Cancer Research UK Viral Oncology Group, University College London Cancer Institute, University College London, London WC1E 6BT, United Kingdom.
Genes Dev. 2010 Jan 15;24(2):195-205. doi: 10.1101/gad.553410.
Kaposi sarcoma herpesvirus (KSHV) induces transcriptional reprogramming of endothelial cells. In particular, KSHV-infected lymphatic endothelial cells (LECs) show an up-regulation of genes associated with blood vessel endothelial cells (BECs). Consequently, KSHV-infected tumor cells in Kaposi sarcoma are poorly differentiated endothelial cells, expressing markers of both LECs and BECs. MicroRNAs (miRNAs) are short noncoding RNA molecules that act post-transcriptionally to negatively regulate gene expression. Here we validate expression of the KSHV-encoded miRNAs in Kaposi sarcoma lesions and demonstrate that these miRNAs contribute to viral-induced reprogramming by silencing the cellular transcription factor MAF (musculoaponeurotic fibrosarcoma oncogene homolog). MAF is expressed in LECs but not in BECs. We identify a novel role for MAF as a transcriptional repressor, preventing expression of BEC-specific genes, thereby maintaining the differentiation status of LECs. These findings demonstrate that viral miRNAs could influence the differentiation status of infected cells, and thereby contribute to KSHV-induced oncogenesis.
卡波西肉瘤疱疹病毒（KSHV）诱导内皮细胞的转录重编程。具体而言，KSHV 感染的淋巴管内皮细胞（LEC）表现出与血管内皮细胞（BEC）相关的基因上调。因此，卡波西肉瘤中的 KSHV 感染肿瘤细胞是分化不良的内皮细胞，表达 LEC 和 BEC 的标志物。微小 RNA（miRNA）是短的非编码 RNA 分子，通过转录后作用负调控基因表达。在这里，我们验证了 KSHV 编码的 miRNA 在卡波西肉瘤病变中的表达，并证明这些 miRNA 通过沉默细胞转录因子 MAF（肌动蛋白-aponeurotic 纤维肉瘤癌基因同源物）来促进病毒诱导的重编程。MAF 在 LEC 中表达，但不在 BEC 中表达。我们确定了 MAF 的一个新作用，作为转录抑制因子，防止 BEC 特异性基因的表达，从而维持 LEC 的分化状态。这些发现表明病毒 miRNA 可能影响感染细胞的分化状态，并因此有助于 KSHV 诱导的肿瘤发生。
