Journal
CANCER LETTERS
Volume 336, Issue 1, Pages 167-173Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2013.04.024
Keywords
TGF-beta 1; TWIST1; STAT3; HIF-1 alpha; Prostate cancer cell invasion
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Funding
- National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea [121182]
- Basic Science Research Program through the National Research Foundation of Korea (NRF)
- Ministry of Education, Science and Technology [2011-0015761]
- National Research Foundation of Korea [2011-0015761] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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TGF-beta 1 induces epithelial-mesenchymal transition (EMT) to stimulate cancer cell progression, and TWIST1 is a critical regulator of EMT. In the present study, we determined the underlying mechanisms of TGF-beta 1 -induced TWIST1 expression and its effect on prostate cancer cell invasion. TGF-beta 1 stimulated STAT3 phosphorylation and HIF-1a expression. Silencing either STAT3 or HIF-1 alpha efficiently attenuated TGF-beta 1-induced TVVIST1 expression. Further ectopic expression of a dominant negative mutant of STAT3 reduced TGF-01-induced TWIST1 expression. In addition, STAT3 and HIF-1 alpha up-regulated TWIST1 expression by direct binding to a TWIST1 promoter. Strikingly, STAT3 also enhanced TGF-beta 1 -induced TWIST1 expression through HIF-1 alpha stabilization. Collectively, we demonstrate a mechanistic cascade of TGF-beta 1 up-regulating STAT3 activation and HIF-1 alpha stabilization and subsequent TWIST1 expression, leading to prostate cancer invasion. (C) 2013 Elsevier Ireland Ltd. All rights reserved.
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