CircRNA ARFGEF1 functions as a ceRNA to promote oncogenic KSHV-encoded viral interferon regulatory factor induction of cell invasion and angiogenesis by upregulating glutaredoxin 3.
CircRNA ARFGEF1 functions as a ceRNA to promote oncogenic KSHV-encoded viral interferon regulatory factor induction of cell invasion and angiogenesis by upregulating glutaredoxin 3.
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CircRNA ARFGEF1 作为 ceRNA 发挥作用，通过上调谷氧还蛋白 3 促进致癌 KSHV 编码的病毒干扰素调节因子诱导细胞侵袭和血管生成
DOI：
10.1371/journal.ppat.1009294
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发表时间：
2021-03
期刊：
影响因子：
6.7
通讯作者：
Lu C
中科院分区：
文献类型：
--
作者：
Yao S;Jia X;Wang F;Sheng L;Song P;Cao Y;Shi H;Fan W;Ding X;Gao SJ;Lu C
环状rna （circRNAs）是一种新型单链非编码rna，可以诱骗其他rna抑制其功能。卡波西肉瘤（KS）是一种高度血管生成和侵袭性血管肿瘤，常见于艾滋病患者，由致癌的卡波西肉瘤相关疱疹病毒（KSHV）引起。我们最近的研究表明，kshv编码的病毒干扰素调节因子1 （vIRF1）诱导细胞侵袭、血管生成和细胞转化；然而，circrna在KSHV vIRF1中的作用在很大程度上是未知的。在此，转录组分析鉴定了内皮细胞系中受vIRF1调控的22个差异表达的细胞环状rna。其中circARFGEF1是上调幅度最大的circRNA。在机制上，vIRF1通过结合转录因子淋巴增强子结合因子1 （Lef1）诱导circARFGEF1转录。重要的是，circARFGEF1的上调是virf1诱导的细胞运动、增殖和体内血管生成所必需的。circARFGEF1通过结合并诱导miR-125a-3p的降解而作为一种竞争性内源性rna （ceRNAs）发挥作用。质谱分析表明，glutaredoxin 3 （GLRX3）是miR-125a-3p的直接靶点。GLRX3基因敲低会损害vIRF1诱导的细胞运动、增殖和血管生成。综上所述，vIRF1转录激活circARFGEF1，可能通过与Lef1结合，通过抑制miR-125a-3p和诱导GLRX3来促进细胞致癌表型。这些发现定义了virf1诱导肿瘤发生的新机制，并为靶向这些分子治疗kshv相关癌症奠定了科学基础。卡波西氏肉瘤相关疱疹病毒（KSHV）是卡波西氏肉瘤（KS）的病因，这种肉瘤经常发生在艾滋病患者身上。我们和其他人已经证明，kshv编码的病毒干扰素调节因子1 （vIRF1）在kshv诱导的癌症发病机制中起着至关重要的作用。KSHV基因组转录病毒环状rna (circRNAs)，然而，细胞环状rna在virf1诱导的肿瘤发生中的作用仍然未知。CircRNAs作为miRNAs的竞争性内源性rna (ceRNAs)，通过调控miRNA-mRNA网络影响mRNA的稳定性和蛋白表达。我们发现vIRF1与亲本基因ARFGEF1的启动子结合，并通过与转录因子淋巴增强子结合因子1 （Lef1）的相互作用激活circARFGEF1的转录。CircARFGEF1通过结合并诱导miR-125a-3p的降解来发挥ceRNA的作用，从而消除了该miRNA对其直接靶向GLRX3的抑制作用。值得注意的是，circARFGEF1/miR-125a-3p/GLRX3轴是vIRF1诱导细胞运动、增殖和体内血管生成所必需的。总之，我们的研究描述了kshv通过病毒致癌基因劫持宿主环状rna诱导肿瘤发生的新机制。
Circular RNAs (circRNAs) are novel single-stranded noncoding RNAs that can decoy other RNAs to inhibit their functions. Kaposi’s sarcoma (KS), caused by oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV), is a highly angiogenic and invasive vascular tumor of endothelial origin commonly found in AIDS patients. We have recently shown that KSHV-encoded viral interferon regulatory factor 1 (vIRF1) induces cell invasion, angiogenesis and cellular transformation; however, the role of circRNAs is largely unknown in the context of KSHV vIRF1. Herein, transcriptome analysis identified 22 differentially expressed cellular circRNAs regulated by vIRF1 in an endothelial cell line. Among them, circARFGEF1 was the highest upregulated circRNA. Mechanistically, vIRF1 induced circARFGEF1 transcription by binding to transcription factor lymphoid enhancer binding factor 1 (Lef1). Importantly, upregulation of circARFGEF1 was required for vIRF1-induced cell motility, proliferation and in vivo angiogenesis. circARFGEF1 functioned as a competing endogenous RNAs (ceRNAs) by binding to and inducing degradation of miR-125a-3p. Mass spectrometry analysis demonstrated that glutaredoxin 3 (GLRX3) was a direct target of miR-125a-3p. Knockdown of GLRX3 impaired cell motility, proliferation and angiogenesis induced by vIRF1. Taken together, vIRF1 transcriptionally activates circARFGEF1, potentially by binding to Lef1, to promote cell oncogenic phenotypes via inhibiting miR-125a-3p and inducing GLRX3. These findings define a novel mechanism responsible for vIRF1-induced oncogenesis and establish the scientific basis for targeting these molecules for treating KSHV-associated cancers. Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi’s sarcoma (KS), which frequently occurs in people with AIDS. We and others had proved that KSHV-encoded viral interferon regulatory factor 1 (vIRF1) was crucial in the pathogenesis of KSHV-induced cancers. KSHV genome transcribes viral circular RNAs (circRNAs), however, the role of cellular circRNAs in vIRF1-induced tumorigenesis remains unknown. CircRNAs serves as competitive endogenous RNAs (ceRNAs) of miRNAs, thus regulating miRNA-mRNA network to influence mRNA stability and protein expression. Here we found that vIRF1 binds to the promoter of the parental gene ARFGEF1 and activate circARFGEF1 transcription through interaction with transcription factor lymphoid enhancer binding factor 1 (Lef1). CircARFGEF1 functioned as a ceRNA by binding to and inducing degradation of miR-125a-3p, thereby abrogating the inhibition effect of this miRNA on its direct targeting of GLRX3. Significantly, circARFGEF1/miR-125a-3p/GLRX3 axis was required for vIRF1 induction of cell motility, proliferation and in vivo angiogenesis. In summary, our study describes a novel mechanism of KSHV-induced oncogenesis by hijacking host circRNAs through a viral oncogene.
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影响因子：
8
作者：
Gao, SJ;Boshoff, C;Moore, PS
通讯作者：
Moore, PS
影响因子：
3.4
作者：
Chu, Ping;Xu, Lina;Su, Haiying
通讯作者：
Su, Haiying
PinX1 通过 mir-125a-3p/VEGF 信号通路抑制肾癌血管生成
影响因子：
9.8
作者：
Hou, Pingfu;Li, Hailong;Bai, Jin
通讯作者：
Bai, Jin
DOI：
10.1261/rna.047126.114
发表时间：
2014-12
期刊：
RNA (New York, N.Y.)
影响因子：
--
作者：
Lasda E;Parker R
通讯作者：
Parker R
影响因子：
5.4
作者：
Brulois, Kevin F.;Chang, Heesoon;Jung, Jae U.
通讯作者：
Jung, Jae U.