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Published on: October 4, 2019
Modulation of miR-21 signaling by MPS1 in human glioblastoma
Uday B Maachani1, Anita Tandle1, Uma Shankavaram1
1Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
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-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.
Insights
Monopolar spindle 1 (MPS1) kinase inhibition upregulates tumor suppressors PDCD4 and MSH2 by downregulating miR-21 in glioblastoma. This reveals a potential therapeutic strategy targeting MPS1 and miR-21 for glioblastoma treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Monopolar spindle 1 (MPS1) is a crucial kinase for spindle assembly checkpoint and has roles beyond mitosis.
- Earlier research highlighted MPS1's involvement in glioblastoma (GBM) radiosensitization.
- Elevated microRNA-21 (miR-21) expression in GBM correlates with chemo- and radioresistance.
Purpose of the Study:
- To investigate MPS1-mediated cell signaling pathways in GBM.
- To explore the relationship between MPS1, miR-21, and GBM cell proliferation.
- To elucidate the prognostic significance of miR-21, PDCD4, and MSH2 in GBM.
Main Methods:
- Utilized reverse phase protein arrays (RPPAs) to analyze MPS1-mediated signaling.
- Assessed the impact of MPS1 inhibition on PDCD4, MSH2, and miR-21 expression.
- Investigated the effect of MPS1 and miR-21 modulation on GBM cell proliferation.
- Examined MPS1's role in SMAD3/SMAD2 phosphorylation.
Main Results:
- MPS1 inhibition upregulated tumor suppressors PDCD4 and MSH2 by downregulating miR-21.
- Both MPS1 and miR-21 depletion suppressed GBM cell proliferation.
- Ectopic miR-21 expression rescued GBM cell growth upon MPS1 inhibition.
- MPS1 mediated SMAD3 phosphorylation, suggesting a mechanism for miR-21 regulation.
- miR-21, PDCD4, and MSH2 levels showed prognostic value in GBM subtypes.
Conclusions:
- MPS1 plays a significant role in TGF-β/SMAD signaling through miR-21 regulation in GBM.
- Targeting MPS1 and modulating miR-21 presents a potential therapeutic strategy for GBM.
- Understanding the interplay of MPS1, miR-21, and tumor suppressors offers new avenues for GBM treatment.
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