Thyroid Transcription Factor 1 Reprograms Angiogenic Activities of Secretome.
Thyroid Transcription Factor 1 Reprograms Angiogenic Activities of Secretome.
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DOI：
10.1038/srep19857
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发表时间：
2016-02-25
影响因子：
4.6
通讯作者：
Mu D
中科院分区：
文献类型：
--
作者：
Wood LW;Cox NI;Phelps CA;Lai SC;Poddar A;Talbot C Jr;Mu D
通过甲状腺转录因子1（TTF - 1）表达增加和缺失两种策略，我们表明TTF - 1对血管内皮生长因子（VEGF）具有正向调节作用，并且VEGF启动子元件包含多个TTF - 1反应序列。VEGF的主要信号受体，即血管内皮生长因子受体2（VEGFR2），似乎也受到TTF - 1的直接正向调节。TTF - 1依赖的VEGF上调对雷帕霉素中度敏感，这意味着哺乳动物雷帕霉素靶蛋白（mTOR）部分参与其中。然而，缺氧并没有进一步提高TTF - 1阳性肺癌细胞分泌的VEGF水平。TTF - 1诱导的VEGF上调发生在条件培养基的两个部分（外泌体和去除外泌体的培养基（EDM））。令人惊讶的是，TTF - 1阳性肺癌细胞的EDM（称为EDM - TTF - 1+）在内皮细胞管形成实验中显示出抗血管生成活性。机制研究表明，EDM - TTF - 1+中粒细胞 - 巨噬细胞集落刺激因子（GM - CSF）水平的升高赋予了抗血管生成活性。在人类肺癌中，TTF - 1和GM - CSF的表达呈现出具有统计学意义的正相关。总之，这项研究提供的证据表明，TTF - 1可能将肺癌分泌的蛋白质组重编程为一种抗血管生成状态，为长期以来观察到的TTF - 1阳性肺腺癌预后良好这一现象提供了新的依据。
Through both gain- and loss-of-TTF-1 expression strategies, we show that TTF-1 positively regulates vascular endothelial growth factor (VEGF) and that the VEGF promoter element contains multiple TTF-1-responsive sequences. The major signaling receptor for VEGF, i.e VEGFR2, also appears to be under a direct and positive regulation of TTF-1. The TTF-1-dependent upregulation of VEGF was moderately sensitive to rapamycin, implicating a partial involvement of mammalian target of rapamycin (mTOR). However, hypoxia did not further increase the secreted VEGF level of the TTF-1+ lung cancer cells. The TTF-1-induced VEGF upregulation occurs in both compartments (exosomes and exosome-depleted media (EDM)) of the conditioned media. Surprisingly, the EDM of TTF-1+ lung cancer cells (designated EDM-TTF-1+) displayed an anti-angiogenic activity in the endothelial cell tube formation assay. Mechanistic studies suggest that the increased granulocyte-macrophage colony-stimulating factor (GM-CSF) level in the EDM-TTF-1+ conferred the antiangiogenic activities. In human lung cancer, the expression of TTF-1 and GM-CSF exhibits a statistically significant and positive correlation. In summary, this study provides evidence that TTF-1 may reprogram lung cancer secreted proteome into an antiangiogenic state, offering a novel basis to account for the long-standing observation of favorable prognosis associated with TTF-1+ lung adenocarcinomas.