Cisplatin-selected resistance is associated with increased motility and stem-like properties via activation of STAT3/Snail axis in atypical teratoid/rhabdoid tumor cells
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Wei-Hsiu Liu1,2, Ming-Teh Chen3,4,*, Mong-Lien Wang3,5, Yi-Yen Lee5,7,*, Guang-Yuh Chiou6, Chian-Shiu Chien3,9, Pin-I Huang5,8, Yi-Wei Chen5,8, Ming-Chao Huang3,7, Shih-Hwa Chiou3,5,9, Yang-Hsin Shih3,4, Hsin-I Ma1,2
1Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
2Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan
3School of Medicine, National Yang-Ming University, Taipei, Taiwan
4Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital & National Yang-Ming University, Taipei, Taiwan
5Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
6College of Biological Science and Technology, National Chiao Tung Univeristy, Taiwan
7Division of Pediatric Neurosurgery, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan
8Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan
9Department of Medical Research and Education, Taipei Veterans General Hospital, Taiwan
*These authors have contributed equally to this work
Hsin-I Ma, e-mail: [email protected]
Keywords: Atypical teratoid/rhabdoid tumor (ATRT), STAT3, Snail, oncogenic resistance and cisplatin
Received: August 24, 2014 Accepted: November 11, 2014 Published: January 31, 2015
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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