转录因子MEF2A介导BRAF突变型甲状腺乳头状癌发生发展的新机制

Transcription factor MEF2A regulates the expression of key factors involved in the survival and differentiation of multiple cell types. In our previous study, we have clarified the detailed protein degradation mechanism of MEF2A. Recently, we further found that MEF2A was overexpressed in papillary thyroid cancer, which was closely related to BRAF V600E mutation. The oncogene BRAF V600E is the most frequent genetic event in papillary thyroid cancer and is associated with poorer prognosis. However, the detailed mechanism underlying papillary thyroid cancer tumorigenesis driven by the BRAF mutation is still unknown. It has been reported that BRAF mutation could induce the expression of Twist. Twist is a kind of E box-binding transcription factor. By gene promoter analysis, several potential E box binding sequences were identified within the promoter regions of MEF2A. To date, MMP-10 is the only known tumor-associated target gene located downstream of MEF2A. In the present study, we propose a “BRAF-Twist-MEF2A-MMP10 signaling transduction” hypothesis. The expression of MEF2A was further compared in normal thyroid tissues and tumor tissues from PTC patients. The statuses of the BRAF gene in PTC patient samples were also analysed to confirm the correlation between MEF2A overexpression and BRAF mutation. The stable cells with MEF2A gene overexpressed or knockdown as well as the mouse xenograft tumor models were established. The effects of MEF2A regulation in the steps of tumor cell proliferation, migration, adhesion were examined. By advanced molecular biological methods, such as luciferase reporter gene assay, EMSA, CHIP, RNAi, the role of MEF2A underlying papillary thyroid cancer tumorigenesis driven by the BRAF mutation was investigated. This study provides a potential molecular target for targeted therapy of PTC.

转录因子MEF2A调节多种细胞的存活与分化，我们已阐明其蛋白降解机制，并进一步发现MEF2A在甲状腺乳头状癌（PTC）中过表达，且与影响PTC发生发展及预后的重要遗传学事件 BRAF V600E突变密切相关，但其间的详细分子机理有待研究。BRAF突变可诱导Twist表达，MEF2A启动子具Twist潜在结合序列，MMP-10是MEF2A下游唯一已知肿瘤相关靶基因，我们提出“BRAF-Twist-MEF2A-MMP10分子信号传导”假说。本项目拟比较甲状腺正常及癌组织中MEF2A表达差异并结合BRAF分型，确认MEF2A过表达与BRAF突变的相关性；建立MEF2A过表达与敲低细胞及动物肿瘤模型，考察MEF2A对肿瘤细胞增殖、迁移、粘附等环节的影响；采用报告基因、EMSA、CHIP、RNAi等手段，探索MEF2A介导BRAF突变型PTC发生发展的分子机制，为PTC的干预提供新的可能的分子靶点。

转录因子MEF2A调节多种细胞的存活与分化，我们已阐明其蛋白降解机制，并进一步发现MEF2A在甲状腺乳头状癌（PTC）中过表达，且与影响PTC发生发展及预后的重要遗传学事件 BRAF V600E突变密切相关，但其间的详细分子机理有待研究。本项目比较甲状腺正常及癌组织中MEF2A表达差异并结合BRAF分型，确认MEF2A过表达与BRAF突变的相关性,为PTC的干预提供新的可能的分子靶点。我们结合临床甲状腺疾病患者样本发现了甲状腺癌炎性微环境可介导碘-131抵抗的现象。我们从甲状腺不同程度病变患者IL-6和IL-8炎症因子的血清学检测出发，找寻诱导肿瘤炎性微环境形成的关键因素。研究发现甲状腺癌组织中炎症因子表达升高并且甲状腺肿瘤组织中内质网应激处于活化状态。接下来，我们考察了炎症因子IL-6和IL-8对甲状腺肿瘤细胞的生物学效应，发现IL-6和IL-8均可诱导甲状腺癌细胞去分化，降低肿瘤细胞对碘-131的摄取。我们的研究从“内质网应激-肿瘤炎性微环境”角度进一步完善了诱导甲状腺癌细胞产生放射性碘抵抗的调控机制。

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