The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance

EMBO Molecular Medicine

Florian A. Siebzehnrubl⁵  Daniel J. Silver⁵  Bugra Tugertimur⁵  Loic P. Deleyrolle⁵  Dorit Siebzehnrubl⁴  Matthew R. Sarkisian⁴  Kelly G. Devers²  Antony T. Yachnis²  Marius D. Kupper⁶  Daniel Neal⁵  Nancy H. Nabilsi³  Michael P. Kladde³  Oleg Suslov⁵  Simone Brabletz¹  Thomas Brabletz¹  Brent A. Reynolds⁵ 

[1] Department of Visceral Surgery, University Hospital Freiburg, Freiburg, Germany;Department of Pathology, University of Florida, Gainesville, FL, USA;Department of Biochemistry and Molecular Biology, University of Florida Shands Cancer Center Program in Cancer Genetics, Epigenetics and Tumor Virology, Gainesville, FL, USA;Department of Neuroscience, University of Florida, Gainesville, FL, USA;Department of Neurosurgery, University of Florida, Gainesville, FL, USA;Institute for Reconstructive Neurobiology, University of Bonn, Germany

关键词: brain;    cancer stem cell;    EMT;    glioma;    xenograft;   

DOI  :  10.1002/emmm.201302827

来源: Wiley

【 摘 要 】

Abstract

Glioblastoma remains one of the most lethal types of cancer, and is the most common brain tumour in adults. In particular, tumour recurrence after surgical resection and radiation invariably occurs regardless of aggressive chemotherapy. Here, we provide evidence that the transcription factor ZEB1 (zinc finger E-box binding homeobox 1) exerts simultaneous influence over invasion, chemoresistance and tumourigenesis in glioblastoma. ZEB1 is preferentially expressed in invasive glioblastoma cells, where the ZEB1-miR-200 feedback loop interconnects these processes through the downstream effectors ROBO1, c-MYB and MGMT. Moreover, ZEB1 expression in glioblastoma patients is predictive of shorter survival and poor Temozolomide response. Our findings indicate that this regulator of epithelial-mesenchymal transition orchestrates key features of cancer stem cells in malignant glioma and identify ROBO1, OLIG2, CD133 and MGMT as novel targets of the ZEB1 pathway. Thus, ZEB1 is an important candidate molecule for glioblastoma recurrence, a marker of invasive tumour cells and a potential therapeutic target, along with its downstream effectors.

【 授权许可】

CC BY   
Copyright © 2013 EMBO Molecular Medicine

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