Dataset Information

Modulation of miR-21 signaling by MPS1 in human glioblastoma.

ABSTRACT: 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-?/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.

SUBMITTER: Maachani UB

PROVIDER: S-EPMC5288158 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Modulation of miR-21 signaling by MPS1 in human glioblastoma.

Maachani Uday B UB Tandle Anita A Shankavaram Uma U Kramp Tamalee T Camphausen Kevin K

Oncotarget 20160801 33

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 tumo ...[more]

PMID: 25991676

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Project description:Brucella spp. infection results in compromised Type1 (Th1) cellular immune response. Several reports have described an immunomodulatory function for Brucella major outer membrane protein Omp25. However, the mechanism by which Omp25 modulates macrophage dysfunction has not been defined. Herein, we reported that Omp25-deficient mutant of Brucella suis exhibited an enhanced ability to induce interleukin (IL)-12 whereas ectopic expression of Omp25 protein inhibited TLR agonists-induced IL-12 p70 production through suppression of both IL-12 p40 and p35 subunit expression in THP-1 cells. In addition, Omp25 significantly upregulated miR-155, -23b and -21-5p, as well as the immunomodulator molecule programmed death-1 (PD-1) in monocyte/macrophages. The upregulation of miR-155 and -23b correlated temporally with decreased TAB2 levels, IκB phosphorylation and IL-12 p40 levels by targeting TAB2 and il12B 3' untranslated region (UTR), respectively, while miR-21-5p increase directly led to the reduction of lipopolysaccharide (LPS)/R848-induced IL-12 p35 protein by targeting il12A 3'UTR. Consistent with this finding, reduction of miR-155 and -23b attenuated the inhibitory effects of Omp25 on LPS/R848-induced IL-12 p40 expression at both transcriptional and posttranscriptional levels, while reduction of miR-21-5p attenuated the inhibitory effects of Omp25 on LPS/R848-induced IL-12 p35 expression at the posttranscriptional level, together significantly enhanced IL-12 p70 production upon LPS/R848 stimulation. We also found that blocking PD-1 signaling decreased the expression of miR-155, -23b and -21-5p induced by Omp25 and enhanced IL-12 production in monocyte/macrophages. Altogether, these data demonstrate that Brucella Omp25 induces miR-155, -23b and -21-5p to negatively regulate IL-12 production at both transcriptional and posttranscriptional levels via regulation of PD-1 signaling, which provides an entirely new mechanism underlying monocyte/macrophages dysfunction during Brucella spp. infection.

Project description:BackgroundGlioblastomas exhibit a high level of chemotherapeutic resistance, including to the antimitotic agents vincristine and taxol. During the mitotic agent-induced arrest, glioblastoma cells are able to perform damage-control and self-repair to continue proliferation. Monopolar spindle 1 (MPS1/TTK) is a checkpoint kinase and a gatekeeper of the mitotic arrest.MethodsWe used glioblastoma cells to determine the expression of MPS1 and to determine the effects of MPS1 inhibition on mitotic errors and cell viability in combination with vincristine and taxol. The effect of MPS1 inhibition was assessed in different orthotopic glioblastoma mouse models (n = 3-7 mice/group). MPS1 expression levels were examined in relation to patient survival.ResultsUsing publicly available gene expression data, we determined that MPS1 overexpression corresponds positively with tumor grade and negatively with patient survival (two-sided t test, P < .001). Patients with high MPS1 expression (n = 203) had a median and mean survival of 487 and 913 days (95% confidence intervals [CI] = 751 to 1075), respectively, and a 2-year survival rate of 35%, whereas patients with intermediate MPS1 expression (n = 140) had a median and mean survival of 858 and 1183 days (95% CI = 1177 to 1189), respectively, and a 2-year survival rate of 56%. We demonstrate that MPS1 inhibition by RNAi results in sensitization to antimitotic agents. We developed a selective small-molecule inhibitor of MPS1, MPS1-IN-3, which caused mitotic aberrancies in glioblastoma cells and, in combination with vincristine, induced mitotic checkpoint override, increased aneuploidy, and augmented cell death. MPS1-IN-3 sensitizes glioblastoma cells to vincristine in orthotopic mouse models (two-sided log-rank test, P < .01), resulting in prolonged survival without toxicity.ConclusionsOur results collectively demonstrate that MPS1, a putative therapeutic target in glioblastoma, can be selectively inhibited by MPS1-IN-3 sensitizing glioblastoma cells to antimitotic drugs.

Dataset Information

Modulation of miR-21 signaling by MPS1 in human glioblastoma.

Publications

Modulation of miR-21 signaling by MPS1 in human glioblastoma.

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