# Role of RNA activation in Tumor Progression and Metastasis

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2022 · $379,391

## Abstract

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.

## Key facts

- **NIH application ID:** 10464902
- **Project number:** 5R01CA229907-04
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Pradeep Chaluvally-Raghavan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $379,391
- **Award type:** 5
- **Project period:** 2019-09-10 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10464902

## Citation

> US National Institutes of Health, RePORTER application 10464902, Role of RNA activation in Tumor Progression and Metastasis (5R01CA229907-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10464902. Licensed CC0.

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