Sperm associated antigen 9 promotes oncogenic KSHV-encoded interferon regulatory factor-induced cellular transformation and angiogenesis by activating the JNK/VEGFA pathway
Sperm associated antigen 9 promotes oncogenic KSHV-encoded interferon regulatory factor-induced cellular transformation and angiogenesis by activating the JNK/VEGFA pathway
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精子相关抗原 9 通过激活 JNK/VEGFA 途径促进致癌 KSHV 编码的干扰素调节因子诱导的细胞转化和血管生成
DOI：
10.1371/journal.ppat.1008730
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发表时间：
2020-08-01
期刊：
影响因子：
6.7
通讯作者：
Lu, Chun
中科院分区：
文献类型：
--
作者：
Li, Wan;Wang, Fei;Lu, Chun
卡波西肉瘤（Kaposi's sarcoma，KS）是由卡波西肉瘤相关疱疹病毒（Kaposi's sarcoma-associated herpesvirus，KSHV）引起的一种高度血管增生性的内皮细胞播散性肿瘤，常见于艾滋病患者。我们最近已经表明，KSHV编码的病毒干扰素调节因子1（vIRF 1）介导KSHV诱导的细胞运动（PLoS Pathog. 2019年1月30日;15（1）：e1007578）。然而，vIRF 1在KSHV诱导的细胞转化和血管生成中的作用仍然未知。在这里，我们表明，vIRF 1通过上调精子相关抗原9（SPAG 9）促进血管生成，使用两种体内血管生成模型，包括鸡胚绒毛尿囊膜试验（CAM）和小鼠基质胶塞血管生成试验。机制上，vIRF 1与转录因子Lef 1相互作用以促进SPAG 9转录。vIRF 1诱导的SPAG 9促进促分裂原活化蛋白激酶激酶4（MKK 4）与JNK 1/2的相互作用，以增加它们的磷酸化，导致增强的VEGFA表达、血管生成、细胞增殖和迁移。最后，KSHV基因组中ORF-K9的基因缺失消除了KSHV诱导的细胞转化并损害了血管生成。我们的研究结果表明，vIRF 1通过激活JNK/VEGFA信号通路，转录激活SPAG 9的表达，从而促进血管生成和肿瘤发生。这些新的研究结果定义了KSHV诱导SPAG 9/JNK/VEGFA通路的机制，并建立了靶向这一通路治疗KSHV相关cancer.Author总结Kaposi肉瘤相关疱疹病毒（KSHV）编码的病毒干扰素调节因子1（vIRF 1）是KSHV诱导的血管生成和肿瘤发生所必需的，但其潜在机制尚未阐明。精子相关抗原9（SPAG 9）是一种特征性很强的癌蛋白，在多种人类肿瘤中高度表达。然而，SPAG 9是否可以作为KS发展的促进剂还没有调查。在这里，我们揭示了vIRF 1通过与Lef 1形成转录因子复合物来增强SPAG 9的转录。vIRF 1诱导的SPAG 9上调促进促分裂原活化蛋白激酶激酶4（MKK 4）与JNK的相互作用，共同导致增强的JNK磷酸化。JNK通路的激活诱导VEGFA表达，有助于KSHV诱导的细胞转化和血管生成。综上所述，本研究发现了vIRF 1诱导血管生成和肿瘤发生的新机制，揭示了SPAG 9/JNK/VEGFA通路作为KS治疗的潜在靶点。
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 twoin vivoangiogenesis 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 ofORF-K9from KSHV genome abolishes KSHV-induced cellular transformation and impairs angiogenesis. Our results reveal that vIRF1 transcriptionally activatesSPAG9expression 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.Author summary Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded viral interferon regulatory factor 1 (vIRF1) is essential for KSHV-induced angiogenesis and tumorigenesis, but the underlying mechanism has not been elucidated. Sperm associated antigen 9 (SPAG9) is a well-characterized oncoprotein, highly expressed in a variety of human cancer. However, whether SPAG9 could act as a promoter of KS development has not been investigated. Here, we reveal that vIRF1 enhances SPAG9 transcription by forming a transcription factor complex with Lef1. vIRF1-induced SPAG9 upregulation promotes the interaction of mitogen-activated protein kinase kinase 4 (MKK4) with JNK together leading to enhanced JNK phosphorylation. Activation of the JNK pathway induces VEGFA expression, contributing to KSHV-induced cellular transformation and angiogenesis. In summary, this work discovers a novel mechanism of vIRF1 induction of angiogenesis and tumorigenesis, and reveals SPAG9/JNK/VEGFA pathway as a potential target for KS therapy.