Our studies identified that microRNAs amplified in the 3q26.2 locus are critical players in the progression and metastasis of ovarian cancer (Cancer Cell, 2014 and Cell Reports, 2016). Our data demonstrate that microRNA miR551b is amplified and overexpressed as a consequence of 3q26.2 locus amplification, and is an unexpected driver in ovarian cancer. miRNAs are thought to primarily downregulate mRNA expression through decreasing mRNA stability and protein translation through binding complementary ?seed? sequences in the 3'UTR. However, the mechanism by which miR551b contributes to the progression and metastasis of ovarian cancer and whether it represents a novel targetable avenue remains to be ascertained. Our studies identified an unexpected seed match of miR551b on the STAT3, NOS2 and STAT5 promoter in the 5'UTR upstream of the transcription initiation codon at a site of predicted binding for multiple transcription factors (TFs). Our data shows that miR551b directly interacts with the STAT3 promoter, and activates STAT3 transcription through a mechanism called RNA activation (RNAa). We identified that tumor cells employ the RNAa mechanism for rapid induction of oncogenes for the progression and metastasis. We further demonstrate that RNAa mediated induction of STAT3 transcription factor upregulates STAT3-induced cytokines, including Oncostatin M (OSM) and Interleukin-31 as well as their receptors, OSMR and IL31R. We hypothesize that the above receptor-ligand interactions launch a self-reinforcing feed-forward loop that establishes a targetable ?oncogene addiction? pathway in tumor cells. While the respective growth factors like OSM, IL31, VEGFA and their receptors and VEGFR, IL31R and OSMR, activate autocrine signaling for oncogenic addictions in tumor cells; growth factors like OSM and VEGF induces paracrine effect in tumor endothelial cells for neo-angiogenesis, a vehicle for tumor metastasis. Thus interfering the RNAa mechanism induced by miR551b will provide an unprecedented opportunity to disrupt tumor progression and metastasis. To disrupt the ?signaling addiction mechanism?; we propose to use anti-miR551b encapsulated in nanoliposme for in vivo delivery to inhibit the progression and metastasis of ovarian cancer. In brief, our studies on the role of miR551b in ovarian cancer are designed to increase our understanding on the roles of microRNA amplifications in ovarian cancer. We expect that our studies on miR551b will help us to identify novel mechanisms and therapeutic approaches for ovarian cancer. miR551b is highly amplified and overexpressed in breast, lung and cervical cancers. Therefore, we expect that our results can be translated broadly into other cancers that encompass miR551b amplification.

Public Health Relevance

Our preliminary data demonstrates an unexpected role of microRNAs on transcriptional activation of master regulator STAT3 oncogene in ovarian cancer. Using cellular, molecular, biochemical approaches (in vitro), animal studies, bioinformatical and computational methods (in silico), we will elucidate individual and collective effect of microRNA-551b aberrations and RNA activation resulted due to the 3q26.2 amplification and their potential role in the tumorigenesis and progression of ovarian cancer. Based on our results, our study will result a paradigm shift in our understanding of the transcriptional and posttranscriptional effects of microRNAs and identify novel biomarkers and therapeutic targets to treat ovarian cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Progression and Metastasis Study Section (TPM)
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Watson, Joanna M
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Medical College of Wisconsin
Obstetrics & Gynecology
Schools of Medicine
United States
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