Downregulation of ERG and FLI1 expression in endothelial cells triggers endothelial-to-mesenchymal transition.
Downregulation of ERG and FLI1 expression in endothelial cells triggers endothelial-to-mesenchymal transition.
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DOI：
10.1371/journal.pgen.1007826
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发表时间：
2018-11
期刊：
影响因子：
4.5
通讯作者：
Minami T
中科院分区：
文献类型：
--
作者：
Nagai N;Ohguchi H;Nakaki R;Matsumura Y;Kanki Y;Sakai J;Aburatani H;Minami T
内皮细胞(EC)在病理环境中的可塑性最近被认为是疾病进展的驱动因素。内皮-间充质转化(EndMT)是一种内皮细胞获得间质属性的过程，已被广泛描述为包括癌症在内的一系列病理过程。然而，在肿瘤微环境中调节EndMT的机制以及EndMT在肿瘤进展中的作用尚不完全清楚。在这里，我们发现两个ETS家族转录因子ERG和FLI1的联合敲除导致了内皮细胞的EndMT和动态表观遗传变化。全基因组分析表明，ERG和FLI1是EC特异性基因的关键转录激活因子，其中microRNA-126部分阻断了EndMT的诱导。此外，我们还证明，在肿瘤微环境中，丰富的可溶性因子下调了肿瘤内皮细胞中ERG和FLI1的表达。这些数据为了解EndMT的机制、ERG和FLI1在ECs中的作用以及EC在病理条件下的行为提供了新的见解。分化的细胞具有维持生命活动的独特特性。然而，由于基因表达失调，细胞在病理环境中偶尔会表现出异常行为。内皮细胞向间充质细胞转变(EndMT)是一种内皮细胞失去特性而获得间充质样属性的现象。虽然EndMT在包括癌症在内的各种疾病中都有观察到，并增加了纤维化和血管缺陷，但EndMT的诱导机制尚不完全清楚。在这里，我们发现EndMT是通过减少ERG和FLI1的表达来触发的，这两个基因最近被认为是内皮细胞(ECs)中的关键转录因子。机制上，ERG和FLI1通过表观遗传调控激活EC特异性基因和抑制间充质样基因，以防止EndMT。此外，我们还证明了在内皮细胞中特异表达的microRNA-126是ERG/FLI1调控EndMT的关键下游靶点。最后，我们发现ERG和FLI1在肿瘤内皮细胞中的表达减少，这表明EndMT是在肿瘤微环境中诱导的。综上所述，这些发现表明ERG和FLI1的缺失导致了内皮细胞在病理条件下的异常行为。
Endothelial cell (EC) plasticity in pathological settings has recently been recognized as a driver of disease progression. Endothelial-to-mesenchymal transition (EndMT), in which ECs acquire mesenchymal properties, has been described for a wide range of pathologies, including cancer. However, the mechanism regulating EndMT in the tumor microenvironment and the contribution of EndMT in tumor progression are not fully understood. Here, we found that combined knockdown of two ETS family transcription factors, ERG and FLI1, induces EndMT coupled with dynamic epigenetic changes in ECs. Genome-wide analyses revealed that ERG and FLI1 are critical transcriptional activators for EC-specific genes, among which microRNA-126 partially contributes to blocking the induction of EndMT. Moreover, we demonstrated that ERG and FLI1 expression is downregulated in ECs within tumors by soluble factors enriched in the tumor microenvironment. These data provide new insight into the mechanism of EndMT, functions of ERG and FLI1 in ECs, and EC behavior in pathological conditions. Differentiated cells possess unique characteristics to maintain vital activities. However, cells occasionally show abnormal behavior in pathological settings due to dysregulated gene expression. Endothelial-to-mesenchymal transition (EndMT) is a phenomenon in which endothelial cells lose their characteristics and acquire mesenchymal-like properties. Although EndMT is observed in various diseases including cancer, and augments fibrosis and vascular defects, the mechanism of EndMT induction is not fully understood. Here, we show that EndMT is triggered via reduced expression of ERG and FLI1, which have recently been recognized as pivotal transcription factors in endothelial cells (ECs). Mechanistically, ERG and FLI1 activate EC-specific genes and repress mesenchymal-like genes via epigenetic regulation to prevent EndMT. Furthermore, we demonstrate that microRNA-126, which is specifically expressed in ECs, is the key downstream target of ERG/FLI1 for regulating EndMT. Finally, we show that ERG and FLI1 expression is decreased in ECs within tumors, suggesting that EndMT is induced in the tumor microenvironment. Collectively, these findings indicate that loss of ERG and FLI1 leads to the aberrant behavior of ECs in pathological conditions.
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影响因子：
64.5
作者：
Ginsberg M;James D;Ding BS;Nolan D;Geng F;Butler JM;Schachterle W;Pulijaal VR;Mathew S;Chasen ST;Xiang J;Rosenwaks Z;Shido K;Elemento O;Rabbany SY;Rafii S
通讯作者：
Rafii S
影响因子：
14.9
作者：
Kanki Y;Nakaki R;Shimamura T;Matsunaga T;Yamamizu K;Katayama S;Suehiro JI;Osawa T;Aburatani H;Kodama T;Wada Y;Yamashita JK;Minami T
通讯作者：
Minami T
影响因子：
11.8
作者：
Birdsey, Graeme M.;Shah, Aarti V.;Dufton, Neil;Reynolds, Louise E.;Almagro, Lourdes Osuna;Yang, Youwen;Aspalter, Irene M.;Khan, Samia T.;Mason, Justin C.;Dejana, Elisabetta;Goettgens, Berthold;Hodivala-Dilke, Kairbaan;Gerhardt, Holger;Adams, Ralf H.;Randi, Anna M.
通讯作者：
Randi, Anna M.
影响因子：
4.6
作者：
Fish, Jason E.;Gutierrez, Manuel Cantu;Wythe, Joshua D.
通讯作者：
Wythe, Joshua D.
影响因子：
5.6
作者：
Chrobak, Izabela;Lenna, Stefania;Stawski, Lukasz;Trojanowska, Maria
通讯作者：
Trojanowska, Maria