Kaposi's sarcoma-associated herpesvirus-encoded interleukin-6 and G-protein-coupled receptor regulate angiopoletin-2 expression in lymphatic endothelial cells
Kaposi's sarcoma-associated herpesvirus-encoded interleukin-6 and G-protein-coupled receptor regulate angiopoletin-2 expression in lymphatic endothelial cells
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DOI：
10.1158/0008-5472.can-06-3321
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发表时间：
2007-05-01
期刊：
影响因子：
11.2
通讯作者：
Boshoff, Chris
中科院分区：
文献类型：
--
作者：
Vart, Richard J.;Nikitenko, Leonid L.;Boshoff, Chris
卡波西肉瘤（Kaposi's sarcoma，KS）是由卡波西肉瘤相关疱疹病毒（Kaposi's sarcoma-associated herpesvirus，KSHV）引起的一种恶性肿瘤，由与淋巴管内皮细胞（lymphatic endothelial cell，LEC）相关的增殖梭形细胞组成。血管生成素-2（Ang 2）是一种分泌的促血管生成和淋巴管生成分子。在这里，我们显示了Ang 2蛋白在KS中的表达，并证实KSHV感染上调LEC中的Ang 2。我们发现，旁分泌机制有助于这种上调。构建了单个KSHV编码基因的慢病毒文库，包括大多数已知的潜伏基因和一系列裂解病毒基因，以研究这种上调的潜在机制。两个裂解基因，病毒白细胞介素6（vIL 6）和病毒G蛋白偶联受体（vGPCR），上调血管生成素2在LEC中的表达。vIL 6和vGPCR在KSHV感染的LEC中表达，并以旁分泌方式引起Ang 2的上调。KSHV、vIL 6和vGPCR通过丝裂原活化蛋白激酶（MAPK）途径上调Ang 2。基因表达微阵列分析确定了其他几种受KSHV影响的血管生成分子，包括血管内皮生长因子（VEGF）/VEGF受体（VEGFR）轴，这也受到LEC中vIL 6和vGPCR的影响，以及基质金属蛋白酶，这可能与Ang 2协同作用，促进KS的发展。这些研究结果支持的旁分泌和自分泌作用的裂解KSHV编码的蛋白质，vIL 6和vGPCR，在KS发病机制，并确定Ang 2作为一个潜在的治疗靶点，这种肿瘤。
Kaposi's sarcoma (KS) is caused by Kaposi's sarcoma-associated herpesvirus (KSHV) and consists of proliferating spindle cells, which are related to lymphatic endothelial cells (LEC). Angiopoietin-2 (Ang2) is a secreted proangiogenic and lymphangiogenic molecule. Here, we show the expression of Ang2 protein in KS and confirm that KSHV infection upregulates Ang2 in LEC. We show that a paracrine mechanism contributes to this up-regulation. A lentiviral library of individual KSHV-encoding genes, comprising the majority of known latent genes and a selection of lytic viral genes, was constructed to investigate the underlying mechanism of this up-regulation. Two lytic genes, viral interleukin-6 (vIL6) and viral G-protein-coupled receptor (vGPCR), up-regulated Ang2 expression in LEC. Both vIL6 and vGPCR are expressed in KSHV-infected LEC and caused up-regulation of Ang2 in a paracrine manner. KSHV, vIL6, and vGPCR up-regulated Ang2 through the mitogen-activated protein kinase (MAPK) pathway. Gene expression microarray analysis identified several other angiogenic molecules affected by KSHV, including the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis, which is also affected by vIL6 and vGPCR in LEC, and matrix metalloproteinases, which could act in concert with Ang2 to contribute to KS development. These findings support the paracrine and autocrine roles of the lytic KSHV-encoded proteins, vIL6 and vGPCR, in KS pathogenesis and identify Ang2 as a potential therapeutic target for this neoplasm.