A viral microRNA downregulates metastasis suppressor CD82 and induces cell invasion and angiogenesis by activating the c-Met signaling.
A viral microRNA downregulates metastasis suppressor CD82 and induces cell invasion and angiogenesis by activating the c-Met signaling.
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病毒 microRNA 下调转移抑制因子 CD82，并通过激活 c-Met 信号传导诱导细胞侵袭和血管生成
作者：
Li W;Hu M;Wang C;Lu H;Chen F;Xu J;Shang Y;Wang F;Qin J;Yan Q;Krueger BJ;Renne R;Gao SJ;Lu C
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）引起的最常见的艾滋病相关恶性肿瘤。KS是一种高度播散和血管化的肿瘤，由低分化的梭形内皮细胞组成。KSHV编码12种前体microRNA（pre-miRNAs），产生25种成熟的miRNAs，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。KSHV编码的miR-K12-6（miR-K6）可产生两种成熟的miR-K6- 3 p和miR-K6- 5 p。最近，我们发现miR-K6- 3 p通过直接靶向SH 3结构域结合富含谷氨酸的蛋白（SH 3BGR）来促进细胞迁移和血管生成（PLoS Pathog. 2016;12（4）：e1005605）。在此，通过质谱、生物信息学分析和荧光素酶报告基因分析，我们发现miR-K6- 5 p直接靶向转移抑制分子CD 82的编码序列（CDS）。miR-K6- 5 p的异位表达可特异性抑制内源性CD 82的表达，并在体外强烈促进内皮细胞的侵袭和在体内促进血管生成。过表达CD 82可显著抑制miR-K6- 5 p诱导的细胞侵袭和血管生成。在机制上，CD 82直接与c-Met相互作用以抑制其活化。MiR-K6- 5 p直接抑制CD 82，解除其对c-Met活化的抑制并诱导细胞侵袭和血管生成。从KSHV基因组中删除miR-K6消除了KSHV对CD 82的抑制，导致KSHV对c-Met途径的活化受损，以及KSHV诱导的侵袭和血管生成。总之，这些结果表明，通过抑制CD 82，KSHV miR-K6- 5 p通过激活c-Met途径促进细胞侵袭和血管生成。我们的研究结果表明，KSHV miRNA可能在KSHV诱导的恶性肿瘤的传播和血管生成中发挥重要作用。
Kaposi’s sarcoma (KS) is the most common AIDS-associated malignancy etiologically caused by Kaposi’s sarcoma-associated herpesvirus (KSHV). KS is a highly disseminated and vascularized tumor comprised of poorly differentiated spindle-shaped endothelial cells. KSHV encodes 12 pre-microRNAs (pre-miRNAs) that yield 25 mature miRNAs, but their roles in KSHV-induced tumor dissemination and angiogenesis remain largely unknown. KSHV-encoded miR-K12-6 (miR-K6) can produce two mature miRNAs, miR-K6-3p and miR-K6-5p. Recently, we have shown that miR-K6-3p promoted cell migration and angiogenesis by directly targeting SH3 domain binding glutamate-rich protein (SH3BGR) (PLoS Pathog. 2016;12(4):e1005605). Here, by using mass spectrometry, bioinformatics analysis and luciferase reporter assay, we showed that miR-K6-5p directly targeted the coding sequence (CDS) of CD82 molecule (CD82), a metastasis suppressor. Ectopic expression of miR-K6-5p specifically inhibited the expression of endogenous CD82 and strongly promoted endothelial cells invasion in vitro and angiogenesis in vivo. Overexpression of CD82 significantly inhibited cell invasion and angiogenesis induced by miR-K6-5p. Mechanistically, CD82 directly interacted with c-Met to inhibit its activation. MiR-K6-5p directly repressed CD82, relieving its inhibition on c-Met activation and inducing cell invasion and angiogenesis. Deletion of miR-K6 from KSHV genome abrogated KSHV suppression of CD82 resulting in compromised KSHV activation of c-Met pathway, and KSHV-induced invasion and angiogenesis. In conclusion, these results show that by inhibiting CD82, KSHV miR-K6-5p promotes cell invasion and angiogenesis by activating the c-Met pathway. Our findings illustrate that KSHV miRNAs may play an essential role in the dissemination and angiogenesis of KSHV-induced malignancies.
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