Oncogenic BRAF disrupts thyroid morphogenesis and function via twist expression
Oncogenic BRAF disrupts thyroid morphogenesis and function via twist expression
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DOI：
10.7554/elife.20728.001
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发表时间：
2017-03-28
期刊：
影响因子：
7.7
通讯作者：
Houvras, Yariv
中科院分区：
文献类型：
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作者：
Anelli, Viviana;Villefranc, Jacques A.;Houvras, Yariv
甲状腺癌是常见的，但促进肿瘤形成的改变顺序还不完全清楚。在这里，我们描述了一种新的模型，甲状腺癌的斑马鱼，揭示了时间的变化，由于BRAF（V600 E）。通过使用实时体内成像，我们观察到甲状腺发育早期甲状腺滤泡结构的破坏。使用BRAF和MEK抑制剂的组合治疗逆转了BRAF（V600 E）诱导的发育效应。在甲状腺细胞中表达BRAF（V600 E）的成年斑马鱼发展为浸润性癌。我们从斑马鱼甲状腺癌中鉴定出一个基因表达特征，它可以预测乳头状甲状腺癌患者的无病生存率。基因表达研究提名TWIST 2作为BRAF下游的关键效应子。使用CRISPR/Cas9遗传修饰TWIST 2直向同源物，我们抑制了BRAF（V600 E）的作用，并恢复了甲状腺形态和激素合成。这些数据表明TWIST 2的表达在BRAF（V600 E）介导的转化的早期步骤中起作用。
Thyroid cancer is common, yet the sequence of alterations that promote tumor formation are incompletely understood. Here, we describe a novel model of thyroid carcinoma in zebrafish that reveals temporal changes due to BRAF(V600E). Through the use of real-time in vivo imaging, we observe disruption in thyroid follicle structure that occurs early in thyroid development. Combinatorial treatment using BRAF and MEK inhibitors reversed the developmental effects induced by BRAF(V600E). Adult zebrafish expressing BRAF(V600E) in thyrocytes developed invasive carcinoma. We identified a gene expression signature from zebrafish thyroid cancer that is predictive of disease-free survival in patients with papillary thyroid cancer. Gene expression studies nominated TWIST2 as a key effector downstream of BRAF. Using CRISPR/Cas9 to genetically inactivate a TWIST2 orthologue, we suppressed the effects of BRAF(V600E) and restored thyroid morphology and hormone synthesis. These data suggest that expression of TWIST2 plays a role in an early step of BRAF(V600E)-mediated transformation.