Loss of BAP1 Is Associated with Upregulation of the NFkB Pathway and Increased HLA Class I Expression in Uveal Melanoma
Loss of BAP1 Is Associated with Upregulation of the NFkB Pathway and Increased HLA Class I Expression in Uveal Melanoma
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DOI：
10.3390/cancers11081102
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发表时间：
2019-08-01
期刊：
影响因子：
5.2
通讯作者：
Jager, Martine J.
中科院分区：
文献类型：
--
作者：
Souri, Zahra;Wierenga, Annemijn P. A.;Jager, Martine J.
预后不全葡萄膜黑色素瘤（UM）的特征之一是炎症表型，其特征是大量浸润的T细胞和巨噬细胞，以及高HLA I类表达。我们想知道这种炎症是如何调节的，并认为炎症最重要的调节因子之一NFkB通路可能起作用。我们使用Illumina HT12V4阵列分析了64个UM样本中HLA I类及其调控因子和NFkB转录家族成员的表达。免疫组化染色检测HLAⅰ类表达及浸润免疫细胞。通过Affymetrix Nsp阵列获得染色体状态信息。我们的分析表明，NFkB1、NFkB2和RELB的表达与HLA I类表达水平、浸润T细胞和巨噬细胞数量呈正相关，而SPP1和PPAR γ呈负相关。在单体3/ bap1阴性的肿瘤中，NFkB1和NFkB2水平升高，SPP1和PPAR γ水平降低。在非炎症性UM中也是如此，这表明我们的观察不仅涉及浸润的白细胞，还涉及肿瘤细胞本身。我们报道NFkB通路与UM中的炎症和HLA I类表达相关，当BAP1表达缺失时，NFkB通路上调。
One of the characteristics of prognostically infaust uveal melanoma (UM) is an inflammatory phenotype, which is characterized by high numbers of infiltrating T cells and macrophages, and a high HLA Class I expression. We wondered how this inflammation is regulated, and considered that one of the most important regulators of inflammation, the NFkB pathway, might play a role. We analyzed 64 UM samples for expression of HLA Class I, its regulators, and of members of the NFkB transcription family, using an Illumina HT12V4 array. HLA Class I expression and infiltrating immune cells were also determined by immunohistochemical staining. Information was obtained regarding chromosome status by Affymetrix Nsp array. Our analysis shows that expression of NFkB1, NFkB2 and RELB positively correlates with the level of HLA Class I expression and the number of infiltrating T cells and macrophages, while SPP1 and PPAR gamma are negatively correlated. Increased levels of NFkB1 and NFkB2 and decreased levels of SPP1 and PPAR gamma are seen in Monosomy 3/BAP1-negative tumors. This is also the case in non-inflammatory UM, indicating that our observation not only involves infiltrating leukocytes but the tumor cells themselves. We report that the NFkB pathway is associated with inflammation and HLA Class I expression in UM, and is upregulated when BAP1 expression is lost.