STAT3 inhibition suppresses proliferation of retinoblastoma through down-regulation of positive feedback loop of STAT3/miR-17-92 clusters

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Title
STAT3 inhibition suppresses proliferation of retinoblastoma through down-regulation of positive feedback loop of STAT3/miR-17-92 clusters
Author(s)
D H Jo; J H Kim; C S Cho; Y L Cho; H O Jun; Y S Yu; Jeong Ki Min; J H Kim
Bibliographic Citation
Oncotarget, vol. 5, no. 22, pp. 11513-11525
Publication Year
2014
Abstract
Retinoblastoma, the most common intraocular malignant tumor in children, is characterized by the loss of both functional alleles of RB1 gene, which however alone cannot maintain malignant characteristics of retinoblastoma cells. Nevertheless, the investigation of other molecular aberrations such as matrix metalloproteinases (MMPs) and miRNAs is still lacking. In this study, we demonstrate that STAT3 is activated in retinoblastoma cells, Ki67-positive areas of in vivo orthotopic tumors in BALB/c nude mice, and human retinoblastoma tissues of the advanced stage. Furthermore, target genes of STAT3 including BCL2, BCL2L1, BIRC5, and MMP9 are up-regulated in retinoblastoma cells compared to other retinal constituent cells. Interestingly, STAT3 inhibition by targeted siRNA suppresses the proliferation of retinoblastoma cells and the formation of in vivo orthotopic tumors. In line with these results, STAT3 siRNA effectively induces down-regulation of target genes of STAT3. In addition, miRNA microarray analysis and further real-time PCR experiments with STAT3 siRNA treatment show that STAT3 activation is related to the up-regulation of miR-17-92 clusters in retinoblastoma cells via positive feedback loop between them. In conclusion, we suggest that STAT3 inhibition could be a potential therapeutic approach in retinoblastoma through the suppression of tumor proliferation.
Keyword
miR-17-92RetinoblastomaSTAT3 transcription factor
ISSN
1949-2553
Publisher
Impact Journals
DOI
http://dx.doi.org/10.18632/oncotarget.2546
Type
Article
Appears in Collections:
Division of Biomedical Research > Biotherapeutics Translational Research Center > 1. Journal Articles
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