mTOR Pathway Overactivation in BRAF Mutated Papillary Thyroid Carcinoma
mTOR Pathway Overactivation in BRAF Mutated Papillary Thyroid Carcinoma
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DOI：
10.1210/jc.2011-2748
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发表时间：
2012-07-01
影响因子：
5.8
通讯作者：
Soares, Paula
中科院分区：
文献类型：
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作者：
Faustino, Alexandra;Couto, Joana P.;Soares, Paula
内容：有几个遗传和分子证据表明，在甲状腺肿瘤的雷帕霉素（mTOR）通路的哺乳动物靶失调。RET/PTC和突变型RAS激活磷脂酰肌醇-3-激酶/AKT通路已被证实，但BRAF（V600 E）突变的数据尚未报道。目的：本研究的目的是评估恶性甲状腺病变中mTOR通路的激活模式，以及它是否与已知的遗传改变相关，结果：通过免疫组化检测，我们观察到mTOR通路蛋白在甲状腺癌，特别是常规甲状腺乳头状癌（cPTC）中表达上调/激活。mTOR信号传导的过度活化在携带BRAF（V600 E）突变的cPTC样品中特别明显。用BRAF表达载体以及通过小干扰RNA敲低BRAF的转染测定揭示了BRAF表达与mTOR通路激活之间的正相关性，这似乎是由pLKB 1 Ser 428介导的，并且成为促成BRAF突变与mTOR通路上调之间的关联的可能机制。当我们评估了雷帕霉素在甲状腺癌细胞系的生长，我们检测到，细胞系与活化突变的MAPK途径显示出较高的敏感性，以这种drug.Conclusions：我们确定，AKT/mTOR途径是特别过度激活人类cPTC窝藏BRAF（V600 E）突变。此外，我们的研究结果表明，mTOR通路可能是一个很好的目标，以提高某些类型的甲状腺癌的治疗效果，即在那些窝藏BRAF（V600 E）突变。（临床内分泌代谢杂志97：E1139-E1149，2012）
Context: There are several genetic and molecular evidences suggesting dysregulation of the mammalian target of rapamycin (mTOR) pathway in thyroid neoplasia. Activation of the phosphatidylinositol-3-kinase/AKT pathway by RET/PTC and mutant RAS has already been demonstrated, but no data have been reported for the BRAF(V600E) mutation.Objective: The aim of this study was to evaluate the activation pattern of the mTOR pathway in malignant thyroid lesions and whether it may be correlated with known genetic alterations, as well as to explore the mechanisms underlying mTOR pathway activation in these neoplasias.Results: We observed, by immunohistochemical evaluation, an up-regulation/activation of the mTOR pathway proteins in thyroid cancer, particularly in conventional papillary thyroid carcinoma (cPTC). Overactivation of the mTOR signaling was particularly evident in cPTC samples harboring the BRAF(V600E) mutation. Transfection assays with BRAF expression vectors as well as BRAF knock down by small interfering RNA revealed a positive association between BRAF expression and mTOR pathway activation, which appears to be mediated by pLKB1 Ser428, and emerged as a possible mechanism contributing to the association between BRAF mutation and mTOR pathway up-regulation. When we evaluated the rapamycin in the growth of thyroid cancer cell lines, we detected that cell lines with activating mutations in the MAPK pathway show a higher sensitivity to this drug.Conclusions: We determined that the AKT/mTOR pathway is particularly overactivated in human cPTC harboring the BRAF(V600E) mutation. Moreover, our results suggest that the mTOR pathway could be a good target to enhance therapy effects in certain types of thyroid carcinoma, namely in those harboring the BRAF(V600E) mutation. (J Clin Endocrinol Metab 97: E1139-E1149, 2012)