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

Maachani, Uday B; Tandle, Anita; Shankavaram, Uma; Kramp, Tamalee; Camphausen, Kevin

Maachani, Uday B; Tandle, Anita; Shankavaram, Uma; Kramp, Tamalee; Camphausen, Kevin.

Afiliación

Maachani UB; Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Tandle A; Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Shankavaram U; Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Kramp T; Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Camphausen K; Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Oncotarget ; 7(33): 52912-52927, 2016 Aug 16.

Article en En | MEDLINE | ID: mdl-25991676

RESUMEN

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-ß/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.

Asunto(s)

Neoplasias Encefálicas/genética; Proteínas de Ciclo Celular/genética; Glioblastoma/genética; MicroARNs/genética; Proteínas Serina-Treonina Quinasas/genética; Proteínas Tirosina Quinasas/genética; Transducción de Señal/genética; Proteínas Reguladoras de la Apoptosis/genética; Proteínas Reguladoras de la Apoptosis/metabolismo; Neoplasias Encefálicas/metabolismo; Neoplasias Encefálicas/patología; Proteínas de Ciclo Celular/metabolismo; Línea Celular Tumoral; Proliferación Celular/efectos de los fármacos; Proliferación Celular/genética; Proliferación Celular/efectos de la radiación; Regulación Neoplásica de la Expresión Génica; Glioblastoma/metabolismo; Glioblastoma/terapia; Humanos; Proteína 2 Homóloga a MutS/genética; Proteína 2 Homóloga a MutS/metabolismo; Fosforilación; Proteínas Serina-Treonina Quinasas/metabolismo; Proteínas Tirosina Quinasas/metabolismo; Interferencia de ARN; Proteínas de Unión al ARN/genética; Proteínas de Unión al ARN/metabolismo; Proteína smad3/metabolismo

Palabras clave

MPS1; MSH2; MiR21; PDCD4; TGF-ß/SMAD signaling; glioblastoma multiforme

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Proteínas Tirosina Quinasas / Transducción de Señal / Proteínas Serina-Treonina Quinasas / Glioblastoma / Proteínas de Ciclo Celular / MicroARNs Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Oncotarget Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

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