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Chromosome 1q ceRNAs in Melanoma Progression and Metastasis

Award Number: R01CA259046
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Chromosome 1q ceRNAs in Melanoma Progression and Metastasis - PROJECT SUMMARY Metastasis is the main cause of deaths related to malignant melanoma. Studies over the last decade have revealed that the metastatic process is not primarily driven by genetic changes. Instead, deregulation of gene expression through epigenetic, transcriptional, or posttranscriptional mechanisms as well as copy number alterations may promote melanoma metastasis. Our previous work described how messenger RNAs engage in protein coding-independent posttranscriptional regulation by sequestering microRNAs (miRNAs) from other transcripts, and we termed such natural miRNA sponges competitive endogenous RNAs (ceRNAs). Deregulated ceRNA expression has been causally linked to cancer development, and thus genomic copy number gains of ceRNA genes may be an important driver of malignant progression of melanoma. We have identified a cluster of melanoma ceRNA genes localized on chromosome 1q, which undergoes copy number gains (1qGAIN) in 25-50% of melanoma. 1qGAIN is more frequent in metastases, suggesting that 1qGAIN ceRNAs may contribute to melanoma progression. Our predictions identified CEP170 as a potent 1qGAIN ceRNA, and preliminary experiments revealed its oncogenic role in vitro and in vivo. Two additional 1qGAIN ceRNAs, NUCKS1 and ZC3H11A, exhibited oncogenic potential and enhanced the CEP170-mediated effects. Thus, gains of 1q may lead to overexpression of multiple ceRNAs that promote melanoma metastasis by sequestering tumor suppressive miRNAs. We have identified five metastasis-associated miRNAs that are sequestered by CEP170 and that promote melanoma cell migration and invasion. In this proposal, we will systematically examine the oncogenic role of 1qGAIN ceRNAs in melanoma metastasis. Specifically, in Aim 1 we will examine if the 3'UTR of CEP170 promotes melanoma dissemination in a miRNA binding site-specific manner using metastasis and autochthonous models. In Aim 2 we will assess if the release of miRNAs from the endogenous CEP170 transcript opposes metastasis, and if these miRNAs have tumor suppressive activity in melanoma cells. Moreover, we will identify and characterize downstream effectors that mediate the CEP170- provoked phenotype. Finally, in Aim 3 we will examine if NUCKS1 and ZC3H11A boost the effect of CEP170 by augmenting miRNA sequestration. We will also test if any of the remaining 1qGAIN ceRNAs, ten in total, possess oncogenic activity and cooperate with CEP170. We expect that our study will reveal the biological relevance of 1qGAIN ceRNAs to melanoma metastasis and further elucidate the mechanisms underlying ceRNA- mediated melanoma progression and metastasis.


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: 2025 ( Subtotal = $416,938 )
2025	2025	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	5	3/20/2025	NON-COMPETING CONTINUATION	$375,244
2025	2025	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	002	5	5/22/2025	NON-COMPETING CONTINUATION	$41,694
2025	2025	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	001	5	5/5/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $416,938

Issue Date FY: 2024 ( Subtotal = $509,000 )
2024	2024	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	001	4	9/16/2024	SUPPLEMENT FOR EXPANSION	$112,908
2024	2024	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	4	5/8/2024	NON-COMPETING CONTINUATION	$396,092
														Subtotal = $509,000

Issue Date FY: 2023 ( Subtotal = $408,600 )
2023	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	3	6/5/2023	NON-COMPETING CONTINUATION	$408,600
														Subtotal = $408,600

Issue Date FY: 2022 ( Subtotal = $408,595 )
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	2	4/29/2022	NON-COMPETING CONTINUATION	$408,595
														Subtotal = $408,595

Issue Date FY: 2021 ( Subtotal = $416,938 )
2021	2021	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	1	4/26/2021	NEW	$416,938
														Subtotal = $416,938

Grand Total All Awards = $2,160,071

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Chromosome 1q ceRNAs in Melanoma Progression and Metastasis

Award Number: R01CA259046

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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