Kaposi's sarcoma-associated herpesvirus G-protein coupled receptor activates the canonical Wnt/β-catenin signaling pathway.
Kaposi's sarcoma-associated herpesvirus G-protein coupled receptor activates the canonical Wnt/β-catenin signaling pathway.
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DOI：
10.1186/s12985-014-0218-8
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发表时间：
2014-12-17
期刊：
影响因子：
4.8
通讯作者：
Sullivan DE
中科院分区：
文献类型：
--
作者：
Angelova M;Ferris M;Swan KF;McFerrin HE;Pridjian G;Morris CA;Sullivan DE
KSHV是一种致瘤性γ-疱疹病毒，已被确定为卡波西肉瘤（KS）的病因，卡波西肉瘤是一种多灶性高度血管化的肿瘤，是与获得性免疫缺陷综合征（艾滋病）相关的最常见的恶性肿瘤。该病毒编码一种组成型活性趋化因子受体同源物，vGPCR，具有强大的血管生成和致瘤特性，对KSHV病理生物学至关重要。迄今为止，许多信号通路已被确定为介导vGPCR致癌潜力的关键。在这项研究中，我们发现了一个新的途径，即Wnt/β-catenin途径，该途径在内皮细胞中被vGPCR表达失调。内皮细胞中vGPCR的表达增强了β-catenin的细胞核积累，这与β-catenin转录活性的增加有关。通过vGPCR激活β-catenin信号通路依赖于PI3K/Akt通路，因为用PI3K药理抑制剂处理表达vGPCR的细胞，导致β-catenin驱动的报告基因激活降低，β-catenin靶基因表达显著降低，内皮管形成减少。鉴于Wnt/β-catenin信号在血管生成和肿瘤发生中的关键作用，本研究的发现提示了kshv诱导恶性肿瘤的新机制。本文的在线版本（doi:10.1186/s12985-014-0218-8）包含补充材料，可供授权用户使用。
KSHV is a tumorigenic γ-herpesvirus that has been identified as the etiologic agent of Kaposi’s sarcoma (KS), a multifocal highly vascularized neoplasm that is the most common malignancy associated with acquired immunodeficiency syndrome (AIDS). The virus encodes a constitutively active chemokine receptor homologue, vGPCR that possesses potent angiogenic and tumorigenic properties, and is critical for KSHV pathobiology. To date, a number of signaling pathways have been identified as key in mediating vGPCR oncogenic potential. In this study, we identify a novel pathway, the Wnt/β-catenin pathway, which is dysregulated by vGPCR expression in endothelial cells. Expression of vGPCR in endothelial cells enhances the nuclear accumulation of β-catenin, that correlates with an increase in β-catenin transcriptional activity. Activation of β-catenin signaling by vGPCR is dependent on the PI3K/Akt pathway, as treatment of vGPCR-expressing cells with a pharmacological inhibitor of PI3K, leads to a decreased activation of a β-catenin-driven reporter, a significant decrease in expression of β-catenin target genes, and reduced endothelial tube formation. Given the critical role of Wnt/β-catenin signaling in angiogenesis and tumorigenesis, the findings from this study suggest a novel mechanism in KSHV-induced malignancies. The online version of this article (doi:10.1186/s12985-014-0218-8) contains supplementary material, which is available to authorized users.
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影响因子：
11.2
作者：
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影响因子：
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作者：
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