Tissue transglutaminase links TGF-β, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer.

Academic Article

Abstract

  • Tissue transglutaminase (TG2), an enzyme involved in cell proliferation, differentiation and apoptosis is overexpressed in ovarian carcinomas, where it modulates epithelial-to-mesenchymal transition (EMT) and promotes metastasis. Its regulation in ovarian cancer (OC) remains unexplored. Here, we show that transforming growth factor (TGF)-β, a cytokine involved in tumor dissemination is abundantly secreted in the OC microenvironment and induces TG2 expression and enzymatic activity. This is mediated at transcriptional level by SMADs and by TGF-β-activated kinase 1-mediated activation of the nuclear factor-κB complex. TGF-β-stimulated OC cells aggregate as spheroids, which enable peritoneal dissemination. We show that TGF-β-induced TG2 regulates EMT, formation of spheroids and OC metastasis. TG2 knock-down in OC cells decreases the number of cells harboring a cancer stem cell phenotype (CD44+/CD117+). Furthermore, CD44+/CD117+ cells isolated from human ovarian tumors express high levels of TG2. In summary, TGF-β-induced TG2 enhances ovarian tumor metastasis by inducing EMT and a cancer stem cell phenotype.
  • Authors

    Published In

  • Oncogene  Journal
  • Keywords

  • Cell Line, Tumor, Enzyme Activation, Epithelial-Mesenchymal Transition, Female, GTP-Binding Proteins, Humans, Hyaluronan Receptors, Neoplasm Metastasis, Neoplastic Stem Cells, Ovarian Neoplasms, Proto-Oncogene Proteins c-kit, Transforming Growth Factor beta, Transglutaminases
  • Digital Object Identifier (doi)

    Author List

  • Cao L; Shao M; Schilder J; Guise T; Mohammad KS; Matei D
  • Start Page

  • 2521
  • End Page

  • 2534
  • Volume

  • 31
  • Issue

  • 20