Targeted expression of BRAFV600E in thyroid cells of transgenic mice results in papillary thyroid cancers that undergo dedifferentiation
Targeted expression of BRAFV600E in thyroid cells of transgenic mice results in papillary thyroid cancers that undergo dedifferentiation
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DOI：
10.1158/0008-5472.can-05-0047
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发表时间：
2005-05-15
期刊：
影响因子：
11.2
通讯作者：
Fagin, JA
中科院分区：
文献类型：
--
作者：
Knauf, JA;Ma, XL;Fagin, JA
BRAF（T1799A）突变是甲状腺乳头状癌（PTC）中最常见的基因改变。它也存在于一部分甲状腺微小乳头状癌中，这与它在肿瘤起始中的作用相符。具有BRAF（T1799A）突变的PTC通常具有侵袭性，且处于更晚期阶段。BRAF（T1799A）在高细胞变异型PTC以及由PTC发展而来的低分化和未分化癌中具有较高的患病率。为了探究BRAF（V600E）在甲状腺癌发病机制中的作用，我们利用牛甲状腺球蛋白启动子将其表达靶向转基因FVB/N小鼠的甲状腺细胞。培育了两个Tg - BRAF（V600E）品系（Tg - BRAF2和Tg - BRAF3）用于详细分析。Tg - BRAF2和Tg - BRAF3小鼠的促甲状腺激素水平升高（分别>7倍和约2倍）。这可能是由于甲状腺过氧化物酶、钠碘同向转运体和甲状腺球蛋白表达降低所致。所有品系似乎都成功代偿了甲状腺功能障碍，因为血清甲状腺素/三碘甲状腺原氨酸和体格生长正常。转基因小鼠的甲状腺在5周龄时显著增大。在Tg - BRAF2小鼠中，分别在12周和22周时，15只动物中有14只以及14只动物中有13只出现PTC，其中83%表现出高细胞特征，83%有侵袭区域，48%有低分化癌病灶。Tg - BRAF3小鼠也会发生PTC，尽管患病率较低（在12周和22周时分别为12只中的3只和9只中的4只）。Tg - BRAF2小鼠在5个月时生存率降低30%。总之，BRAF（V600E）在甲状腺特异性表达会诱导甲状腺肿和侵袭性PTC，并转变为低分化癌。这与人类BRAF阳性PTC的表型非常相似，并支持该癌基因在其发病机制中的关键作用。
The BRAF(T1799A) mutation is the most common genetic alteration in papillary thyroid carcinomas (PTC). It is also found in a subset of papillary microcarcinomas, consistent with a role in tumor initiation. PTCs with BRAF(T1799A) are often invasive and present at a more advanced stage. BKAF(T1799A) is found with high prevalence in tall-cell variant PTCs and in poorly differentiated and undifferentiated carcinomas arising from PTCs. To explore the role of BRAF(V600E) in thyroid cancer pathogenesis, we targeted its expression to thyroid cells of transgenic FVB/N mice with a bovine thyroglobulin promoter. Two Tg-BKAF(V600E) lines (Tg-BRAF2 and Tg-BRAF3) were propagated for detailed analysis. Tg-BKAF2 and Tg-BRAF3 mice had increased thyroid-stimulating hormone levels (> 7-and similar to 2-fold, respectively). This likely resulted from decreased expression of thyroid peroxidase, sodium iodine symporter, and thyroglobulin. All lines seemed to successfully compensate for thyroid dysfunction, as serum thyroxine/triiodothyronine and somatic growth were normal. Thyroid glands of transgenic mice were markedly enlarged by 5 weeks of age. In Tg-BRAF2 mice, PTCs were present at 12 and 22 weeks in 14 of 15 and 13 of 14 animals, respectively, with 83% exhibiting tall-cell features, 83% areas of invasion, and 48% foci of poorly differentiated carcinoma. Tg-BRAF3 mice also developed PTCs, albeit with lower prevalence (3 of 12 and 4 of 9 at 12 and 22 weeks, respectively). Tg-BRAF2 mice had a 30% decrease in survival at 5 months. In summary, thyroid-specific expression of BRAF(V600E) induces goiter and invasive PTC, which transitions to poorly differentiated carcinomas. This closely recapitulates the phenotype of BRAF-positive PTCs in humans and supports a key role for this oncogene in its pathogenesis.