Gene regulation and functional alterations induced by Kaposi's sarcoma-associated herpesvirus-encoded ORFK13/vFLIP in endothelial cells.
Gene regulation and functional alterations induced by Kaposi's sarcoma-associated herpesvirus-encoded ORFK13/vFLIP in endothelial cells.
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内皮细胞中卡波西肉瘤相关疱疹病毒编码的 ORFK13/vFLIP 诱导的基因调控和功能改变。
DOI：
10.1128/jvi.01871-08
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发表时间：
2009
影响因子：
5.4
通讯作者：
Tosato,Giovanna
中科院分区：
文献类型：
--
作者：
Sakakibara,Shuhei;Pise-Masison,CynthiaA;Brady,JohnN;Tosato,Giovanna
卡波西肉瘤（Kaposi's sarcoma，KS）是由KS相关疱疹病毒（KSHV）感染内皮细胞引起的血管增生性炎症性疾病，ORFK 13/vFLIP是KS中表达的KSHV基因之一，编码一个188个氨基酸的蛋白，可与IκB激酶（IKK）复合物结合，激活NF-κB。我们研究了ORFK 13/vFLIP对KS表型的贡献和治疗靶向的潜力。ORFK 13/vFLIP逆转录病毒转导入原代人内皮细胞诱导KS细胞特有的梭形形态，并促进KS血管系统典型的异常血管网络的形成;上调促炎细胞因子、趋化因子和干扰素应答基因的表达;并刺激KS病变特征性炎性细胞的粘附。胸苷磷酸化酶（Thymidine phosphorylase，TPK）是一种由ORFK 13/vFLIP诱导的细胞内酶，可将前体药物5-氟-5-脱氧尿苷（5-dFUrd）代谢为5-氟尿苷（5-fluouridine，5-FU），后者是一种有效的胸苷合成酶抑制剂，可阻断DNA和RNA的合成。当进行细胞毒性测试时，5-dFUrd（0.1至1 μM）选择性地杀死表达ORFK 13/vFLIP的内皮细胞，而不杀死对照细胞。这些结果表明，ORFK 13/vFLIP直接和间接有助于KS的炎症和血管表型，并确定5-dFUrd作为一种潜在的新药物，靶向KSHV潜伏期治疗KS和其他KSHV相关的恶性肿瘤。
Kaposi's sarcoma (KS) is an angioproliferative inflammatory disorder induced by endothelial cell infection with the KS-associated herpesvirus (KSHV).ORFK13/vFLIP, one of the KSHV genes expressed in KS, encodes a 188-amino-acid protein which binds to the Iκb kinase (IKK) complex to activate NF-κB. We examinedORFK13/vFLIPcontribution to KS phenotype and potential for therapeutic targeting. Retroviral transduction ofORFK13/vFLIPinto primary human endothelial cells induces the spindle morphology distinctive of KS cells and promotes the formation of abnormal vascular networks typical of KS vasculature; upregulates the expression of proinflammatory cytokines, chemokines, and interferon-responsive genes; and stimulates the adhesion of inflammatory cells characteristic of KS lesions. Thymidine phosphorylase, a cellular enzyme markedly induced byORFK13/vFLIP, can metabolize the prodrug 5-fluoro-5-deoxyuridine (5-dFUrd) to 5-fluouridine (5-FU), a potent thymidine synthase inhibitor, which blocks DNA and RNA synthesis. When tested for cytotoxicity, 5-dFUrd (0.1 to 1 μM) selectively killedORFK13/vFLIP-expressing endothelial cells while sparing control cells. These results demonstrate thatORFK13/vFLIPdirectly and indirectly contributes to the inflammatory and vascular phenotype of KS and identify 5-dFUrd as a potential new drug that targets KSHV latency for the treatment of KS and other KSHV-associated malignancies.