Suppression of STAT3 NH2‐terminal domain chemosensitizes medulloblastoma cells by activation of protein inhibitor of activated STAT3 via de‐repression by microRNA‐21

Medulloblastoma (MB) is a malignant pediatric brain tumor with poor prognosis. Signal transducers and activators of transcription‐3 (STAT3) is constitutively activated in MB where it functions as an oncoprotein, mediating cancer progression and metastasis. Here, we have delineated the functional rol...

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Bibliographic Details
Published in:Molecular carcinogenesis 2018-04, Vol.57 (4), p.536-548
Main Authors: Ray, Sutapa, Coulter, Don W., Gray, Shawn D., Sughroue, Jason A., Roychoudhury, Shrabasti, McIntyre, Erin M., Chaturvedi, Nagendra K., Bhakat, Kishor K., Joshi, Shantaram S., McGuire, Timothy R., Sharp, John G.
Format: Article
Language:English
Subjects:
Apoptosis
Brain tumors
Cancer
CCAAT/enhancer-binding protein
Cell cycle
Cell migration
Cisplatin
DNA microarrays
Gene expression
Growth inhibition
Homology
Medulloblastoma
Mesenchyme
Metastases
MicroRNAs
miRNA
miR‐21
MYC
Myc protein
p53 Protein
Pathogenesis
Pediatrics
PIAS3
Proteins
Signal transduction
STAT3
Stat3 protein
Structure-function relationships
Transcription factors
Transducers
Tumors
Wnt protein
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Summary:Medulloblastoma (MB) is a malignant pediatric brain tumor with poor prognosis. Signal transducers and activators of transcription‐3 (STAT3) is constitutively activated in MB where it functions as an oncoprotein, mediating cancer progression and metastasis. Here, we have delineated the functional role of activated STAT3 in MB, by using a cell permeable STAT3‐NH2 terminal domain inhibitor (S3‐NTDi) that specifically perturbs the structure/function of STAT3. We have implemented several biochemical experiments using human MB tumor microarray (TMA) and pediatric MB cell lines, derived from high‐risk SHH‐TP53‐mutated and MYC‐amplified Non‐WNT/SHH tumors. Treatment of MB cells with S3‐NTDi leads to growth inhibition, cell cycle arrest, and apoptosis. S3‐NTDi downregulated expression of STAT3 target genes, delayed migration of MB cells, attenuated epithelial‐mesenchymal transition (EMT) marker expressions and reduced cancer stem‐cell associated protein expressions in MB‐spheres. To elucidate mechanisms, we showed that S3‐NTDi induce expression of pro‐apoptotic gene, C/EBP‐homologous protein (CHOP), and decrease association of STAT3 to the proximal promoter of CCND1 and BCL2. Of note, S3‐NTDi downregulated microRNA‐21, which in turn, de‐repressed Protein Inhibitor of Activated STAT3 (PIAS3), a negative regulator of STAT3 signaling pathway. Furthermore, combination therapy with S3‐NTDi and cisplatin significantly decreased highly aggressive MYC‐amplified MB cell growth and induced apoptosis by downregulating STAT3 regulated proliferation and anti‐apoptotic gene expression. Together, our results revealed an important role of STAT3 in regulating MB pathogenesis. Disruption of this pathway with S3‐NTDi, therefore, may serves as a promising candidate for targeted MB therapy by enhancing chemosensitivity of MB cells and potentially improving outcomes in high‐risk patients.
ISSN:0899-1987
1098-2744
DOI:10.1002/mc.22778