Direct Upregulation of STAT3 by MicroRNA-551b-3p Deregulates Growth and Metastasis of Ovarian Cancer.

Abstract

3q26.2 amplification in high-grade serous ovarian cancer leads to increased expression of mature microRNA miR551b-3p, which is associated with poor clinical outcome. Importantly, miR551b-3p contributes to resistance to apoptosis and increased survival and proliferation of cancer cells in vitro and in vivo. miR551b-3p upregulates STAT3 protein levels, and STAT3 is required for the effects of miR551b-3p on cell proliferation. Rather than decreasing levels of target mRNA as expected, we demonstrate that miR551b-3p binds a complementary sequence on the STAT3 promoter, recruiting RNA polymerase II and the TWIST1 transcription factor to activate STAT3 transcription, and thus directly upregulates STAT3 expression. Furthermore, anti-miR551b reduced STAT3 expression in ovarian cancer cells in vitro and in vivo and reduced ovarian cancer growth in vivo. Together, our data demonstrate a role for miR551b-3p in transcriptional activation. Thus, miR551b-3p represents a promising candidate biomarker and therapeutic target in ovarian cancer.

• Authors: Pradeep Chaluvally-Raghavan, Kang Jin Jeong, Sunila Pradeep, Andreia Machado Silva, Shuangxing Yu, Wenbin Liu, Tyler Moss, Cristian Rodriguez-Aguayo, Dong Zhang, Prahlad Ram, Jinsong Liu, Yiling Lu, Gabriel Lopez-Berestein, George A Calin, Anil K Sood, Gordon B Mills
• Journal: Cell reports (Cell Rep) Vol. 15 Issue 7 Pg. 1493-1504 (05 17 2016) ISSN: 2211-1247 [Electronic] United States
• PMID: 27160903 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• MIRN-551 microRNA, human
• MicroRNAs
• Nuclear Proteins
• STAT3 Transcription Factor
• TWIST1 protein, human
• Twist-Related Protein 1
• RNA Polymerase II

Topics

• Animals
• Carcinoma, Ovarian Epithelial
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Cell Self Renewal
• Cell Survival (genetics)
• Down-Regulation (genetics)
• Female
• Gene Amplification
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Gene Silencing
• Humans
• Mice, Nude
• MicroRNAs (metabolism)
• Neoplasm Metastasis
• Neoplasms, Glandular and Epithelial (genetics, pathology)
• Nuclear Proteins (metabolism)
• Ovarian Neoplasms (genetics, pathology)
• Promoter Regions, Genetic (genetics)
• RNA Polymerase II (metabolism)
• STAT3 Transcription Factor (genetics, metabolism)
• Spheroids, Cellular (metabolism, pathology)
• Transcription, Genetic
• Treatment Outcome
• Tumor Burden (genetics)
• Twist-Related Protein 1 (metabolism)
• Up-Regulation (genetics)