Journal
BMC CANCER
Volume 13, Issue -, Pages -Publisher
BMC
DOI: 10.1186/1471-2407-13-371
Keywords
BAP1; Uveal melanoma; Differentiation; Stem cell; Metastasis; Tumor suppressor
Categories
Funding
- NIH [5R01 CA12597007, 1R01 CA16187001]
- Melanoma Research Alliance
- Melanoma Research Foundation
- Tumori Foundation
- Research to Prevent Blindness
- Joanna M. Nicolay Melanoma Foundation
- Cancer Biology Pathway of the Division of Biology and Biomedical Sciences at Washington University
- NIH Vision Core Grant [P30 EY02687]
- Research to Prevent Blindness, Inc.
- NCI Cancer Center Support Grant [P30 CA91842]
- ICTS/CTSA Grant from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) [UL1RR024992]
- NIH Roadmap for Medical Research
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Background: Uveal melanoma is a highly aggressive cancer with a strong propensity for metastasis, yet little is known about the biological mechanisms underlying this metastatic potential. We recently showed that most metastasizing uveal melanomas, which exhibit a class 2 gene expression profile, contain inactivating mutations in the tumor suppressor BAP1. The aim of this study was to investigate the role of BAP1 in uveal melanoma progression. Methods: Uveal melanoma cells were studied following RNAi-mediated depletion of BAP1 using proliferation, BrdU incorporation, flow cytometry, migration, invasion, differentiation and clonogenic assays, as well as in vivo tumorigenicity experiments in NOD-SCID-Gamma mice. Results: Depletion of BAP1 in uveal melanoma cells resulted in a loss of differentiation and gain of stem-like properties, including expression of stem cell markers, increased capacity for self-replication, and enhanced ability to grow in stem cell conditions. BAP1 depletion did not result in increased proliferation, migration, invasion or tumorigenicity. Conclusions: BAP1 appears to function in the uveal melanocyte lineage primarily as a regulator of differentiation, with cells deficient for BAP1 exhibiting stem-like qualities. It will be important to elucidate how this effect of BAP1 loss promotes metastasis and how to reverse this effect therapeutically.
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