Department of Microbiology, Nanjing Medical University, Nanjing, People's Republic of China.
Department of Gynecology, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Hospital, Nanjing Medical University, Nanjing, People's Republic of China.
PLoS Pathog. 2020 Aug 10;16(8):e1008730. doi: 10.1371/journal.ppat.1008730. eCollection 2020 Aug.
Kaposi's sarcoma (KS), caused by Kaposi's sarcoma-associated herpesvirus (KSHV), is a highly angioproliferative disseminated tumor of endothelial cells commonly found in AIDS patients. We have recently shown that KSHV-encoded viral interferon regulatory factor 1 (vIRF1) mediates KSHV-induced cell motility (PLoS Pathog. 2019 Jan 30;15(1):e1007578). However, the role of vIRF1 in KSHV-induced cellular transformation and angiogenesis remains unknown. Here, we show that vIRF1 promotes angiogenesis by upregulating sperm associated antigen 9 (SPAG9) using two in vivo angiogenesis models including the chick chorioallantoic membrane assay (CAM) and the matrigel plug angiogenesis assay in mice. Mechanistically, vIRF1 interacts with transcription factor Lef1 to promote SPAG9 transcription. vIRF1-induced SPAG9 promotes the interaction of mitogen-activated protein kinase kinase 4 (MKK4) with JNK1/2 to increase their phosphorylation, resulting in enhanced VEGFA expression, angiogenesis, cell proliferation and migration. Finally, genetic deletion of ORF-K9 from KSHV genome abolishes KSHV-induced cellular transformation and impairs angiogenesis. Our results reveal that vIRF1 transcriptionally activates SPAG9 expression to promote angiogenesis and tumorigenesis via activating JNK/VEGFA signaling. These novel findings define the mechanism of KSHV induction of the SPAG9/JNK/VEGFA pathway and establish the scientific basis for targeting this pathway for treating KSHV-associated cancers.
卡波氏肉瘤（KS）是由卡波氏肉瘤相关疱疹病毒（KSHV）引起的，是一种常见于艾滋病患者的高度血管增生性播散性内皮细胞肿瘤。我们最近表明，KSHV 编码的病毒干扰素调节因子 1（vIRF1）介导 KSHV 诱导的细胞迁移（PLoS Pathog. 2019 Jan 30;15(1):e1007578）。然而，vIRF1 在 KSHV 诱导的细胞转化和血管生成中的作用尚不清楚。在这里，我们通过两种体内血管生成模型，包括鸡胚绒毛尿囊膜（CAM）和小鼠基质胶塞血管生成试验，显示 vIRF1 通过上调精子相关抗原 9（SPAG9）促进血管生成。在机制上，vIRF1 与转录因子 Lef1 相互作用，促进 SPAG9 的转录。vIRF1 诱导的 SPAG9 促进丝裂原活化蛋白激酶激酶 4（MKK4）与 JNK1/2 的相互作用，增加它们的磷酸化，从而增强 VEGFA 的表达、血管生成、细胞增殖和迁移。最后，从 KSHV 基因组中删除 ORF-K9 可消除 KSHV 诱导的细胞转化并损害血管生成。我们的研究结果表明，vIRF1 通过激活 JNK/VEGFA 信号转导转录激活 SPAG9 的表达，从而促进血管生成和肿瘤发生。这些新发现定义了 KSHV 诱导 SPAG9/JNK/VEGFA 通路的机制，并为靶向该通路治疗 KSHV 相关癌症奠定了科学基础。
