Kaposi's sarcoma associated herpes virus (KSHV) induced COX-2: a key factor in latency, inflammation, angiogenesis, cell survival and invasion.
Kaposi's sarcoma associated herpes virus (KSHV) induced COX-2: a key factor in latency, inflammation, angiogenesis, cell survival and invasion.
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DOI：
10.1371/journal.ppat.1000777
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发表时间：
2010-02-12
期刊：
影响因子：
6.7
通讯作者：
Chandran B
中科院分区：
文献类型：
--
作者：
Sharma-Walia N;Paul AG;Bottero V;Sadagopan S;Veettil MV;Kerur N;Chandran B
Kaposi's sarcoma (KS), an enigmatic endothelial cell vascular neoplasm, is characterized by the proliferation of spindle shaped endothelial cells, inflammatory cytokines (ICs), growth factors (GFs) and angiogenic factors. KSHV is etiologically linked to KS and expresses its latent genes in KS lesion endothelial cells. Primary infection of human micro vascular endothelial cells (HMVEC-d) results in the establishment of latent infection and reprogramming of host genes, and cyclooxygenase-2 (COX-2) is one of the highly up-regulated genes. Our previous study suggested a role for COX-2 in the establishment and maintenance of KSHV latency. Here, we examined the role of COX-2 in the induction of ICs, GFs, angiogenesis and invasive events occurring during KSHV de novo infection of endothelial cells. A significant amount of COX-2 was detected in KS tissue sections. Telomerase-immortalized human umbilical vein endothelial cells supporting KSHV stable latency (TIVE-LTC) expressed elevated levels of functional COX-2 and microsomal PGE2 synthase (m-PGES), and secreted the predominant eicosanoid inflammatory metabolite PGE2. Infected HMVEC-d and TIVE-LTC cells secreted a variety of ICs, GFs, angiogenic factors and matrix metalloproteinases (MMPs), which were significantly abrogated by COX-2 inhibition either by chemical inhibitors or by siRNA. The ability of these factors to induce tube formation of uninfected endothelial cells was also inhibited. PGE2, secreted early during KSHV infection, profoundly increased the adhesion of uninfected endothelial cells to fibronectin by activating the small G protein Rac1. COX-2 inhibition considerably reduced KSHV latent ORF73 gene expression and survival of TIVE-LTC cells. Collectively, these studies underscore the pivotal role of KSHV induced COX-2/PGE2 in creating KS lesion like microenvironment during de novo infection. Since COX-2 plays multiple roles in KSHV latent gene expression, which themselves are powerful mediators of cytokine induction, anti-apoptosis, cell survival and viral genome maintainence, effective inhibition of COX-2 via well-characterized clinically approved COX-2 inhibitors could potentially be used in treatment to control latent KSHV infection and ameliorate KS. Kaposi's sarcoma associated herpes virus (KSHV), with a 160 kb DNA genome, has evolved with two distinct life cycle phases, namely latency and lytic replication. KS, a complex angioproliferative disease, is regulated by a balance between pro-angiogenic and anti-angiogenic factors. In our previous study, we showed that KSHV modulates host factors COX-2/PGE2 for its own advantage to promote its latent (persistent) infection. The premise that COX-2 is involved in growth and progression of several types of solid cancers and inflammation associated diseases has been well documented but has never been studied in KS. Here, utilizing COX-2 inhibition strategies, including chemical inhibition and a gene silencing approach, we systematically identified the potential role of KSHV induced COX-2/PGE2 in viral pathogenesis related events such as secretion of inflammatory and angiogenic cytokines, MMPs and cell adhesion in de novo infected or latently infected endothelial cells. We report that COX-2/PGE2 inhibition down-regulates viral latent gene expression and survival of latently infected endothelial cells. The data emanating from our in vitro studies is valuable, informative and requires further examination using an in vitro angiogenic model and in vivo nude mice model to further validate COX-2 as a novel therapeutic to target latent infection and the associated diseases like KS.
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影响因子：
4.7
作者：
Erkanli, Serkan;Bolat, Filiz;Kuscu, Esra
通讯作者：
Kuscu, Esra
影响因子：
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DOI：
10.1073/pnas.96.8.4546
发表时间：
1999-04-13
影响因子：
11.1
作者：
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通讯作者：
Boshoff, C
影响因子：
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作者：
Blackbourn, DJ;Lennette, E;Levy, JA
通讯作者：
Levy, JA