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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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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,


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, (click to view)

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,

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Oncogene 2017 05 2236(38) 5407-5420 doi 10.1038/onc.2017.139

Abstract

Kaposi’s sarcoma (KS) as the most common AIDS-associated malignancy is etiologically caused by KS-associated herpesvirus (KSHV). KS is a highly disseminated and vascularized tumor. KSHV encodes 12 pre-microRNAs that yield 25 mature microRNAs (miRNAs), but their roles in KSHV-induced tumor metastasis and angiogenesis remain largely unclear. KSHV-encoded miR-K12-6 (miR-K6) can generate two mature miRNAs, miR-K6-5p and miR-K6-3p. Recently, we have shown that miR-K6-3p induced cell migration and angiogenesis via directly targeting SH3 domain binding glutamate-rich protein (SH3BGR). Here, by using mass spectrometry, bioinformatics analysis and luciferase reporter assay, we showed that miR-K6-5p directly targeted the coding sequence 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 and angiogenesis. 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. Lack of miR-K6 abrogated KSHV suppression of CD82 resulting in compromised KSHV activation of c-Met pathway, and KSHV induction of cell invasion and angiogenesis. In conclusion, our data show that by reducing CD82, KSHV miR-K6-5p expedites cell invasion and angiogenesis by activating the c-Met pathway. Our findings illustrate that KSHV miRNAs may be critical for the dissemination and angiogenesis of KSHV-induced malignant tumors.

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