BAP1 deficiency causes loss of melanocytic cell identity in uveal melanoma

BMC Cancer

Katie A Matatall²  Olga A Agapova²  Michael D Onken²  Lori A Worley²  Anne M Bowcock¹  J William Harbour³ 

[1] Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA

[2] Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, USA

[3] Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA

关键词: Tumor suppressor;    Metastasis;    Stem cell;    Differentiation;    Uveal melanoma;    BAP1;   

Others  :  1079619
DOI  :  10.1186/1471-2407-13-371

 received in 2013-01-02, accepted in 2013-08-01,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Matatall et al.; licensee BioMed Central Ltd.

【 图 表 】

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