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

Oncogene. 2012 May 17;31(20):2521-34. doi: 10.1038/onc.2011.429. Epub 2011 Oct 3.

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Line, Tumor
  • Enzyme Activation
  • Epithelial-Mesenchymal Transition* / genetics
  • Female
  • GTP-Binding Proteins
  • Humans
  • Hyaluronan Receptors
  • Neoplasm Metastasis
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Ovarian Neoplasms / enzymology
  • Ovarian Neoplasms / pathology*
  • Proto-Oncogene Proteins c-kit
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Transglutaminases / genetics
  • Transglutaminases / metabolism*

Substances

  • Hyaluronan Receptors
  • Transforming Growth Factor beta
  • transglutaminase 2
  • Transglutaminases
  • Proto-Oncogene Proteins c-kit
  • GTP-Binding Proteins