Cisplatin-selected resistance is associated with increased motility and stem-like properties via activation of STAT3/Snail axis in atypical teratoid/rhabdoid tumor cells

Abstract

// Wei-Hsiu Liu 1, 2 , Ming-Teh Chen 3, 4, * , Mong-Lien Wang 3, 5 , Yi-Yen Lee 5, 7, * , Guang-Yuh Chiou 6 , Chian-Shiu Chien 3, 9 , Pin-I Huang 5, 8 , Yi-Wei Chen 5, 8 , Ming-Chao Huang 3, 7 , Shih-Hwa Chiou 3, 5, 9 , Yang-Hsin Shih 3, 4 , Hsin-I Ma 1, 2 1 Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan 2 Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan 3 School of Medicine, National Yang-Ming University, Taipei, Taiwan 4 Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital & National Yang-Ming University, Taipei, Taiwan 5 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan 6 College of Biological Science and Technology, National Chiao Tung Univeristy, Taiwan 7 Division of Pediatric Neurosurgery, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan 8 Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan 9 Department of Medical Research and Education, Taipei Veterans General Hospital, Taiwan * These authors have contributed equally to this work Correspondence to: Hsin-I Ma, e-mail: uf004693@mail2000.com.tw Keywords: Atypical teratoid/rhabdoid tumor (ATRT), STAT3, Snail, oncogenic resistance and cisplatin Received: August 24, 2014      Accepted: November 11, 2014      Published: January 31, 2015 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.