Bridgewater Hannah E, Date Kathryn L, O'Neil John D, Hu Chunfang, Arrand John R, Dawson Christopher W, Young Lawrence S
Warwick Medical School, Gibbet Hill Campus, University of Warwick, Coventry CV4 7AL, UK.
Institute for Cancer & Genomic Sciences, College of Medicine & Dentistry, University of Birmingham, Birmingham B15 2TT, UK.
Pathogens. 2020 Jul 21;9(7):594. doi: 10.3390/pathogens9070594.
The Epstein-Barr virus (EBV)-encoded nuclear antigen 1 (EBNA1) protein is expressed in all virus-associated malignancies, where it performs an essential role in the maintenance, replication and transcription of the EBV genome. In recent years, it has become apparent that EBNA1 can also influence cellular gene transcription. Here, we demonstrate that EBNA1 is able to stimulate the expression of the Transforming growth factor-beta (TGFβ) superfamily member, bone morphogenic protein 2 (BMP2), with consequential activation of the BMP signalling pathway in carcinoma cell lines. We show that BMP pathway activation is associated with an increase in the migratory capacity of carcinoma cells, an effect that can be ablated by the BMP antagonist, Noggin. Gene expression profiling of authentic EBV-positive nasopharyngeal carcinoma (NPC) tumours revealed the consistent presence of BMP ligands, established BMP pathway effectors and putative target genes, constituting a prominent BMP "signature" in this virus-associated cancer. Our findings show that EBNA1 is the major viral-encoded protein responsible for activating the BMP signalling pathway in carcinoma cells and supports a role for this pathway in promoting cell migration and possibly, metastatic spread.
爱泼斯坦-巴尔病毒（EBV）编码的核抗原1（EBNA1）蛋白在所有与病毒相关的恶性肿瘤中均有表达，它在EBV基因组的维持、复制和转录中发挥着至关重要的作用。近年来，越来越明显的是，EBNA1也能影响细胞基因转录。在此，我们证明EBNA1能够刺激转化生长因子-β（TGFβ）超家族成员骨形态发生蛋白2（BMP2）的表达，进而激活癌细胞系中的BMP信号通路。我们发现BMP通路激活与癌细胞迁移能力的增强有关，这种效应可被BMP拮抗剂Noggin消除。对真正的EBV阳性鼻咽癌（NPC）肿瘤进行基因表达谱分析，发现始终存在BMP配体、已确定的BMP通路效应器和推定的靶基因，在这种与病毒相关的癌症中构成了显著的BMP“特征”。我们的研究结果表明，EBNA1是负责激活癌细胞中BMP信号通路的主要病毒编码蛋白，并支持该通路在促进细胞迁移以及可能的转移扩散中发挥作用。
