Guo Hong-Guang, Sadowska Mariola, Reid William, Tschachler Erwin, Hayward Gary, Reitz Marvin
Institute of Human Virology, University of Maryland Biotechnology Institute, 725 W. Lombard Street, Baltimore, MD 21201, USA.
J Virol. 2003 Feb;77(4):2631-9. doi: 10.1128/jvi.77.4.2631-2639.2003.
The product of human herpesvirus 8 (HHV-8) open reading frame 74 (ORF74) is related structurally and functionally to cellular chemokine receptors. ORF74 activates several cellular signaling pathways in the absence of added ligands, and NIH 3T3 cells expressing ORF74 are tumorigenic in nude mice. We have generated a line of transgenic (Tg) mice with ORF74 driven by the simian virus 40 early promoter. A minority (approximately 30%) of the Tg mice, including the founder, developed tumors resembling Kaposi's sarcoma (KS) lesions, which occurred most typically on the tail or legs. The tumors were highly vascularized, had a spindle cell component, expressed VEGF-C mRNA, and contained a majority of CD31(+) cells. CD31 and VEGF-C are typically expressed in KS. Tumors generally (but not always) occurred at single sites and most were relatively indolent, although several mice developed large visceral tumors. ORF74 was expressed in a minority of cells in the Tg tumors and in a few other tissues of mice with tumors; mice without tumors did not express detectable ORF74 in any tissues tested. Cell lines established from tumors expressed ORF74 in a majority of cells, expressed VEGF-C mRNA, and were tumorigenic in nude mice. The resultant tumors grew rapidly, metastasized, and continued to express ORF74. Cell lines established from these secondary tumors also expressed ORF74 and were tumorigenic. These data strongly suggest that ORF74 plays a role in the pathology of KS and confirm and extend previous findings on the tumorigenic potential of ORF74.
人类疱疹病毒8型（HHV - 8）开放阅读框74（ORF74）的产物在结构和功能上与细胞趋化因子受体相关。在没有添加配体的情况下，ORF74可激活多种细胞信号通路，并且表达ORF74的NIH 3T3细胞在裸鼠中具有致瘤性。我们构建了一系列由猿猴病毒40早期启动子驱动ORF74的转基因（Tg）小鼠。少数（约30%）Tg小鼠，包括奠基鼠，发生了类似于卡波西肉瘤（KS）损害的肿瘤，最常见于尾巴或腿部。这些肿瘤血管高度丰富，有梭形细胞成分，表达VEGF - C mRNA，并且含有大部分CD31(+)细胞。CD31和VEGF - C通常在KS中表达。肿瘤一般（但并非总是）发生在单个部位，大多数相对生长缓慢，尽管有几只小鼠发生了大的内脏肿瘤。ORF74在Tg肿瘤的少数细胞以及有肿瘤的小鼠的其他一些组织中表达；无肿瘤的小鼠在任何测试组织中均未检测到可表达的ORF74。从肿瘤建立的细胞系在大多数细胞中表达ORF74，表达VEGF - C mRNA，并且在裸鼠中具有致瘤性。产生的肿瘤生长迅速、发生转移，并持续表达ORF74。从这些继发性肿瘤建立的细胞系也表达ORF74并且具有致瘤性。这些数据有力地表明ORF74在KS的病理过程中起作用，并证实和扩展了先前关于ORF74致瘤潜力的研究结果。
