KSHV G-protein coupled receptor vGPCR oncogenic signaling upregulation of Cyclooxygenase-2 expression mediates angiogenesis and tumorigenesis in Kaposi's sarcoma.
KSHV G-protein coupled receptor vGPCR oncogenic signaling upregulation of Cyclooxygenase-2 expression mediates angiogenesis and tumorigenesis in Kaposi's sarcoma.
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KSHV G蛋白偶联受体VGPCR致癌信号传导上调环氧酶-2表达在Kaposi的肉瘤中介导血管生成和肿瘤发生。
DOI：
10.1371/journal.ppat.1009006
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发表时间：
2020-10
期刊：
影响因子：
6.7
通讯作者：
Coso OA
中科院分区：
文献类型：
--
作者：
Medina MV;D Agostino A;Ma Q;Eroles P;Cavallin L;Chiozzini C;Sapochnik D;Cymeryng C;Hyjek E;Cesarman E;Naipauer J;Mesri EA;Coso OA
卡波西肉瘤相关疱疹病毒 (KSHV) vGPCR 是一种组成型活性 G 蛋白偶联受体，可破坏增殖和炎症信号通路以诱导卡波西肉瘤中的细胞转化。环氧合酶-2 (COX-2) 是一种炎症介质，在肿瘤血管生成的激活中发挥关键的调节作用。使用两种不同的转化小鼠模型和带有完整 KSHV 基因组的致瘤细胞，包括带有 vGPCR 缺失的基于 KSHV-Bac16 的突变系统，我们证明 vGPCR 上调 COX-2 表达和活性，通过选择性 MAPK 级联传递信号。我们发现，vGPCR 表达会触发信号通路，从而上调 COX-2 水平，这是由于对其基因启动子区域和成熟 mRNA 中控制 mRNA 稳定性的 3'UTR 区域产生双重影响。这两个事件均由 ERK1/2 MAPK 通路信号介导。在 vGPCR 转化细胞中抑制 COX-2 会损害 vGPCR 驱动的血管生成，并且用 COX-2 选择性抑制药物塞来昔布治疗可显着降低肿瘤生长，表明 COX-2 活性对于体内 vGPCR 致癌性至关重要，并表明 COX-2 介导的血管生成可能在 KS 肿瘤发生中发挥作用。这些结果以及 KS 病变中 COX-2 的过度表达，将 COX-2 定义为预防和治疗 KSHV 肿瘤发生的潜在靶标。卡波西肉瘤 (KS) 是最常见的艾滋病相关癌症 (AIDS-KS)。肿瘤起源于感染致癌病毒（KSHV）的细胞。该病毒编码的基因在受感染细胞中表达具有致癌潜力的蛋白质（vGPCR），该蛋白质能够促进细胞转化和血管生成，从而驱动 KS 肿瘤发生。因此，鉴定由 vGPCR 触发的致癌细胞内信号传导机制可能具有治疗意义。环加氧酶-2 (COX-2) 是一种参与肿瘤血管生成的炎症分子，FDA 批准的多种非甾体类抗炎药和特异性抑制剂可以靶向该分子。在这里，我们证明 vGPCR 通过 ERK1/2 依赖性途径上调转录和 mRNA 稳定性来上调 COX-2 活性和表达。我们还利用 KSHV 感染和小鼠模型表明，COX-2 活性对于 vGPCR 血管生成和肿瘤发生至关重要。与 KS 发病机制中的作用一致，我们发现 vGPCR 上调内皮细胞中的 COX-2 活性，这对于通过 vGPCR 上调 VEGF 至关重要，并且它在 AIDS-KS 病变的 KSHV 感染细胞中表达。这些事实表明 COX-2 是卡波西肉瘤中 vGPCR 血管生成开关的分子成分之一，也是化学预防和治疗的潜在靶点。
Kaposi’s sarcoma-associated herpesvirus (KSHV) vGPCR is a constitutively active G protein-coupled receptor that subverts proliferative and inflammatory signaling pathways to induce cell transformation in Kaposi’s sarcoma. Cyclooxygenase-2 (COX-2) is an inflammatory mediator that plays a key regulatory role in the activation of tumor angiogenesis. Using two different transformed mouse models and tumorigenic full KSHV genome-bearing cells, including KSHV-Bac16 based mutant system with a vGPCR deletion, we demostrate that vGPCR upregulates COX-2 expression and activity, signaling through selective MAPK cascades. We show that vGPCR expression triggers signaling pathways that upregulate COX-2 levels due to a dual effect upon both its gene promoter region and, in mature mRNA, the 3’UTR region that control mRNA stability. Both events are mediated by signaling through ERK1/2 MAPK pathway. Inhibition of COX-2 in vGPCR-transformed cells impairs vGPCR-driven angiogenesis and treatment with the COX-2-selective inhibitory drug Celecoxib produces a significant decrease in tumor growth, pointing to COX-2 activity as critical for vGPCR oncogenicity in vivo and indicating that COX-2-mediated angiogenesis could play a role in KS tumorigenesis. These results, along with the overexpression of COX-2 in KS lesions, define COX-2 as a potential target for the prevention and treatment of KSHV-oncogenesis. Kaposi sarcoma (KS) is the most frequent AIDS-related cancer (AIDS-KS). The tumors originate in cells infected with a cancer-causing virus (KSHV). A gene encoded by the virus expresses a protein with oncogenic potential in the infected cells (vGPCR), which has the ability to promote cell transformation and angiogenesis driving KS tumorigenesis. Therefore, the identification of oncogenic intracellular signalling mechanisms triggered by vGPCR could be of therapeutic interest. Cyclooxygenase-2 (COX-2) is an inflammatory molecule involved in tumor angiogenesis that can be targeted by several FDA-approved non-steroidal anti-inflammatory drugs and specific inhibitors. Here, we demonstrate that vGPCR upregulates COX-2 activity and expression through upregulation of transcription and mRNA stability via an ERK1/2 dependent pathway. We also show that COX-2 activity is critical for vGPCR angiogenesis and oncogenesis using KSHV infection and mouse models. Consistent with a role in KS pathogenesis, we found that vGPCR upregulates COX-2 activity in endothelial cells, that it is essential for VEGF upregulation via vGPCR, and that it is expressed in KSHV infected cells of AIDS-KS lesions. These facts point to COX-2 as one of the molecular components of the vGPCR angiogenic switch in Kaposi Sarcoma and a potential target for chemoprevention and therapy.
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影响因子：
5.4
作者：
Corcoran, Jennifer A.;Khaperskyy, Denys A.;McCormick, Craig
通讯作者：
McCormick, Craig
DOI：
10.1042/bj20141100
发表时间：
2015-04-01
期刊：
The Biochemical journal
影响因子：
--
作者：
通讯作者：
--
影响因子：
6.7
作者：
Cavallin LE;Goldschmidt-Clermont P;Mesri EA
通讯作者：
Mesri EA
影响因子：
15.9
作者：
Benjamin, LE;Golijanin, D;Keshet, E
通讯作者：
Keshet, E
DOI：
10.1084/jem.191.3.417
发表时间：
2000-02-07
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Cesarman E;Mesri EA;Gershengorn MC
通讯作者：
Gershengorn MC