A dual mechanism of activation of the Sonic Hedgehog pathway in anaplastic thyroid cancer: crosstalk with RAS-BRAF-MEK pathway and ligand secretion by tumor stroma.
A dual mechanism of activation of the Sonic Hedgehog pathway in anaplastic thyroid cancer: crosstalk with RAS-BRAF-MEK pathway and ligand secretion by tumor stroma.
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DOI：
10.18632/oncotarget.23388
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发表时间：
2018-01-12
期刊：
影响因子：
--
通讯作者：
Castellone MD
中科院分区：
文献类型：
--
作者：
Parascandolo A;Laukkanen MO;De Rosa N;Ugolini C;Cantisani MC;Cirafici AM;Basolo F;Santoro M;Castellone MD
Sonic Hedgehog(Shh)途径调节包括甲状腺在内的不同器官的胚胎发育。Shh信号的异常激活在几种类型的癌症中被发现，根据最近的证据，它是肿瘤-间质相互作用的重要调节因子。在这项研究中，我们分析了Shh通路在间变性甲状腺癌(ATC)细胞中的表达、激活和调控的分子机制及其参与肿瘤间质相互作用的调控。我们的结果表明，Shh信号在ATC细胞中经历了双重的诱导机制：1)Gly转录因子的基础的非规范的Smo依赖的激活，部分是由Ras/BRAF/MEK致癌途径的相互作用引起的，其特征是甲状腺癌细胞中没有Shh配体的表达；2)癌细胞对肿瘤基质(成纤维细胞和间充质基质细胞，MSCs)分泌的Shh配体的旁分泌反应，诱导癌细胞迁移和体外肿瘤的形成。因此，我们的数据表明Shh是治疗侵袭性甲状腺癌的潜在新靶点。
Sonic Hedgehog (Shh) pathway regulates embryonic development of different organs including the thyroid gland. The aberrant activation of Shh signaling has been found in several types of cancer and according to recent evidences it represents an important regulator of tumor-stroma interaction. In this study, we have analyzed expression, activation and molecular mechanisms regulating the Shh pathway and its involvement in the modulation of tumor stroma interaction in anaplastic thyroid cancer (ATC) cells. Our results suggest that Shh signaling undergoes a dual mechanism of induction in ATC cells: 1) a basal non-canonical Smo-dependent activation of Gli transcription factor that is partly caused by interaction with the RAS/BRAF/MEK oncogenic pathway and is characterized by the absence of Shh ligand expression in thyroid cancer cells and 2) a paracrine response of cancer cells to Shh ligand secreted by tumor stroma (fibroblasts and mesenchymal stromal cells, MSCs) inducing cancer cell migration and in vitro tumorigenesis. Our data therefore suggest Shh as a potential novel therapeutic target in aggressive thyroid cancers.
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