Journal
STEM CELLS
Volume 33, Issue 4, Pages 1063-1074Publisher
WILEY
DOI: 10.1002/stem.1955
Keywords
Hedgehog; Tumor-initiating cell-like properties; Acquired chemoresistance; Twist1; Snail
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Funding
- National Natural Science Foundation of China [81173077]
- Interdisciplinary Cooperation Team Program for Science and Technology Innovation of the Chinese Academy of Sciences
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The Hedgehog (Hh) signaling pathway has been implicated in acquired chemoresistance. However, it remains unclear whether and how the Hh pathway may maintain the chemoresistant phenotype by controlling the tumor-initiating cell-like properties of acquired chemoresistant cancer cells. In this study, using well-established acquired chemoresistant cancer cells and chemosensitive KB cancer cells with artificially elevated Hh pathway activity, we found that Hh pathway activity may transcriptionally control the expression of twist1 and snail, thereby maintaining the tumor-initiating cell-like properties and consequently the chemoresistant phenotype. Meanwhile, we obtained direct evidence that twist1, which may amplify Hh signaling activity and plays an essential role in limb development, is a direct transcriptional target of Gli, similar to snail. We further observed that the expression of ATP-binding cassette (ABC) transporters was dispensable for the chemoresistance mediated by twist1 and snail. Collectively, these findings demonstrate that twist1, together with snail, links the Hh pathway to the tumor-initiating cell-like properties of chemoresistant cells. This consequently promotes chemoresistance independently of ABC transporters, thereby contributing to future development of strategies for combating chemoresistance through Hh pathway interference. Furthermore, our finding that twist1 is a direct target of the transcription factor Gli improves the interpretation of the association between twist1 and the Hh pathway and the nature of the signaling transduction of the Hh pathway. Stem Cells2015;33:1063-1074
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