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Role of RNA activation in Tumor Progression and Metastasis

Award Number: R01CA229907
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/10/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Role of RNA activation in Tumor Progression and Metastasis - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = -$1,178 )
2026	2023	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Biology Research	000	5	1/6/2026	NON-COMPETING CONTINUATION	-$1,178
														Subtotal = -$1,178

Issue Date FY: 2023 ( Subtotal = $334,391 )
2023	2023	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Biology Research	000	5	8/22/2023	NON-COMPETING CONTINUATION	$334,391
														Subtotal = $334,391

Issue Date FY: 2022 ( Subtotal = $379,391 )
2022	2022	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Biology Research	000	4	8/30/2022	NON-COMPETING CONTINUATION	$379,391
														Subtotal = $379,391

Issue Date FY: 2021 ( Subtotal = $341,216 )
2021	2021	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Biology Research	000	3	8/6/2021	NON-COMPETING CONTINUATION	$341,216
														Subtotal = $341,216

Issue Date FY: 2020 ( Subtotal = $341,216 )
2020	2020	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Biology Research	000	2	8/6/2020	NON-COMPETING CONTINUATION	$341,216
														Subtotal = $341,216

Issue Date FY: 2019 ( Subtotal = $353,568 )
2019	2019	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Biology Research	000	1	9/10/2019	NEW	$353,568
														Subtotal = $353,568

Grand Total All Awards = $1,748,604

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Role of RNA activation in Tumor Progression and Metastasis

Award Number: R01CA229907

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/10/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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