Human Immunodeficiency Virus Type 1 Tat Accelerates Kaposi Sarcoma-Associated Herpesvirus Kaposin A-Mediated Tumorigenesis of Transformed Fibroblasts In Vitro as well as in Nude and Immunocompetent Mice
Human Immunodeficiency Virus Type 1 Tat Accelerates Kaposi Sarcoma-Associated Herpesvirus Kaposin A-Mediated Tumorigenesis of Transformed Fibroblasts In Vitro as well as in Nude and Immunocompetent Mice
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人类免疫缺陷病毒 1 型 Tat 加速卡波西肉瘤相关疱疹病毒卡波辛 A 介导的体外转化成纤维细胞以及裸鼠和免疫功能正常小鼠的肿瘤发生
DOI：
10.1593/neo.09494
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发表时间：
2009-12-01
期刊：
影响因子：
4.8
通讯作者：
Lu, Chun
中科院分区：
文献类型：
--
作者：
Chen, Xiuying;Cheng, Lin;Lu, Chun
Kaposi肉瘤相关疱疹病毒(KSHV)是引起Kaposi肉瘤(KS)的必要条件，但不是充分条件。与人类免疫缺陷病毒1型(HIV-1)混合感染，在没有抗逆转录病毒抑制治疗的情况下，极大地增加了KS的风险。此前，我们发现HIV-1反式激活转录蛋白(TAT)是激活KSHV裂解周期复制的重要辅因子。在这里，我们进一步研究了TAT影响KSHV Kaposin A诱导肿瘤发生的可能性，KSHV Kaposin A是KSHV的产物，由KSHV的开放阅读框架K12(KSHV转化基因)编码。通过软琼脂集落形成、H-3-TdR掺入、细胞周期和微阵列基因表达分析，我们证明TAT增强了Kaposin A诱导的NIH3T3细胞的增殖和丝裂原激活的蛋白激酶、信号转导和转录激活因子3以及磷脂酰肌醇3-激酶/蛋白激酶B信号转导。动物实验进一步证明，TAT可加速Kaposin A对裸鼠的致瘤作用。从裸鼠原发肿瘤中获得的细胞成功地在免疫活性小鼠体内诱导肿瘤。这些数据表明，TAT可以加速Kaposin A诱导的肿瘤形成。我们的数据为TAT可能通过与Kaposin A在获得性免疫缺陷综合征(AIDS)相关KS(AIDS-KS)患者中的协同作用而参与KS的发病提供了第一线证据。我们的数据还表明，Kaposin和TAT介导的致癌模型将有助于我们从分子水平上理解AIDS-KS的发病机制，甚至可能对探索AIDS-KS的新治疗方法具有重要意义。
Kaposi sarcoma-associated herpesvirus (KSHV) is necessary but not sufficient to cause Kaposi sarcoma (KS). Coinfection with human immunodeficiency virus type 1 (HIV-1), in the absence of antiretroviral suppressive therapy, drastically increases the risk of KS. Previously, we identified that HIV-1 transactivative transcription protein (Tat) was an important cofactor that activated lytic cycle replication of KSHV. Here, we further investigated the potential of Tat to influence tumorigenesis induced by KSHV Kaposin A, a product of KSHV that was encoded by the open reading frame K12 (a KSHV-transforming gene). By using colony formation in soft agar, H-3-TdR incorporation, cell cycle, and microarray gene expression analyses, we demonstrated that Tat enhanced proliferation as well as mitogen-activated protein kinase, signal transducer and activator of transcription 3, and phosphatidylinositol 3-kinase/protein kinase B signaling induced by Kaposin A in NIH3T3 cells. Animal experiments further demonstrated that Tat accelerated tumorigenesis by Kaposin A in athymic nu/nu mice. Cells obtained from primary tumors of nude mice succeeded inducing tumors in immunocompetent mice. These data suggest that Tat can accelerate tumorigenesis induced by Kaposin A. Our data present the first line of evidence that Tat may participate in KS pathogenesis by collaborating with Kaposin A in acquired immunodeficiency syndrome (AIDS)-related KS (AIDS-KS) patients. Our data also suggest that the model for Kaposin and Tat-mediated oncogenesis will contribute to our understanding of the pathogenesis of AIDS-KS at the molecular level and may even be important in exploring a novel therapeutic method for AIDS-KS.