Oncotarget

Research Papers:

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

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Oncotarget. 2014; 5:11513-11525. https://doi.org/10.18632/oncotarget.2546

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Dong Hyun Jo _, Jin Hyoung Kim, Chang Sik Cho, Young-Lai Cho, Hyoung Oh Jun, Young Suk Yu, Jeong-Ki Min and Jeong Hun Kim

Abstract

Dong Hyun Jo1,2,3, Jin Hyoung Kim1,2, Chang Sik Cho1,2,3, Young-Lai Cho4, Hyoung Oh Jun1,2, Young Suk Yu1,5, Jeong-Ki Min6, Jeong Hun Kim1,2,3,5

1Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea

2Tumor Microenvironment Research Center, Global Core Research Center, Seoul National University, Seoul, Republic of Korea

3Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea

4Center for Nanosafety Metrology, Korea Research Institute of Standards and Science Daejeon, Republic of Korea

5Department of Ophthalmology, College of Medicine, Seoul National University, Seoul, Republic of Korea

6Research Center for Integrated Cellulomics, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea

Correspondence to:

Jeong Hun Kim, e-mail: steph25@snu.ac.kr

Jeong-Ki Min, e-mail: jekmin@kribb.re.kr

Keywords: Retinoblastoma, STAT3 transcription factor, miR-17-92

Received: July 12, 2014     Accepted: September 30, 2014     Published: November 03, 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.