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-B 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.
Original language | English (US) |
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Pages (from-to) | 2521-2534 |
Number of pages | 14 |
Journal | Oncogene |
Volume | 31 |
Issue number | 20 |
DOIs | |
State | Published - May 17 2012 |
Keywords
- TG2
- TGF-β
- cancer stem cells
- epithelial to mesenchymal transition
- metastasis
- ovarian cancer
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research