KSHV-induced notch components render endothelial and mural cell characteristics and cell survival
KSHV-induced notch components render endothelial and mural cell characteristics and cell survival
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DOI：
10.1182/blood-2009-08-236745
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发表时间：
2010-01-28
期刊：
影响因子：
20.3
通讯作者：
Gill, Parkash S.
中科院分区：
文献类型：
--
作者：
Liu, Ren;Li, Xiuqing;Gill, Parkash S.
卡波西肉瘤相关疱疹病毒（KSHV）感染对于卡波西肉瘤（KS）的发展至关重要。众所周知，Notch 信号传导在 KS 细胞存活和 KSHV 进入裂解期中发挥着关键作用。在当前的研究中，我们试图确定 KSHV 是否调节 Notch 成分。与未感染的淋巴管内皮细胞相比，KSHV 感染的淋巴管内皮细胞显示出受体 Notch3 和 Notch4、Notch 配体 Dll4 和 Jagged1 的诱导，并激活了 Notch 受体。此外，KSHV 诱导内皮前体细胞标记物 (CD133) 和壁细胞标记物（钙调蛋白、结蛋白和平滑肌 α 肌动蛋白）的表达，表明存在去分化和转分化。潜伏期蛋白（LANA、vFLIP）和裂解期蛋白（RTA、vGPCR、病毒白介素-6）的过表达进一步支持了 KSHV 病毒蛋白诱导 Notch 受体（Notch2、Notch3）、配体（Dll1、Dll4、Jagged1）、下游靶标（Hey、Hes）和内皮前体 CD133 的直接调节能力。使用 γ 分泌酶抑制剂和可溶性 Dll4 形式的诱饵蛋白靶向 Notch 通路可抑制 KSHV 转化的内皮细胞系的生长。可溶性 Dll4 在体内对 KS 肿瘤异种移植物也具有高度活性。它抑制肿瘤细胞生长，诱导肿瘤细胞死亡，并减少血管灌注。因此，可溶性 Dll4 是临床研究的候选者。 （血。2010；115：887-895）
Kaposi sarcoma-associated herpesvirus (KSHV) infection is essential to the development of Kaposi sarcoma (KS). Notch signaling is also known to play a pivotal role in KS cell survival and lytic phase entrance of KSHV. In the current study, we sought to determine whether KSHV regulates Notch components. KSHV-infected lymphatic endothelial cells showed induction of receptors Notch3 and Notch4, Notch ligands Dll4 and Jagged1, and activated Notch receptors in contrast to uninfected lymphatic endothelial cells. In addition, KSHV induced the expression of endothelial precursor cell marker (CD133) and mural cell markers (calponin, desmin, and smooth muscle alpha actin), suggesting dedifferentiation and trans-differentiation. Overexpression of latency proteins (LANA, vFLIP) and lytic phase proteins (RTA, vGPCR, viral interleukin-6) further supported the direct regulatory capacity of KSHV viral proteins to induce Notch receptors (Notch2, Notch3), ligands (Dll1, Dll4, Jagged1), downstream targets (Hey, Hes), and endothelial precursor CD133. Targeting Notch pathway with gamma-secretase inhibitor and a decoy protein in the form of soluble Dll4 inhibited growth of KSHV-transformed endothelial cell line. Soluble Dll4 was also highly active in vivo against KS tumor xenograft. It inhibited tumor cell growth, induced tumor cell death, and reduced vessel perfusion. Soluble Dll4 is thus a candidate for clinical investigation. (Blood. 2010;115:887-895)