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Abstract：
Interferon consensus sequence-binding protein (ICSBP) is a transcription factor induced by interferon gamma (IFN-γ) and a member of the interferon regulatory factor (IRF) family. ICSBP is predominantly expressed in hematopoietic cells and regulates the immune response and cell growth and differentiation. However, little is known about its function in non-hematopoietic cells. Here we show a novel function for ICSBP in epithelial-to-mesenchymal transition (EMT)-like phenomena (ELP), cell motility, and invasion in human osteosarcoma cell lines, including U2OS cells. IFN-γ treatment induced ICSBP expression and EMT-like morphological change in U2OS cells, which were suppressed by ICSBP knockdown. To further investigate the role of ICSBP in ELP, we established a stable U2OS cell line that overexpresses ICSBP. ICSBP expression caused U2OS cells to have a more elongated shape and an increased vimentin and fibronectin expression. ICSBP expression also promoted adhesiveness, motility, and invasiveness of U2OS cells. ICSBP upregulated transforming growth factor (TGF)-β receptors and activated TGF-β signaling cascades, which were responsible for ELP as well as increased cell motility and invasion. In addition, ICSBP-induced TGF-β receptor activation resulted in the upregulation of Snail. Knockdown of Snail attenuated the ICSBP-induced augmentation of cell motility and invasion. Upregulation of Snail, ELP, and increased invasion by ICSBP expression were also observed in other osteosarcoma cell lines, such as Saos-2 and 143B. Furthermore, ICSBP and TGF-β receptor I were expressed in 45/54 (84%) and 47/54 (87%) of human osteosarcoma tissues, respectively, and showed significant correlation (r=0.47, P=0.0007) with respect to their expression levels. Taken altogether, these data demonstrate a novel function for ICSBP in ELP, cell motility, and invasion through the TGF-β and Snail signaling pathways.
摘要：
干扰素共有序列结合蛋白（ICSBP）是干扰素γ（IFN-γ）诱导的转录因子，是干扰素调节因子（IRF）家族的成员。ICSBP主要在造血细胞中表达并调节免疫应答和细胞生长和分化。然而,对其在非造血细胞中的功能知之甚少。在这里，我们展示了ICSBP在上皮-间质转化（EMT）样现象（ELP）中的新功能，细胞运动性,以及在人类骨肉瘤细胞系中的侵袭，包括U2OS细胞。IFN-γ处理诱导U2OS细胞ICSBP表达和EMT样形态改变,被ICSBP敲除抑制。为了进一步研究ICSBP在ELP中的作用，我们建立了过表达ICSBP的稳定U2OS细胞系。ICSBP表达导致U2OS细胞具有更细长的形状和增加的波形蛋白和纤连蛋白表达。ICSBP表达也促进粘附性，运动性,和U2OS细胞的侵袭性。ICSBP上调转化生长因子（TGF）-β受体和激活的TGF-β信号级联，它们负责ELP以及增加细胞运动和侵袭。此外,ICSBP诱导的TGF-β受体激活导致Snail的上调。Snail的敲除减弱了ICSBP诱导的细胞运动和侵袭的增强。蜗牛的上调，ELP,在其他骨肉瘤细胞系中也观察到ICSBP表达增加的侵袭，例如Saos-2和143B。此外，ICSBP和TGF-β受体I在45/54（84％）和47/54（87％）的人骨肉瘤组织中表达，分别,并显示其表达水平的显着相关性（r=0.47，P=0.0007）。总之，这些数据证明了ICSBP在ELP中的新功能，细胞运动性,并通过TGF-β和Snail信号通路进行侵袭。
