Interaction of BRAF-induced ETS factors with mutant TERT promoter in papillary thyroid cancer
Interaction of BRAF-induced ETS factors with mutant TERT promoter in papillary thyroid cancer
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DOI：
10.1530/erc-17-0562
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发表时间：
2019-06-01
影响因子：
3.9
通讯作者：
Park, Young Joo
中科院分区：
文献类型：
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作者：
Song, Young Shin;Yoo, Seong-Keun;Park, Young Joo
BRAF（V600E）和TERT启动子突变对乳头状甲状腺癌（PTC）不良临床预后的协同作用已得到证实。这一现象的潜在机制已被提出：BRAF（V600E）突变激活MAPK通路可能上调e - 26 （ETS）转录因子，通过结合TERT启动子突变产生的ETS结合位点增加TERT的表达；然而，这还没有得到充分的证实。本文提供了在PTC中由ETS因子介导的BRAF（V600E）和TERT启动子突变之间相互作用的转录组学见解。对来自The Cancer Genome Atlas的266个ptc和本研究所的65个ptc的RNA测序数据进行基因表达变化和相关分子通路的分析，并通过体外实验验证转录组学分析结果。BRAF（V600E）和TERT启动子突变共存导致TERT mRNA表达增加（fold change, 16.17； q值= 7.35 × 10(-12) vs无突变）。在ETS家族转录因子中，ETV1、ETV4和ETV5通过BRAF(V600E)/MAPK通路激活而上调。这些BRAF（V600E）诱导的ETS因子选择性地结合突变体TERT启动子。BRAF（V600E）激活的分子通路通过加入TERT启动子突变进一步增强，与免疫应答或粘附分子相关的通路因TERT表达而上调。BRAF（V600E）和TERT启动子突变对PTC肿瘤侵袭和进展的协同作用机制可能与TERT表达增加有关，这可能是由BRAF诱导的几种ETS转录因子上调引起的。
Synergistic effects of BRAF(V600E) and TERT promoter mutations on the poor clinical outcomes in papillary thyroid cancer (PTC) have been demonstrated. The potential mechanism of this phenomenon has been proposed: MAPK pathway activation by the BRAF(V600E) mutation may upregulate E-twenty six (ETS) transcription factors, increasing TERT expression by binding to the ETS-binding site generated by the TERT promoter mutation; however, it has not yet been fully proven. This article provides transcriptomic insights into the interaction between BRAF(V600E) and TERT promoter mutations mediated by ETS factors in PTC. RNA sequencing data on 266 PTCs from The Cancer Genome Atlas and 65 PTCs from our institute were analyzed for gene expression changes and related molecular pathways, and the results of transcriptomic analyses were validated by in vitro experiments. TERT mRNA expression was increased by the coexistence of BRAF(V600E) and TERT promoter mutations (fold change, 16.17; q-value = 7.35 x 10(-12) vs no mutation). In the ETS family of transcription factors, ETV1, ETV4 and ETV5 were upregulated by the BRAF(V600E)/MAPK pathway activation. These BRAF(V600E)-induced ETS factors selectively bound to the mutant TERT promoter. The molecular pathways activated by BRAF(V600E) were further augmented by adding the TERT promoter mutation, and the pathways related to immune responses or adhesion molecules were upregulated by TERT expression. The mechanism of the synergistic effect between BRAF(V600E) and TERT promoter mutations on cancer invasiveness and progression in PTC may be explained by increased TERT expression, which may result from the BRAF-induced upregulation of several ETS transcription factors.