β-arrestin-1 mediates nicotine-induced metastasis through E2F1 target genes that modulate epithelial-mesenchymal transition.
β-arrestin-1 mediates nicotine-induced metastasis through E2F1 target genes that modulate epithelial-mesenchymal transition.
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DOI：
10.1158/0008-5472.can-14-0681
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发表时间：
2015-03-15
期刊：
影响因子：
11.2
通讯作者：
Chellappan S
中科院分区：
文献类型：
--
作者：
Pillai S;Trevino J;Rawal B;Singh S;Kovacs M;Li X;Schell M;Haura E;Bepler G;Chellappan S
吸烟是非小细胞肺癌（NSCLC）发展的一个主要危险因素，非小细胞肺癌占所有肺癌的80%。尼古丁是烟草烟雾中的主要成瘾成分，它能诱导非小细胞肺癌细胞系的增殖、侵袭和上皮 - 间质转化（EMT），并促进小鼠非小细胞肺癌的转移。在此我们证明，支架蛋白β - 抑制蛋白 - 1对于尼古丁介导的间充质基因波形蛋白和纤连蛋白以及EMT调节因子ZEB1和ZEB2的诱导是必需的。尼古丁诱导细胞形态改变并破坏紧密连接，这与EMT一致；这些变化需要β - 抑制蛋白 - 1，而不是β - 抑制蛋白 - 2。β - 抑制蛋白 - 1通过E2F1转录因子的介导促进间充质基因以及ZEB1和ZEB2的表达；这需要Src激酶活性。用尼古丁刺激多种非小细胞肺癌细胞系导致β - 抑制蛋白 - 1和E2F1在波形蛋白、纤连蛋白、ZEB1和ZEB2启动子上的募集增强。此外，在人类非小细胞肺癌肿瘤中，与这些启动子相关的β - 抑制蛋白 - 1和E2F1明显更多，并且在人类非小细胞肺癌样本中β - 抑制蛋白 - 1水平与波形蛋白和纤连蛋白水平相关。缺乏β - 抑制蛋白 - 1的A549 - 荧光素酶细胞在原位植入SCID - beige小鼠肺部时，肿瘤生长和转移能力显著降低。综上所述，这些研究揭示了β - 抑制蛋白 - 1在非小细胞肺癌生长和转移中的新作用。
Cigarette smoking is a major risk factor in the development of non-small cell lung cancer (NSCLC), which accounts for 80% of all lung cancers. Nicotine, the major addictive component of tobacco smoke, can induce proliferation, invasion and epithelial-mesenchymal transition (EMT) in NSCLC cell lines and promote metastasis of NSCLC in mice. Here we demonstrate that the scaffolding protein β-arrestin-1 is necessary for nicotine-mediated induction of mesenchymal genes vimentin and fibronectin as well as EMT regulators ZEB1 and ZEB2. Nicotine induced changes in cell morphology and ablate tight junctions consistent with EMT; β-arrestin-1, but not β-arrestin-2, was required for these changes. β-arrestin-1 promoted the expression of the mesenchymal genes as well as ZEB1 and ZEB2 through the mediation of the E2F1 transcription factor; this required Src kinase activity. Stimulation of multiple NSCLC cell lines with nicotine led to enhanced recruitment of β-arrestin-1 and E2F1 on vimentin, fibronectin, ZEB1 and ZEB2 promoters. Further, there was significantly more β-arrestin-1 and E2F1 associated with these promoters in human NSCLC tumors and β-arrestin-1 levels correlated with vimentin and fibronectin levels in human NSCLC samples. A549-luciferase cells lacking β-arrestin-1 showed a significantly reduced capacity for tumor growth and metastasis when orthotopically implanted into the lungs of SCID-beige mice. Taken together, these studies reveal a novel role for β-arrestin-1 in the growth and metastasis of NSCLC.