title: Tissue transglutaminase links TGF-β, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer.
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.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: L
authors.initials: L
authors.lastname: Cao
authors.forename: M
authors.initials: M
authors.lastname: Shao
authors.forename: J
authors.initials: J
authors.lastname: Schilder
authors.forename: T
authors.initials: T
authors.lastname: Guise
authors.forename: K S
authors.initials: KS
authors.lastname: Mohammad
authors.forename: D
authors.initials: D
authors.lastname: Matei
mesh_terms: D045744:Cell Line, Tumor; D004789:Enzyme Activation; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D019204:GTP-Binding Proteins; D006801:Humans; D018960:Hyaluronan Receptors; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000473:pathology*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D019009:Proto-Oncogene Proteins c-kit; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018960:Hyaluronan Receptors; D016212:Transforming Growth Factor beta; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019009:Proto-Oncogene Proteins c-kit; D019204:GTP-Binding Proteins