The SH3BGR/STAT3 Pathway Regulates Cell Migration and Angiogenesis Induced by a Gammaherpesvirus MicroRNA.
The SH3BGR/STAT3 Pathway Regulates Cell Migration and Angiogenesis Induced by a Gammaherpesvirus MicroRNA.
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SH3BGR/STAT3 通路调节伽马疱疹病毒 MicroRNA 诱导的细胞迁移和血管生成
DOI：
10.1371/journal.ppat.1005605
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发表时间：
2016-04
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：
Li W;Yan Q;Ding X;Shen C;Hu M;Zhu Y;Qin D;Lu H;Krueger BJ;Renne R;Gao SJ;Lu C
卡波西肉瘤（KS）相关疱疹病毒（KSHV）是一种γ疱疹病毒，与KS，一种高度扩散的过度增殖的梭形内皮细胞的血管生成性肿瘤的病因相关。KSHV编码25种成熟microRNA，但它们在KSHV诱导的肿瘤播散和血管生成中的作用仍不清楚。在这里，我们研究了KSHV编码的miR-K12-6- 3 p（miR-K6- 3 p）促进内皮细胞迁移和血管生成，这是肿瘤扩散和血管生成的潜在机制。我们发现miR-K6- 3 p的异位表达促进了内皮细胞的迁移和血管生成。质谱、生物信息学和荧光素酶报告基因分析表明，miR-K6- 3 p直接靶向SH 3结构域结合谷氨酸丰富蛋白（SH 3BGR）的3'非翻译区（UTR）序列。SH 3BGR的过表达逆转了miR-K6- 3 p诱导的细胞迁移和血管生成。从机制上讲，miR-K6- 3 p下调SH 3BGR，从而使STAT 3从SH 3BGR直接结合和抑制中解脱出来，这是miR-K6- 3 p最大程度激活STAT 3以及诱导细胞迁移和血管生成所必需的。最后，从KSHV基因组中删除miR-K6消除了其对SH 3BGR/STAT 3途径以及KSHV诱导的迁移和血管生成的作用。我们的研究结果表明，通过抑制SH 3BGR，miR-K6- 3 p通过激活STAT 3途径增强细胞迁移和血管生成，从而有助于KSHV诱导的恶性肿瘤的传播和血管生成。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，KS）感染引起的一种以血管生成和侵袭性为特征的内皮细胞肿瘤。在体外，KSHV感染的内皮细胞显示出增加的侵袭性和血管生成性。KSHV编码12种前体miRNAs（pre-miRNAs），其被加工成至少25种成熟miRNAs。然而，这些miRNAs在KSHV诱导的肿瘤扩散和血管生成中的作用仍然未知。在这里，我们研究了KSHV编码的miR-K12-6- 3 p（miR-K6- 3 p）促进内皮细胞迁移和血管生成，这是肿瘤扩散和血管生成的潜在机制。我们证明了miR-K6- 3 p通过直接靶向SH 3结构域结合富含谷氨酸蛋白（SH 3BGR）促进细胞迁移和血管生成。此外，我们发现，STAT 3，这是负调控SH 3BGR介导的miR-K6- 3 p诱导的细胞迁移和血管生成。MiR-K6- 3 p下调SH 3BGR，从而减轻SH 3BGR对STAT 3的直接抑制，导致STAT 3的活化和诱导细胞迁移和血管生成。这些结果鉴定了miR-K6- 3 p及其下游途径作为治疗KSHV相关恶性肿瘤的潜在治疗靶点。
Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV) is a gammaherpesvirus etiologically associated with KS, a highly disseminated angiogenic tumor of hyperproliferative spindle endothelial cells. KSHV encodes 25 mature microRNAs but their roles in KSHV-induced tumor dissemination and angiogenesis remain unknown. Here, we investigated KSHV-encoded miR-K12-6-3p (miR-K6-3p) promotion of endothelial cell migration and angiogenesis, which are the underlying mechanisms of tumor dissemination and angiogenesis. We found that ectopic expression of miR-K6-3p promoted endothelial cell migration and angiogenesis. Mass spectrometry, bioinformatics and luciferase reporter analyses revealed that miR-K6-3p directly targeted sequence in the 3’ untranslated region (UTR) of SH3 domain binding glutamate-rich protein (SH3BGR). Overexpression of SH3BGR reversed miR-K6-3p induction of cell migration and angiogenesis. Mechanistically, miR-K6-3p downregulated SH3BGR, hence relieved STAT3 from SH3BGR direct binding and inhibition, which was required for miR-K6-3p maximum activation of STAT3 and induction of cell migration and angiogenesis. Finally, deletion of miR-K6 from the KSHV genome abrogated its effect on the SH3BGR/STAT3 pathway, and KSHV-induced migration and angiogenesis. Our results illustrated that, by inhibiting SH3BGR, miR-K6-3p enhances cell migration and angiogenesis by activating the STAT3 pathway, and thus contributes to the dissemination and angiogenesis of KSHV-induced malignancies. Kaposi’s Sarcoma (KS), caused by infection of Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV), is a tumor of endothelial cells characterized by angiogenesis and invasiveness. In vitro, KSHV-infected endothelial cells display an increased invasiveness and angiogenicity. KSHV encodes twelve precursor miRNAs (pre-miRNAs), which are processed into at least 25 mature miRNAs. However, the roles of these miRNAs in KSHV-induced tumor dissemination and angiogenesis remain unknown. Here, we investigated KSHV-encoded miR-K12-6-3p (miR-K6-3p) promotion of endothelial cell migration and angiogenesis, which are the underlying mechanisms of tumor dissemination and angiogenesis. We demonstrated that miR-K6-3p promoted cell migration and angiogenesis by directly targeting SH3 domain binding glutamate-rich protein (SH3BGR). Furthermore, we found that STAT3, which was negatively regulated by SH3BGR mediated miR-K6-3p-induced cell migration and angiogenesis. MiR-K6-3p downregulation of SH3BGR, hence relieved SH3BGR direct inhibition of STAT3 resulting in the activation of STAT3 and induction of cell migration and angiogenesis. These results identify miR-K6-3p and its the downstream pathway as potential therapeutic targets for the treatment of KSHV-associated malignancies.