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首页> 外文期刊>Nucleic Acids Research >HIV-1 Nef and KSHV oncogene K1 synergistically promote angiogenesis by inducing cellular miR-718 to regulate the PTEN/AKT/mTOR signaling pathway
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HIV-1 Nef and KSHV oncogene K1 synergistically promote angiogenesis by inducing cellular miR-718 to regulate the PTEN/AKT/mTOR signaling pathway

机译：HIV-1 Nef和KSHV癌基因K1通过诱导细胞miR-718调节PTEN / AKT / mTOR信号通路来协同促进血管生成

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摘要

Kaposi's sarcoma (KS) is an AIDS-defining cancer with aberrant neovascularization caused by KS-associated herpesvirus (KSHV). Although the interaction between HIV-1 and KSHV plays a pivotal role in promoting the aggressive manifestations of KS, the pathogenesis underlying AIDS-KS remains largely unknown. Here we examined HIV-1 Nef protein promotion of KSHV oncoprotein K1-induced angiogenesis. We showed that both internalized and ectopic expression of Nef in endothelial cells synergized with K1 to facilitate vascular tube formation and cell proliferation, and enhance angiogenesis in a chicken CAM model. In vivo experiments further indicated that Nef accelerated K1-induced angiogenesis and tumorigenesis in athymic nuu mice. Mechanistic studies revealed that Nef and K1 synergistically activated PI3K/AKT/mTOR signaling by downregulating PTEN. Furthermore, Nef and K1 induced cellular miR-718, which inhibited PTEN expression by directly targeting a seed sequence in the 3' UTR of its mRNA. Inhibition of miR-718 expression increased PTEN synthesis and suppressed the synergistic effect of Nef- and K1-induced angiogenesis and tumorigenesis. These results indicate that, by targeting PTEN, miR-718 mediates Nef- and K1-induced angiogenesis via activation of AKT/mTOR signaling. Our results demonstrate an essential role of miR-718/AKT/mTOR axis in AIDS-KS and thus may represent an attractive therapeutic target.
机译：卡波西氏肉瘤（KS）是一种由艾滋病相关的疱疹病毒（KSHV）引起的新血管化异常的艾滋病定义癌症。尽管HIV-1和KSHV之间的相互作用在促进KS的侵袭性表现中起着关键作用，但AIDS-KS的发病机理仍是未知之数。在这里，我们检查了KSHV癌蛋白K1诱导的血管生成的HIV-1 Nef蛋白促进作用。我们表明，在与K1协同作用的内皮细胞中，Nef的内在表达和异位表达均可促进血管形成和细胞增殖，并增强鸡CAM模型中的血管生成。体内实验进一步表明，Nef促进了无胸腺nu / nu小鼠中K1诱导的血管生成和肿瘤发生。机理研究表明，Nef和K1通过下调PTEN协同激活PI3K / AKT / mTOR信号传导。此外，Nef和K1诱导了细胞miR-718，该细胞通过直接靶向其mRNA 3'UTR中的种子序列来抑制PTEN表达。抑制miR-718表达可增加PTEN合成，并抑制Nef和K1诱导的血管生成和肿瘤发生的协同作用。这些结果表明，通过靶向PTEN，miR-718通过激活AKT / mTOR信号传导介导Nef和K1诱导的血管生成。我们的结果证明了miR-718 / AKT / mTOR轴在AIDS-KS中的重要作用，因此可能代表了有吸引力的治疗靶标。

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