Maachani Uday B, Tandle Anita, Shankavaram Uma, Kramp Tamalee, Camphausen Kevin
Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Oncotarget. 2016 Aug 16;7(33):52912-52927. doi: 10.18632/oncotarget.4143.
Monopolar spindle 1 (MPS1) is an essential spindle assembly checkpoint (SAC) kinase involved in determining spindle integrity. Beyond its mitotic functions, it has been implicated in several other signaling pathways. Our earlier studies have elaborated on role of MPS1 in glioblastoma (GBM) radiosensitization. In this study using reverse phase protein arrays (RPPAs), we assessed MPS1 mediated cell signaling pathways and demonstrated that inhibiting MPS1 could upregulate the expression of the tumor suppressor PDCD4 and MSH2 genes, by down regulating micro RNA-21 (miR-21). In GBMs miR-21 expression is significantly elevated and is associated with chemo and radioresistance. Both MPS1 and miR-21 depletion suppressed GBM cell proliferation, whereas, ectopic expression of miR-21 rescued GBM cell growth from MPS1 inhibition. Further, we demonstrate that MPS1 mediates phosphorylation of SMAD3 but not SMAD2 in GBM cells; A possible mechanism behind miR-21 modulation by MPS1. Collectively, our results shed light onto an important role of MPS1 in TGF-β/SMAD signaling via miR-21 regulation. We also, show the prognostic effect of miR-21, PDCD4 and MSH2 levels to patient survival across different GBM molecular subtypes. This scenario in which miR-21 is modulated by MPS1 inhibition may be exploited as a potential target for effective GBM therapy.
单极纺锤体1（MPS1）是一种重要的纺锤体组装检查点（SAC）激酶，参与确定纺锤体的完整性。除了其有丝分裂功能外，它还涉及其他几种信号通路。我们早期的研究阐述了MPS1在胶质母细胞瘤（GBM）放射增敏中的作用。在这项使用反向蛋白质阵列（RPPA）的研究中，我们评估了MPS1介导的细胞信号通路，并证明抑制MPS1可通过下调微小RNA-21（miR-21）来上调肿瘤抑制因子PDCD4和MSH2基因的表达。在GBM中，miR-21表达显著升高，并与化疗和放疗抗性相关。MPS1和miR-21的缺失均抑制GBM细胞增殖，而miR-21的异位表达可使GBM细胞生长从MPS1抑制中恢复。此外，我们证明MPS1在GBM细胞中介导SMAD3的磷酸化，但不介导SMAD2的磷酸化；这是MPS1调节miR-21的一种可能机制。总体而言，我们的结果揭示了MPS1通过miR-21调节在TGF-β/SMAD信号传导中的重要作用。我们还展示了miR-21、PDCD4和MSH2水平对不同GBM分子亚型患者生存的预后影响。这种通过抑制MPS1调节miR-21的情况可能被用作有效治疗GBM的潜在靶点。
