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The STAT3/Slug Axis Enhances Radiation-Induced Tumor Invasion and Cancer Stem-like Properties in Radioresistant Glioblastoma

by Jang-Chun Lin 1,2,3, Jo-Ting Tsai 2,3, Tsu-Yi Chao 1,4, Hsin-I Ma 5,6 and Wei-Hsiu Liu 5,6,*
1
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11042, Taiwan
2
Department of Radiation Oncology, Shuang Ho Hospital, Taipei Medical University, Taipei 23561, Taiwan
3
Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11042, Taiwan
4
Division of Hematology/Oncology, Shuang-Ho Hospital, Taipei Medical University, Taipei 23561, Taiwan
5
Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical Center, No. 325, Sec. 2, Cheng-Kung Road, Taipei 11490, Taiwan
6
Department of Surgery, School of Medicine, National Defense Medical Center, Taipei 11490, Taiwan
*
Author to whom correspondence should be addressed.
Cancers 2018, 10(12), 512; https://doi.org/10.3390/cancers10120512
Received: 27 November 2018 / Revised: 7 December 2018 / Accepted: 11 December 2018 / Published: 13 December 2018
Glioblastoma multiforme (GBM) requires radiotherapy (RT) as a part of definitive management strategy. RT is highly effective, destroying cancer cells that may exist around the surgical tumor bed. However, GBM still has a poor prognosis and a high local recurrence rate after RT. Accumulating research indicates that GBM contains cancer stem-like cells (CSCs), which are radioresistant and result in therapeutic failure. Additionally, GBM cells can aggressively invade normal brain tissue, inducing therapeutic failure. Using clinical observations, we evaluated the effect of radiation on tumor control. We also explored the biomolecular pathways that connect radioresistance and CSC- and epithelial-mesenchymal transition (EMT)-associated phenotypes in patient-derived GBM cells. Transwell and microarray assay demonstrated that radioresistant GBM cells (GBM-R2I2) exhibit increased invasion and self-renewal abilities compared with parental GBM cells. Finally, to identify potential mechanisms underlying these observations, we used a PCR array to search for molecular markers of cell motility. Signal transducer and activator of transcription 3 (STAT3) directly bound to the Slug promoter in a chromatin immunoprecipitation assay. Reduced STAT3 decreased Slug expression and suppressed cell invasion in GBM-R2I2 cells while increasing Slug reversed these effects. In addition, STAT3 knockdown significantly inhibited CSC properties, synergistically increased the radiotherapeutic effect, and effectively increased the survival rate in vivo. We deciphered a new pathway of GBM radioresistance, invasion, and recurrence via the STAT3/Slug axis that could be a new target of GBM therapy. View Full-Text
Keywords: glioblastoma; STAT3; slug; radioresistance; cancer stem cell (CSC) glioblastoma; STAT3; slug; radioresistance; cancer stem cell (CSC)
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MDPI and ACS Style

Lin, J.-C.; Tsai, J.-T.; Chao, T.-Y.; Ma, H.-I.; Liu, W.-H. The STAT3/Slug Axis Enhances Radiation-Induced Tumor Invasion and Cancer Stem-like Properties in Radioresistant Glioblastoma. Cancers 2018, 10, 512.

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