Mikheev Andrei M, Mikheeva Svetlana A, Tokita Mari, Severs Liza J, Rostomily Robert C
Department of Neurological Surgery, Houston Methodist Hospital and Research Institute, Houston, Texas, USA.
Department of Neurological Surgery and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA.
Oncotarget. 2017 Nov 21;8(64):107716-107729. doi: 10.18632/oncotarget.22593. eCollection 2017 Dec 8.
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.
Twist1是上皮-间质转化和癌转移的主要调节因子。Twist1也与人类胶质瘤恶性程度增加有关。然而，在不同致癌转化模式的背景下，抑制Twist1对胶质瘤模型中肿瘤发生的影响尚未得到明确描述。在这里，我们使用移植转化神经祖细胞（NPC）的原位小鼠胶质瘤模型来证明Twist1功能丧失对肿瘤发生的影响。在HPV E6/7 Ha-RasV12转化的NPC中，shRNA介导的Twist敲低以及在p53敲低和Ha-RasV12表达转化的Twist1 fl/fl NPC中Cre介导的Twist1缺失后，观察到致瘤性降低。相比之下，Twist1缺失对通过共表达Akt和Ha-RasV12转化的NPC的致瘤性没有影响。我们证明了组成型Cre表达导致Twist1缺失具有显著的脱靶效应，当通过瞬时施用重组Cre蛋白实现Twist1缺失时，这种效应完全逆转。这些发现共同表明，Twist1在这些模型中的功能高度依赖于NPC转化的特定致癌背景。因此，在评估作用机制和开发针对人类胶质瘤中Twist1的治疗方法时，可能需要考虑Twist1发挥作用的驱动突变背景。
