cancers in conditional transgenic Tg(LNL-BrafV600E) mice injected in the thyroid with adenovirus expressing Cre under control of the thyroglobulin promoter (Ad-TgP-Cre). In this study, we first demonstrated that BrafCA/+ mice carrying a Cre-activated allele of BrafV600E exhibited higher transformation efficiency than Tg(LNL-BrafV600E) mice when crossed with TPO-Cre mice. As a result, most BrafCA/+ mice injected with Ad-TgP-Cre developed thyroid cancers in 1 year. Histologic examination showed follicular or cribriform-like structures with positive TG and PAX staining and no colloid formation. Some tumors also had papillary structure component with lower TG expression. Concomitant PTEN haploinsufficiency in injected BrafCA/+;Ptenf/+ mice induced tumors predominantly exhibiting papillary structures and occasionally undifferentiated solid patterns with normal to low PAX expression and low to absent TG expression. Typical nuclear features of human PTC and extrathyroidal invasion were observed primarily in the latter mice. The percentages of pERK-, Ki67- and TUNEL-positive cells were all higher in the latter. In conclusion, we established novel thyroid cancer mouse models in which postnatal expression of BRAFV600E alone under physiologic TSH levels induces PTC. Simultaneous PTEN haploinsufficiency tends to promote tumor growth and de-differentiation.
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DOI：
10.1158/1541-7786.mcr-14-0158-t
发表时间：
2014-07
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Charles RP;Silva J;Iezza G;Phillips WA;McMahon M
通讯作者：
McMahon M
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
1.5
作者：
Kusakabe, T;Kawaguchi, A;Kimura, S
通讯作者：
Kimura, S
影响因子：
6.6
作者：
Alvarez-Nuñez, F;Bussaglia, E;Matias-Guju, X
通讯作者：
Matias-Guju, X
影响因子：
11.2
作者：
Knauf, JA;Ma, XL;Fagin, JA
通讯作者：
Fagin, JA