Abstract |
Atypical teratoid/rhabdoid tumor (ATRT) is a malignant pediatric brain tumor with great recurrence after complete surgery and chemotherapy. Here, we demonstrate that cisplatin treatment selects not only for resistance but also for a more oncogenic phenotype characterized by high self-renewal and invasive capabilities. These phenomena are likely due to STAT3 upregulatoin which occurred simultaneously with higher expression of Snail, an activator of epithelial-mesenchymal transition (EMT), in ATRT-CisR cells. STAT3 knockdown effectively suppressed Snail expression and blocked motility and invasion in ATRT-CisR cells, while overexpressing Snail reversed these effects. Chromatin immunoprecipitation assay indicated that STAT3 directly bound to Snail promoter. Moreover, STAT3 knockdown effectively suppressed cancer stem-like properties, synergistically enhanced the chemotherapeutic effect, and significantly improved survival rate in ATRT-CisR-transplanted immunocompromised mice. Finally, immunohistochemistrical analysis showed that STAT3 and Snail were coexpressed at high levels in recurrent ATRT tissues. Thus, the STAT3/Snail pathway plays an important role in oncogenic resistance, rendering cells not only drug-resistant but also increasingly oncogenic (invasion, EMT and recurrence). Therefore, the STAT3/Snail could be a target for ATRT treatment.
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Authors | Wei-Hsiu Liu, Ming-Teh Chen, Mong-Lien Wang, Yi-Yen Lee, Guang-Yuh Chiou, Chian-Shiu Chien, Pin-I Huang, Yi-Wei Chen, Ming-Chao Huang, Shih-Hwa Chiou, Yang-Hsin Shih, Hsin-I Ma |
Journal | Oncotarget
(Oncotarget)
Vol. 6
Issue 3
Pg. 1750-68
(Jan 30 2015)
ISSN: 1949-2553 [Electronic] United States |
PMID | 25638155
(Publication Type: Journal Article)
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Chemical References |
- Antineoplastic Agents
- STAT3 Transcription Factor
- STAT3 protein, human
- Snail Family Transcription Factors
- Transcription Factors
- Cisplatin
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Topics |
- Animals
- Antineoplastic Agents
(pharmacology)
- Brain Neoplasms
(drug therapy, metabolism, pathology)
- Cell Line, Tumor
- Cell Movement
(physiology)
- Cisplatin
(pharmacology)
- Drug Resistance, Neoplasm
- Female
- Heterografts
- Humans
- Male
- Mice
- Mice, SCID
- Rhabdoid Tumor
(drug therapy, metabolism, pathology)
- STAT3 Transcription Factor
(metabolism)
- Signal Transduction
- Snail Family Transcription Factors
- Transcription Factors
(metabolism)
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