KSHV Regulation of Fibulin-2 in Kaposi's Sarcoma Implications for Tumorigenesis
KSHV Regulation of Fibulin-2 in Kaposi's Sarcoma Implications for Tumorigenesis
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DOI：
10.1016/j.ajpath.2011.05.024
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发表时间：
2011-09-01
影响因子：
6
通讯作者：
Hayward, Gary S.
中科院分区：
文献类型：
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作者：
Alcendor, Donald J.;Knobel, Susan;Hayward, Gary S.
卡波西肉瘤是一种血管增生性肿瘤，由卡波西肉瘤相关疱疹病毒（KSHV）感染血管内皮细胞引起。纤维蛋白，与细胞外基质（ECM）蛋白相关的蛋白质，可能具有肿瘤抑制和致癌活性。我们发现，fibulin-2蛋白和mRNA的表达下降了50倍和26倍，分别在10天的KSHV感染的真皮微血管内皮细胞（DMVEC）。使用定量RT-PCR，我们发现了5倍和25倍的减少纤蛋白2细胞外基质结合伴侣，纤连蛋白和弹性蛋白原，分别。10天的时间过程转录分析表明，除了fibulin-2，在KSHV感染的DMVEC中，fibulin 3和5的表达降低，fibulin 1C/1D增加，fibulin 4，6和7不变。KSHV潜伏相关核抗原（拉娜）转录水平在同一时期持续上升。添加重组fibulin-3或-5 48小时，以10天的KSHV感染的细胞引起抑制KSHV诱导的血管内皮生长因子（VEGF）的蛋白和mRNA水平。重组fibulin-3也显著降低VEGF受体3的表达。在胸腔积液淋巴瘤细胞系中，表达不同水平的KSHV裂解复制，我们观察到没有可检测到的fibulin-2或-5的表达。最后，与患者非肿瘤对照组相比，来自KSHV感染的LANA阳性患者细胞的组织微阵列中的fibulin-2表达降低。了解KSHV和纤维蛋白之间的相互作用可能会导致开发新的治疗卡波西肉瘤的疗法。(Am J Pathol 2011，179：1443-1454; DOI：10.1016/j.ajpath.2011.05.024）。
Kaposi's sarcoma is an angioproliferative tumor caused by Kaposi's sarcoma-associated herpesvirus (KSHV) infection of vascular endothelial cells. Fibufins, proteins that associate with extracellular matrix (ECM) proteins, may have both tumor-suppressive and oncogenic activities. We found that the expression of fibulin-2 protein and mRNA were decreased 50-fold and 26-fold, respectively, in 10-day KSHV-infected dermal microvascular endothelial cells (DMVEC). Using quantitative RT-PCR, we found a fivefold and 25-fold decrease of fibulin-2 extracellular matrix binding partners, fibronectin and tropoelastin, respectively. Time-course transcriptional analyses over 10 days showed that in addition to that of fibulin-2, expression of fibulins 3 and 5 was decreased in KSHV-infected DMVEC, fibulins 1C/1D were increased, and fibulins 4, 6, and 7 were unchanged. KSHV latency-associated nuclear antigen (LANA) transcription levels rose consistently over the same period. Addition of recombinant fibulin-3 or -5 for 48 hours to 10-day KSHV-infected cells caused a suppression of KSHV-induced vascular endothelial growth factor (VEGF) protein and mRNA levels. Recombinant fibulin-3 also significantly reduced VEGF receptor 3 expression. In pleural effusion lymphoma cell lines that express variable levels of KSHV lytic replication, we observed no detectable fibulin-2 or -5 expression. Finally, fibulin-2 expression was decreased in tissue microarrays from KSHV-infected, LANA-positive patient cells as compared to that in patient nontumor controls. Understanding the interactions between KSHV and the fibulins may lead to the development of novel therapies for treatment of Kaposi's sarcoma. (Am J Pathol 2011, 179:1443-1454; DOI: 10.1016/j.ajpath.2011.05.024).