Brouwer Niels J, Wierenga Annemijn P A, Gezgin Gülçin, Marinkovic Marina, Luyten Gregorius P M, Kroes Wilma G M, Versluis Mieke, van der Velden Pieter A, Verdijk Robert M, Jager Martine J
Department of Ophthalmology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Cancers (Basel). 2019 Jul 18;11(7):1004. doi: 10.3390/cancers11071004.
Hypoxia-inducible factor 1-alpha (HIF1a) and its regulator von Hippel-Lindau protein (VHL) play an important role in tumour ischemia. Currently, drugs that target HIF1a are being developed to treat malignancies. Although HIF1a is known to be expressed in uveal melanoma (UM), it is as yet unknown which factors, such as tumour size or genetics, determine its expression. Therefore, we aimed to determine which tumour characteristics relate to HIF1a expression in UM. Data from 64 patients who were enucleated for UM were analysed. Messenger RNA (mRNA) expression was determined with the Illumina HT-12 v4 chip. In 54 cases, the status of chromosomes 3 and 8q, and -associated protein 1 (BAP1) protein expression (immunohistochemistry) were determined. Findings were corroborated using data of 80 patients from the Cancer Genome Atlas (TCGA) study. A significantly increased expression of HIF1a, and a decreased expression of VHL were associated with monosomy 3/loss of BAP1 expression. The relationship between BAP1 loss and HIF1a expression was independent of chromosome 3. The largest basal diameter and tumour thickness showed no relationship with HIF1a. HIF1a expression related to an increased presence of infiltrating T cells and macrophages. From this study, we conclude that HIF1a is strongly related to tumour genetics in UM, especially to loss of BAP1 expression, and less to tumour size. Tumour ischemia is furthermore related to the presence of an inflammatory phenotype.
缺氧诱导因子1α（HIF1α）及其调节因子冯·希佩尔-林道蛋白（VHL）在肿瘤缺血中起重要作用。目前，针对HIF1α的药物正在研发用于治疗恶性肿瘤。尽管已知HIF1α在葡萄膜黑色素瘤（UM）中表达，但尚不清楚哪些因素，如肿瘤大小或遗传学因素，决定其表达。因此，我们旨在确定UM中哪些肿瘤特征与HIF1α表达相关。分析了64例因UM而眼球摘除患者的数据。使用Illumina HT-12 v4芯片测定信使核糖核酸（mRNA）表达。在54例病例中，确定了3号和8q染色体状态以及相关蛋白1（BAP1）蛋白表达（免疫组织化学）。使用来自癌症基因组图谱（TCGA）研究的80例患者的数据证实了研究结果。HIF1α表达显著增加以及VHL表达降低与3号染色体单体性/BAP1表达缺失相关。BAP1缺失与HIF1α表达之间的关系独立于3号染色体。最大基底直径和肿瘤厚度与HIF1α无相关性。HIF1α表达与浸润性T细胞和巨噬细胞数量增加相关。从本研究中，我们得出结论，HIF1α在UM中与肿瘤遗传学密切相关，尤其是与BAP1表达缺失相关，而与肿瘤大小关系较小。此外，肿瘤缺血与炎症表型的存在相关。
