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発表内容

Title:
Roles of TGF-β signaling in cancer stem cells and tumor microenvironment

Kohei Miyazono, M.D.
Department of Molecular Pathology, University of Tokyo

Abstract:
TGF-β plays multiple roles in growth and differentiation of normal and cancer cells. We have found that autocrine TGF-β signaling plays a critical role in retention of stemness of glioma-initiating cells (GICs). TGF-β induced expression of a transcription factor, Sox2, which is known as an important regulator of maintenance of stemness. Induction of Sox2 by TGF-β was mediated by another transcription factor, Sox4, and Smads activated by TGF-β signaling directly bound to the promoter of Sox4. Inhibitors of TGF-β signaling deprived tumorigenicity of GICs by inducing their differentiation, and these effects were repressed in GICs overexpressing Sox2 or Sox4. These results suggest that the TGF-β-Sox4-Sox2 pathway is an essential pathway for GICs, and that disruption of this pathway may be a novel therapeutic strategy against malignant gliomas.
TGF-β induces epithelial-mesenchymal transition (EMT) through activation of Smad and non-Smad signaling pathways. Multiple transcription factors, including δEF1/ZEB1, SIP1/ZEB2, and Snail/SNAI1, play critical roles in TGF-β-induced EMT. In addition, cross-talk with other signaling pathways plays important roles in induction of EMT. We have found that cells treated by FGF-2 and TGF-β promoted invasion of cancer cells in vitro. Mechanisms of action of FGF signaling in TGF-β-induced EMT will be discussed.

References:
1. Ikushima H, Miyazono K. (2010) TGF-β signalling: a complex web in cancer progression. Nat Rev Cancer. 10: 415-24.

2. Ikushima H, Todo T, Ino Y, Takahashi M, Miyazawa K, Miyazono K. (2009) Autocrine TGF-β signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors. Cell Stem Cell. 5: 504-14.

3. Saito RA, Watabe T, Horiguchi K, Kohyama T, Saitoh M, Nagase T, Miyazono K. (2009) Thyroid transcription factor-1 inhibits transforming growth factor-β-mediated epithelial-to-mesenchymal transition in lung adenocarcinoma cells. Cancer Res. 69: 2783-91.

4. Horiguchi K, Shirakihara T, Nakano A, Imamura T, Miyazono K, Saitoh M. (2009) Role of Ras signaling in the induction of snail by transforming growth factor-β. J Biol Chem. 284: 245-53.