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

Oncogene volume 31, pages 2521–2534 (2012)Cite this 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.

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Acknowledgements

We thank Drs J Tucholski, H Nakshatri, Y Xu, A Belkin and R Bigsby for reagents and Dr A Belkin for useful discussion. This work was supported by the US Department of Veterans Affairs through a VA Merit Award and by the American Cancer Society through a Research Scholar grant to DM.

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Authors and Affiliations

  1. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    L Cao, M Shao, T Guise, K S Mohammad & D Matei

  2. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA

    L Cao & D Matei

  3. Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, USA

    J Schilder & D Matei

  4. Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA

    J Schilder, T Guise, K S Mohammad & D Matei

  5. VA Roudebush Hospital, Indiana University School of Medicine, Indianapolis, IN, USA

    D Matei

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  1. L Cao
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Correspondence to D Matei.

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Cao, L., Shao, M., Schilder, J. et al. Tissue transglutaminase links TGF-β, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer. Oncogene 31, 2521–2534 (2012). https://doi.org/10.1038/onc.2011.429

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  • DOI: https://doi.org/10.1038/onc.2011.429

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