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BAP1缺陷导致葡萄膜黑色素瘤中黑素细胞特性丧失。

BAP1 deficiency causes loss of melanocytic cell identity in uveal melanoma.

作者信息

Matatall Katie A, Agapova Olga A, Onken Michael D, Worley Lori A, Bowcock Anne M, Harbour J William

机构信息

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

出版信息

BMC Cancer. 2013 Aug 5;13:371. doi: 10.1186/1471-2407-13-371.

DOI:10.1186/1471-2407-13-371
PMID:23915344
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3846494/
Abstract

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.

摘要

背景

葡萄膜黑色素瘤是一种具有高度侵袭性且极易发生转移的癌症，但对于这种转移潜能背后的生物学机制却知之甚少。我们最近发现，大多数发生转移的葡萄膜黑色素瘤呈现2类基因表达谱，其肿瘤抑制因子BAP1存在失活突变。本研究旨在探讨BAP1在葡萄膜黑色素瘤进展中的作用。

方法

利用增殖、BrdU掺入、流式细胞术、迁移、侵袭、分化和克隆形成试验，以及在NOD-SCID-γ小鼠体内进行的致瘤性实验，对RNAi介导的BAP1缺失后的葡萄膜黑色素瘤细胞进行研究。

结果

葡萄膜黑色素瘤细胞中BAP1的缺失导致细胞分化丧失和干细胞样特性增加，包括干细胞标志物的表达、自我复制能力增强以及在干细胞条件下生长能力增强。BAP1缺失并未导致增殖、迁移、侵袭或致瘤性增加。

结论

BAP1在葡萄膜黑色素细胞谱系中似乎主要作为分化调节因子发挥作用，缺乏BAP1的细胞表现出干细胞样特性。阐明BAP1缺失的这种效应如何促进转移以及如何通过治疗逆转这种效应将非常重要。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/579c/3846494/249c9f8cb8aa/1471-2407-13-371-7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/579c/3846494/68ed1abe0e93/1471-2407-13-371-1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/579c/3846494/249c9f8cb8aa/1471-2407-13-371-7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/579c/3846494/68ed1abe0e93/1471-2407-13-371-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/579c/3846494/28705bc05cc2/1471-2407-13-371-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/579c/3846494/72cd89a3adfa/1471-2407-13-371-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/579c/3846494/a7efec511006/1471-2407-13-371-4.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/579c/3846494/c9dc3a066291/1471-2407-13-371-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/579c/3846494/249c9f8cb8aa/1471-2407-13-371-7.jpg

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