# The Role of microRNAs in BRAFV600E-driven Nevus Growth Arrest

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $21,430

## Abstract

PROJECT SUMMARY/ABSTRACT
Malignant melanoma incidence is rapidly increasing, requiring new detection and therapeutic approaches.
Despite the development of targeted therapies, mortality rates of advanced melanoma remain stubbornly high.
If detected in its earliest stages, however, melanoma can often be cured.
Activating V600E mutations in the BRAF proto-oncogene drive approximately 50% of all cutaneous
melanomas. Yet, when a melanocyte (the melanoma cell of origin) acquires a BRAFV600E mutation, the cell
does not immediately transition to malignancy. Instead, it undergoes rapid proliferation followed by growth
arrest resulting in a stable pigmented skin macule known as a benign nevus or mole. Few moles ever progress
to melanoma suggesting that nevus cells have a robust intrinsic defense against hyperproliferation. The
mechanisms underlying BRAFV600E nevus formation, however, remain elusive. To address this critical gap in
our understanding of intrinsic barriers to melanoma progression, I propose to investigate factors controlling
BRAFV600E-driven growth arrest. Addressing this unmet need will deepen our understanding of the events
initiating melanoma while improving our ability to detect nevi at risk for progression to melanoma.
DNA sequencing of human nevi revealed that additional genetic changes do not distinguish proliferating
BRAFV600E melanocytes from the growth-arrested melanocytes of the nevus, suggesting that epigenetic
elements may restrain hyperproliferation. Preliminary data from our lab shows that microRNAs miR-211-5p and
miR-328-3p are upregulated in growth arrested BRAFV600E nevi compared to both normal melanocytes and to
melanomas arising from adjacent benign nevi. Expression of each microRNA in human melanocytes leads to a
growth-arrest phenotype suggesting miRs 211-5p and 328-3p play a functional role in establishing the growth-
arrested state of nevi. Moreover, both microRNAs regulate the mRNA transcripts of YWHAZ, a gene whose
upregulation in correlated with cancer progression and whose downregulation leads triggers cell cycle arrest.
Accordingly, we will investigate the roles of miR-211-5p and miR-328-3p in BRAFV600E-driven nevus formation.
Using CRISPR-mediated genome engineering, synthetic microRNAs, RNA sequencing, and human cells
derived directly from patient nevi, we will specifically determine whether miRs 211-5p and 328-3p deplete
YWHAZ mRNA in BRAFV600E melanocytes leading to growth arrest and serving as a barrier to melanoma.
Successful completion of this proposal will yield new insight into the cell-intrinsic mechanisms that enable
melanocytes to resist BRAFV600E-driven malignant transformation, and further probe how nevi form. Moreover,
this proposal will further our understanding of the key genetic and epigenetic events initiating melanoma while
improving our ability to detect the disease at its earliest time points.

## Key facts

- **NIH application ID:** 9840389
- **Project number:** 5F31CA236376-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Andrew McNeal
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $21,430
- **Award type:** 5
- **Project period:** 2019-01-01 → 2020-06-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840389

## Citation

> US National Institutes of Health, RePORTER application 9840389, The Role of microRNAs in BRAFV600E-driven Nevus Growth Arrest (5F31CA236376-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9840389. Licensed CC0.

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