Oncotarget

Research Papers:

Twist1 mediated regulation of glioma tumorigenicity is dependent on mode of mouse neural progenitor transformation

Andrei M. Mikheev, Svetlana A. Mikheeva, Mari Tokita, Liza J. Severs and Robert C. Rostomily _

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Oncotarget. 2017; 8:107716-107729. https://doi.org/10.18632/oncotarget.22593

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Abstract

Andrei M. Mikheev1,2,*, Svetlana A. Mikheeva1,2, Mari Tokita3, Liza J. Severs4 and Robert C. Rostomily1,2,*

1Department of Neurological Surgery, Houston Methodist Hospital and Research Institute, Houston, Texas, USA

2Department of Neurological Surgery and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA

3Division of Medical Genetics, University of Washington, Seattle, Washington, USA

4Department of Physiology and Biophysics, University of Washington, Seattle, Washington, USA

*Shared senior authorship

Correspondence to:

Robert C. Rostomily, email: rrostomily@houstonmethodist.org

Andrei M. Mikheev, email: amikheev@houstonmethodist.org

Keywords: Twist1; glioma; invasion; p53; Cre recombinase

Abbreviations: TW: Twist1; Rb: Retinoblastoma 1; Ras: Ha-Ras Transforming Protein P21; Akt: Protein Kinase B Alpha; HPV: Human papillomavirus

Received: August 24, 2017     Accepted: November 05, 2017     Published: November 21, 2017

ABSTRACT

Twist1 is a master regulator of epithelial mesenchymal transition and carcinoma metastasis. Twist1 has also been associated with increased malignancy of human glioma. However, the impact of inhibiting Twist1 on tumorigenicity has not been characterized in glioma models in the context of different oncogenic transformation paradigms. Here we used an orthotopic mouse glioma model of transplanted transformed neural progenitor cells (NPCs) to demonstrate the effects of Twist1 loss of function on tumorigenicity. Decreased tumorigenicity was observed after shRNA mediated Twist knockdown in HPV E6/7 Ha-RasV12 transformed NPCs and Cre mediated Twist1 deletion in Twist1 fl/fl NPCs transformed by p53 knockdown and Ha-RasV12 expression. By contrast, Twist1 deletion had no effect on tumorigenicity of NPCs transformed by co-expression of Akt and Ha-RasV12. We demonstrated a dramatic off-target effect of Twist1 deletion with constitutive Cre expression, which was completely reversed when Twist1 deletion was achieved by transient administration of recombinant Cre protein. Together these findings demonstrate that the function of Twist1 in these models is highly dependent on specific oncogenic contexts of NPC transformation. Therefore, the driver mutational context in which Twist1 functions may need to be taken into account when evaluating mechanisms of action and developing therapeutic approaches to target Twist1 in human gliomas.


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