The EBV oncogene LMP1 protects lymphoma cells from cell death through the collagen-mediated activation of DDR1
The EBV oncogene LMP1 protects lymphoma cells from cell death through the collagen-mediated activation of DDR1
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DOI：
10.1182/blood-2013-04-499004
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发表时间：
2013-12-19
期刊：
影响因子：
20.3
通讯作者：
Murray, Paul G.
中科院分区：
文献类型：
--
作者：
Cader, Fathima Zumla;Vockerodt, Martina;Murray, Paul G.
霍奇金淋巴瘤的恶性霍奇金和Reed-Sternberg（HRS）细胞被肿瘤微环境包围，所述肿瘤微环境由多种细胞类型以及非细胞组分如胶原组成。尽管HRS细胞在约50%的病例中携带致癌EB病毒（EBV），但尚不清楚肿瘤微环境是否有助于EBV驱动的淋巴瘤发生。我们发现，在原代人生发中心B细胞（HRS细胞的假定祖细胞）中EBV编码的潜伏膜蛋白1（LMP 1）的表达上调盘状结构域受体1（DDR 1），一种由胶原激活的受体酪氨酸激酶。我们还表明，HRS细胞与胶原蛋白密切相关，经常过度表达DDR 1，短期暴露于胶原蛋白足以激活霍奇金淋巴瘤衍生细胞系中的DDR 1。DDR 1的异位表达显著增加了依托泊苷处理后胶原处理的DG 75伯基特淋巴瘤细胞的存活率。相反，敲除DDR 1显著降低胶原处理的L428霍奇金淋巴瘤细胞在没有特异性凋亡刺激的情况下的存活，表明DDR 1也影响基线存活。我们的研究结果确定了胶原蛋白在保护霍奇金淋巴瘤细胞免于凋亡中的一种迄今为止未知的功能，并表明肿瘤微环境在促进EBV的致癌作用中有重要贡献。
The malignant Hodgkin and Reed-Sternberg (HRS) cells of Hodgkin lymphoma are surrounded by a tumor microenvironment that is composed of a variety of cell types, as well as noncellular components such as collagen. Although HRS cells harbor oncogenic Epstein-Barr virus (EBV) in approximately 50% of cases, it is not known if the tumor microenvironment contributes to EBV-driven lymphomagenesis. We show that expression of the EBV-encoded latent membrane protein-1 (LMP1) in primary human germinal center B cells, the presumed progenitors of HRS cells, upregulates discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase activated by collagen. We also show that HRS cells intimately associated with collagen frequently overexpress DDR1 and that short-term exposure to collagen is sufficient to activate DDR1 in Hodgkin lymphoma-derived cell lines. The ectopic expression of DDR1 significantly increased the survival of collagen-treated DG75 Burkitt lymphoma cells, following etoposide treatment. Conversely, knockdown of DDR1 significantly decreased the survival of collagen-treated L428 Hodgkin lymphoma cells in the absence of specific apoptotic stimulus, suggesting that DDR1 also influences baseline survival. Our results identify a hitherto unknown function for collagen in protecting Hodgkin lymphoma cells from apoptosis and suggest an important contribution of the tumor microenvironment in promoting the oncogenic effects of EBV.