Role of heme oxygenase-1 in the pathogenesis and tumorigenicity of Kaposi's sarcoma-associated herpesvirus.
Role of heme oxygenase-1 in the pathogenesis and tumorigenicity of Kaposi's sarcoma-associated herpesvirus.
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血红素加氧酶-1在卡波西肉瘤相关疱疹病毒发病机制和致瘤性中的作用
DOI：
10.18632/oncotarget.7227
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发表时间：
2016-03-01
期刊：
影响因子：
--
通讯作者：
Qin Z
中科院分区：
文献类型：
--
作者：
Dai L;Qiao J;Nguyen D;Struckhoff AP;Doyle L;Bonstaff K;Del Valle L;Parsons C;Toole BP;Renne R;Qin Z
卡波西肉瘤相关疱疹病毒（KSHV）是包括卡波西肉瘤（KS）在内的几种恶性肿瘤的病原体，其优先出现在免疫功能低下的患者（如HIV+亚群）中，缺乏有效的治疗选择。血红素氧合酶-1（HO-1）是内皮细胞周期调控、增殖和血管生成的重要调节因子。HO-1也被发现在KSHV感染的内皮细胞和口腔AIDS-KS病变中高度表达。我们以前证明，多功能糖蛋白CD 147是KSHV/LANA诱导的内皮细胞侵袭所必需的。在通过微阵列分析鉴定CD 147控制的下游基因的过程中，我们发现与对照细胞相比，在CD 147过表达和KSHV感染的HUVEC细胞中HO-1的表达显著升高。在目前的研究中，我们进一步确定了HO-1的表达和介导的细胞功能的CD 147和KSHV编码的拉娜蛋白的调节。通过RNAi或化学抑制剂SnPP靶向HO-1，通过DNA损伤和坏死过程有效地诱导KSHV感染的内皮细胞（KS的主要细胞组分）的细胞死亡。通过使用KS样裸鼠模型，我们发现SnPP治疗显著抑制KSHV诱导的体内肿瘤发生。综上所述，我们的数据表明HO-1在KSHV感染的内皮细胞的发病机制和肿瘤发生中的重要作用，HO-1表达的潜在调控机制和HO-1的靶向可能代表了一种有前途的治疗策略，针对KSHV相关的恶性肿瘤。
Kaposi's Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several malignancies, including Kaposi's Sarcoma (KS), which preferentially arise in immunocompromised patients such as HIV+ subpopulation and lack effective therapeutic options. Heme oxygenase-1 (HO-1) has been reported as an important regulator of endothelial cell cycle control, proliferation and angiogenesis. HO-1 has also been found to be highly expressed in KSHV-infected endothelial cells and oral AIDS-KS lesions. We previously demonstrate that the multifunctional glycoprotein CD147 is required for KSHV/LANA-induced endothelial cell invasiveness. During the identification of CD147 controlled downstream genes by microarray analysis, we found that the expression of HO-1 is significantly elevated in both CD147-overexpressing and KSHV-infected HUVEC cells when compared to control cells. In the current study, we further identify the regulation of HO-1 expression and mediated cellular functions by both CD147 and KSHV-encoded LANA proteins. Targeting HO-1 by either RNAi or the chemical inhibitor, SnPP, effectively induces cell death of KSHV-infected endothelial cells (the major cellular components of KS) through DNA damage and necrosis process. By using a KS-like nude mouse model, we found that SnPP treatment significantly suppressed KSHV-induced tumorigenesis in vivo. Taken together, our data demonstrate the important role of HO-1 in the pathogenesis and tumorigenesis of KSHV-infected endothelial cells, the underlying regulatory mechanisms for HO-1 expression and targeting HO-1 may represent a promising therapeutic strategy against KSHV-related malignancies.