Upregulation of transforming growth factor-beta type I receptor by interferon consensus sequence-binding protein in osteosarcoma cells

Biochim Biophys Acta Mol Cell Res. 2019 May;1866(5):761-772. doi: 10.1016/j.bbamcr.2019.01.015. Epub 2019 Jan 31.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Neoplasms / genetics
  • Bone Neoplasms / metabolism*
  • Bone Neoplasms / pathology
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / metabolism*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Osteosarcoma / genetics
  • Osteosarcoma / metabolism*
  • Osteosarcoma / pathology
  • Receptor, Transforming Growth Factor-beta Type I / biosynthesis*
  • Receptor, Transforming Growth Factor-beta Type I / genetics
  • Response Elements*
  • Up-Regulation*


  • Interferon Regulatory Factors
  • Neoplasm Proteins
  • interferon regulatory factor-8
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human