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, 1866 (5), 761-772

Upregulation of Transforming Growth Factor-Beta Type I Receptor by Interferon Consensus Sequence-Binding Protein in Osteosarcoma Cells

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Upregulation of Transforming Growth Factor-Beta Type I Receptor by Interferon Consensus Sequence-Binding Protein in Osteosarcoma Cells

Jee Young Sung et al. Biochim Biophys Acta Mol Cell Res.

Abstract

Transforming growth factor-beta (TGF-β) is a known tumor suppressor, which also exerts a tumor promoting activity at an advanced stage of cancer. Previously, we reported that expression of interferon consensus sequence-binding protein (ICSBP), also known as interferon regulatory factor-8, is positively correlated with TGF-β type I receptor (TGF-β RI) expression in osteosarcoma patient tissues. In this study, we demonstrated that ICSBP upregulated TGF-β RI and induced epithelial-to-mesenchymal transition-like phenomena in human osteosarcoma cell lines. As determined by soft agar growth of osteosarcoma cells and xenografted mouse models, ICSBP increased tumorigenicity, which was reversed by ICSBP knock-down or a TGF-β RI inhibitor. To test whether ICSBP directly regulates the promoter activity of TGF-β RI, we performed a TGF-β RI promoter assay, an electro mobility shift assay, and a chromatin immunoprecipitation assay. We observed that TGF-β RI promoter was activated in ICSBP-overexpressing osteosarcoma cells. Exploiting serial deletions and mutations of the TGF-β RI promoter, we found a putative ICSBP-binding site at nucleotides -216/-211 (GGXXTC) in the TGF-β RI promoter. Our data suggest that ICSBP upregulates TGF-β RI expression by binding to this site, causing ICSBP-mediated tumor progression in osteosarcoma cells. In addition, we found a positive correlation between ICSBP and TGF-β RI expression in several types of tumors using the cBioportal database. SUMMARY: We demonstrated that interferon consensus sequence-binding protein upregulates transforming growth factor-beta type I receptor (TGF-β RI) expression by binding to nucleotides -216/-211 (GGXXTC) in the TGF-β RI promoter, which resulted in increased tumorigenicity and tumor progression in human osteosarcoma cells.

Keywords: Interferon consensus sequence-binding protein; Osteosarcoma progression; Promoter activation; Transforming growth factor-beta type I receptor.

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