A KSHV microRNA enhances viral latency and induces angiogenesis by targeting GRK2 to activate the CXCR2/AKT pathway.
A KSHV microRNA enhances viral latency and induces angiogenesis by targeting GRK2 to activate the CXCR2/AKT pathway.
复制标题
KSHV microRNA 通过靶向 GRK2 激活 CXCR2/AKT 途径来增强病毒潜伏期并诱导血管生成。
DOI：
10.18632/oncotarget.8591
复制
发表时间：
2016-05-31
期刊：
影响因子：
--
通讯作者：
Lu C
中科院分区：
文献类型：
--
作者：
Li W;Jia X;Shen C;Zhang M;Xu J;Shang Y;Zhu K;Hu M;Yan Q;Qin D;Lee MS;Zhu J;Lu H;Krueger BJ;Renne R;Gao SJ;Lu C
卡波西肉瘤相关疱疹病毒 (KSHV) 是卡波西肉瘤 (KS)、原发性渗出性淋巴瘤 (PEL) 和多中心卡斯尔曼病 (MCD) 的病原体。这些恶性肿瘤中的大多数肿瘤细胞都被 KSHV 潜伏感染。因此，病毒潜伏期对于肿瘤的发展和肿瘤相关血管生成的诱导至关重要。 KSHV 编码超过二十种 miRNA，但它们在 KSHV 诱导的血管生成中的作用仍不清楚。我们最近发现 miR-K12-3 (miR-K3) 通过靶向 GRK2/CXCR2/AKT 信号传导促进细胞迁移和侵袭 (PLoS Pathog, 2015;11(9):e1005171)。在这里，我们进一步证明了 miR-K3 及其诱导信号通路在 KSHV 潜伏期和 KSHV 诱导的血管生成中的作用。我们发现miR-K3的过度表达不仅通过抑制病毒裂解复制来促进病毒潜伏期，而且还诱导血管生成。此外，GRK2 的敲低可抑制 KSHV 复制，并通过增强 CXCR2/AKT 信号来增强 KSHV 诱导的血管生成。因此，阻断 CXCR2 或 AKT 会增加 KSHV 复制并减少体内 PEL 细胞诱导的血管生成。最后，从病毒基因组中删除 miR-K3 可减少 KSHV 诱导的血管生成并增加 KSHV 复制。这些发现表明，miR-K3/GRK2/CXCR2/AKT 轴在 KSHV 诱导的血管生成中发挥着重要作用，并促进 KSHV 潜伏期，因此可能是 KSHV 相关恶性肿瘤的潜在治疗靶点。
Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). Most tumor cells in these malignancies are latently infected by KSHV. Thus, viral latency is critical for the development of tumor and induction of tumor-associated angiogenesis. KSHV encodes more than two dozens of miRNAs but their roles in KSHV-induced angiogenesis remains unknown. We have recently shown that miR-K12-3 (miR-K3) promoted cell migration and invasion by targeting GRK2/CXCR2/AKT signaling (PLoS Pathog, 2015;11(9):e1005171). Here, we further demonstrated a role of miR-K3 and its induced signal pathway in KSHV latency and KSHV-induced angiogenesis. We found that overexpression of miR-K3 not only promoted viral latency by inhibiting viral lytic replication, but also induced angiogenesis. Further, knockdown of GRK2 inhibited KSHV replication and enhanced KSHV-induced angiogenesis by enhancing the CXCR2/AKT signals. As a result, blockage of CXCR2 or AKT increased KSHV replication and decreased angiogenesis induced by PEL cells in vivo. Finally, deletion of miR-K3 from viral genome reduced KSHV-induced angiogenesis and increased KSHV replication. These findings indicate that the miR-K3/GRK2/CXCR2/AKT axis plays an essential role in KSHV-induced angiogenesis and promotes KSHV latency, and thus may be a potential therapeutic target of KSHV-associated malignancies.
登录
查看更多内容
影响因子：
64.8
作者：
Cullen, Bryan R.
通讯作者：
Cullen, Bryan R.
影响因子：
10.5
作者：
Hansen, Amy;Henderson, Stephen;Boshoff, Chris
通讯作者：
Boshoff, Chris
影响因子：
4.5
作者：
Grundhoff, A;Sullivan, CS;Ganem, D
通讯作者：
Ganem, D
影响因子：
6.7
作者：
Haecker I;Gay LA;Yang Y;Hu J;Morse AM;McIntyre LM;Renne R
通讯作者：
Renne R
影响因子：
5.4
作者：
Bai, Zhiqiang;Huang, Yufei;Gao, Shou-Jiang
通讯作者：
Gao, Shou-Jiang