Selective Ablation of Tumor Suppressors in Parafollicular C Cells Elicits Medullary Thyroid Carcinoma*
Selective Ablation of Tumor Suppressors in Parafollicular C Cells Elicits Medullary Thyroid Carcinoma*
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DOI：
10.1074/jbc.m116.765727
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发表时间：
2017-01
期刊：
影响因子：
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通讯作者：
Hai Song;Chuwen Lin;Erica Yao;Kuan Zhang;Xiaoling Li;Qingzhe Wu;Pao-Tien Chuang
中科院分区：
文献类型：
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作者：
Hai Song;Chuwen Lin;Erica Yao;Kuan Zhang;Xiaoling Li;Qingzhe Wu;Pao-Tien Chuang
在四种不同类型的甲状腺癌中，甲状腺髓样癌的治疗是一个主要的挑战，因为它有早期转移的倾向。为了进一步研究甲状腺髓样癌的分子机制，发现靶向治疗的候选药物，我们基于我们的CGRPCreER小鼠系建立了新的甲状腺髓样癌小鼠模型。该系统能够在甲状腺滤泡旁C细胞中进行基因操作，这些细胞被认为是甲状腺髓样癌的起源细胞。通过来自CGRPCreER的可诱导的Cre重组酶，在成熟的滤泡旁C细胞中选择性地失活肿瘤抑制因子，如p53、Rb和Pten，导致小鼠甲状腺髓样癌的发展。Pten的缺失加速了p53/ rb诱导的甲状腺髓样癌，表明肿瘤抑制因子控制的途径之间存在相互作用。此外，通过CGRPCreER标记分化的滤泡旁C细胞使我们能够跟踪它们在恶性转化为甲状腺髓样肿瘤过程中的命运。我们的研究结果支持分化的滤泡旁C细胞突变事件导致甲状腺髓样癌的模型。通过包括RNA-Seq在内的表达分析，我们发现了去除肿瘤抑制因子后受到干扰的主要信号通路和网络。综上所述，这些研究不仅增加了我们对甲状腺髓样癌的分子认识，而且为设计靶向治疗或其他治疗方式提供了新的候选药物。
Among the four different types of thyroid cancer, treatment of medullary thyroid carcinoma poses a major challenge because of its propensity of early metastasis. To further investigate the molecular mechanisms of medullary thyroid carcinoma and discover candidates for targeted therapies, we developed a new mouse model of medullary thyroid carcinoma based on our CGRPCreER mouse line. This system enables gene manipulation in parafollicular C cells in the thyroid, the purported cells of origin of medullary thyroid carcinoma. Selective inactivation of tumor suppressors, such as p53, Rb, and Pten, in mature parafollicular C cells via an inducible Cre recombinase from CGRPCreER led to development of murine medullary thyroid carcinoma. Loss of Pten accelerated p53/Rb-induced medullary thyroid carcinoma, indicating interactions between pathways controlled by tumor suppressors. Moreover, labeling differentiated parafollicular C cells by CGRPCreER allows us to follow their fate during malignant transformation to medullary thyroid tumor. Our findings support a model in which mutational events in differentiated parafollicular C cells result in medullary thyroid carcinoma. Through expression analysis including RNA-Seq, we uncovered major signaling pathways and networks that are perturbed following the removal of tumor suppressors. Taken together, these studies not only increase our molecular understanding of medullary thyroid carcinoma but also offer new candidates for designing targeted therapies or other treatment modalities.