Di Bartolo Daniel L, Cannon Mark, Liu Yi-Fang, Renne Rolf, Chadburn Amy, Boshoff Chris, Cesarman Ethel
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10021, USA.
Blood. 2008 May 1;111(9):4731-40. doi: 10.1182/blood-2007-09-110544. Epub 2008 Jan 16.
Signaling through the transforming growth factor-beta (TGF-beta) pathway results in growth inhibition and induction of apoptosis in various cell types. We show that this pathway is blocked in Kaposi sarcoma herpesvirus (KSHV)-infected primary effusion lymphoma through down-regulation of the TGF-beta type II receptor (TbetaRII) by epigenetic mechanisms. Our data also suggest that KSHV infection may result in lower expression of TbetaRII in Kaposi sarcoma and multicentric Castleman disease. KSHV-encoded LANA associates with the promoter of TbetaRII and leads to its methylation and to the deacetylation of proximal histones. Reestablishment of signaling through this pathway reduces viability of these cells, inferring that KSHV-mediated blockage of TGF-beta signaling plays a role in the establishment and progression of KSHV-associated neoplasia. These data suggest a mechanism whereby KSHV evades both the antiproliferative effects of TGF-beta signaling by silencing TbetaRII gene expression and immune recognition by suppressing TGF-beta-responsive immune cells through the elevated secretion of TGF-beta1.
通过转化生长因子-β（TGF-β）信号通路可导致多种细胞类型的生长抑制和凋亡诱导。我们发现，在卡波西肉瘤疱疹病毒（KSHV）感染的原发性渗出性淋巴瘤中，该信号通路通过表观遗传机制下调II型TGF-β受体（TβRII）而被阻断。我们的数据还表明，KSHV感染可能导致卡波西肉瘤和多中心Castleman病中TβRII的表达降低。KSHV编码的LANA与TβRII的启动子结合，导致其甲基化以及近端组蛋白的去乙酰化。通过该信号通路重新建立信号传导会降低这些细胞的活力，这表明KSHV介导的TGF-β信号传导阻断在KSHV相关肿瘤的发生和发展中起作用。这些数据提示了一种机制，即KSHV通过沉默TβRII基因表达逃避TGF-β信号传导的抗增殖作用，并通过升高TGF-β1的分泌抑制TGF-β反应性免疫细胞来逃避免疫识别。
