Sung J Y, Park S-Y, Kim J H, Kang H G, Yoon J H, Na Y S, Kim Y-N, Park B-K
Center for Pediatric Oncology, National Cancer Center, Goyang-si, Gyeonggi-do, Korea.
Department of Pathology, National Cancer Center, Goyang-si, Gyeonggi-do, Korea.
Cell Death Dis. 2014 May 15;5(5):e1224. doi: 10.1038/cddis.2014.189.
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.
干扰素共有序列结合蛋白（ICSBP）是一种由γ干扰素（IFN-γ）诱导产生的转录因子，属于干扰素调节因子（IRF）家族成员。ICSBP主要在造血细胞中表达，调节免疫反应以及细胞生长和分化。然而，其在非造血细胞中的功能却鲜为人知。在此，我们展示了ICSBP在人骨肉瘤细胞系（包括U2OS细胞）的上皮-间质转化（EMT）样现象（ELP）、细胞运动和侵袭方面的新功能。IFN-γ处理诱导U2OS细胞中ICSBP表达及EMT样形态变化，而ICSBP敲低可抑制这些变化。为进一步研究ICSBP在ELP中的作用，我们建立了过表达ICSBP的稳定U2OS细胞系。ICSBP表达使U2OS细胞形状更细长，波形蛋白和纤连蛋白表达增加。ICSBP表达还促进了U2OS细胞的黏附性、运动性和侵袭性。ICSBP上调转化生长因子（TGF）-β受体并激活TGF-β信号级联反应，这与ELP以及细胞运动性和侵袭性增加有关。此外，ICSBP诱导的TGF-β受体激活导致Snail上调。敲低Snail可减弱ICSBP诱导的细胞运动性和侵袭增强。在其他骨肉瘤细胞系（如Saos-2和143B）中也观察到ICSBP表达导致Snail上调、ELP及侵袭增加。此外，ICSBP和TGF-β受体I分别在45/54（84%）和47/54（87%）的人骨肉瘤组织中表达，且它们的表达水平显示出显著相关性（r = 0.47，P = 0.0007）。综上所述，这些数据证明了ICSBP在ELP、细胞运动和侵袭方面通过TGF-β和Snail信号通路发挥的新功能。
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