Senol O, Schaaij-Visser T B M, Erkan E P, Dorfer C, Lewandrowski G, Pham T V, Piersma S R, Peerdeman S M, Ströbel T, Tannous B, Saydam N, Slavc I, Knosp E, Jimenez C R, Saydam O
Department of Neurology and Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
OncoProteomics Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Oncogene. 2015 Apr 2;34(14):1790-8. doi: 10.1038/onc.2014.120. Epub 2014 May 26.
miR-200a has been implicated in the pathogenesis of meningiomas, one of the most common central nervous system tumors in humans. To identify how miR-200a contributes to meningioma pathogenesis at the molecular level, we used a comparative protein profiling approach using Gel-nanoLC-MS/MS and identified approximately 130 dysregulated proteins in miR-200a-overexpressing meningioma cells. Following the bioinformatic analysis to identify potential genes targeted by miR-200a, we focused on the non-muscle heavy chain IIb (NMHCIIb), and showed that miR-200a directly targeted NMHCIIb. Considering the key roles of NMHCIIb in cell division and cell migration, we aimed to identify whether miR-200a regulated these processes through NMHCIIb. We found that NMHCIIb overexpression partially rescued miR-200a-mediated inhibition of cell migration, as well as cell growth in vitro and in vivo. Moreover, siRNA-mediated silencing of NMHCIIb expression resulted in a similar migration phenotype in these cells and inhibited meningioma tumor growth in mice. Taken together, these results suggest that NMHCIIb might serve as a novel therapeutic target in meningiomas.
miR-200a与脑膜瘤的发病机制有关，脑膜瘤是人类最常见的中枢神经系统肿瘤之一。为了在分子水平上确定miR-200a如何促进脑膜瘤发病机制，我们使用了一种比较蛋白质谱分析方法，即凝胶-纳升液相色谱-串联质谱法，并在过表达miR-200a的脑膜瘤细胞中鉴定出约130种失调蛋白。在进行生物信息学分析以确定miR-200a靶向的潜在基因后，我们聚焦于非肌肉重链IIb（NMHCIIb），并表明miR-200a直接靶向NMHCIIb。考虑到NMHCIIb在细胞分裂和细胞迁移中的关键作用，我们旨在确定miR-200a是否通过NMHCIIb调节这些过程。我们发现，NMHCIIb的过表达部分挽救了miR-200a介导的对细胞迁移以及体外和体内细胞生长的抑制作用。此外，siRNA介导的NMHCIIb表达沉默在这些细胞中导致了类似的迁移表型，并抑制了小鼠脑膜瘤肿瘤的生长。综上所述，这些结果表明NMHCIIb可能是脑膜瘤的一个新的治疗靶点。
