MiRNA-891a-5p mediates HIV-1 Tat and KSHV Orf-K1 synergistic induction of angiogenesis by activating NF-κB signaling.
MiRNA-891a-5p mediates HIV-1 Tat and KSHV Orf-K1 synergistic induction of angiogenesis by activating NF-κB signaling.
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MiRNA-891a-5p 通过激活 NF-kappaB 信号传导介导 HIV-1 Tat 和 KSHV Orf-K1 协同诱导血管生成。
DOI：
10.1093/nar/gkv988
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发表时间：
2015-10-30
影响因子：
14.9
通讯作者：
Lu C
中科院分区：
文献类型：
--
作者：
Yao S;Hu M;Hao T;Li W;Xue X;Xue M;Zhu X;Zhou F;Qin D;Yan Q;Zhu J;Gao SJ;Lu C
HIV-1和卡波西肉瘤相关疱疹病毒（KSHV）的共同感染是以异常血管生成为特征的侵袭性艾滋病相关卡波西肉瘤（AIDS-KS）的原因。HIV-1和KSHV相互作用对AIDS-KS发病机制和广泛血管生成的影响仍不清楚。在此，我们探讨了HIV-1达特和KSHV癌基因Orf-K1对血管生成的协同作用。我们的研究结果表明，可溶性达特或异位表达达特增强K1诱导的细胞增殖，微管形成和血管生成的绒毛尿囊膜和裸鼠模型。机制研究表明，达特通过增强NF-κB信号通路促进K1诱导的血管生成。在机制上，我们发现达特与K1协同诱导miR-891 a-5 p的表达，其直接靶向IκBα 3′非翻译区，导致NF-κB活化。因此，抑制miR-891 a-5 p可增加IκBα水平，阻止NF-κB p65核转位，并最终抑制达特和K1诱导的血管生成的协同作用。我们的研究结果表明，通过靶向IκBα激活NF-κB通路，miR-891 a-5 p介导达特和K1协同诱导血管生成。因此，miR-891 a-5 p/NF-κB通路在AIDS-KS的发病机制中起重要作用，有望成为AIDS-KS治疗的新靶点。
Co-infection with HIV-1 and Kaposi's sarcoma-associated herpesvirus (KSHV) is the cause of aggressive AIDS-related Kaposi's sarcoma (AIDS-KS) characterized by abnormal angiogenesis. The impact of HIV-1 and KSHV interaction on the pathogenesis and extensive angiogenesis of AIDS-KS remains unclear. Here, we explored the synergistic effect of HIV-1 Tat and KSHV oncogene Orf-K1 on angiogenesis. Our results showed that soluble Tat or ectopic expression of Tat enhanced K1-induced cell proliferation, microtubule formation and angiogenesis in chorioallantoic membrane and nude mice models. Mechanistic studies revealed that Tat promoted K1-induced angiogenesis by enhancing NF-κB signaling. Mechanistically, we showed that Tat synergized with K1 to induce the expression of miR-891a-5p, which directly targeted IκBα 3′ untranslated region, leading to NF-κB activation. Consequently, inhibition of miR-891a-5p increased IκBα level, prevented nuclear translocation of NF-κB p65 and ultimately suppressed the synergistic effect of Tat- and K1-induced angiogenesis. Our results illustrate that, by targeting IκBα to activate the NF-κB pathway, miR-891a-5p mediates Tat and K1 synergistic induction of angiogenesis. Therefore, the miR-891a-5p/NF-κB pathway is important in the pathogenesis of AIDS-KS, which could be an attractive therapeutic target for AIDS-KS.