Abstract
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.
Highlights
Kaposi’s sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus associated with AIDS-associated Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman’s disease (MCD) [1]
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
We demonstrated that miR-K6-3p promoted cell migration and angiogenesis by directly targeting SH3 domain binding glutamate-rich protein (SH3BGR)
Summary
Kaposi’s sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus associated with AIDS-associated Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman’s disease (MCD) [1]. KS is an angiogenic vascular tumor of endothelial spindle cells [2]. Skin lesions are a common manifestation of KS, KS is a highly disseminated tumor often observed as multifocal lesions and in visceral organs. In KS lesions, the majority of the spindle tumor cells are latently infected by KSHV; a small number of them undergo spontaneous lytic replication. Lytic replication generates infectious virions for spreading to other cells and at the same time produces virus-encoded cytokines as well as induces cellular cytokines through viral lytic proteins or de novo viral infection, all of which could contribute to KS pathogenesis by promoting KS angiogenesis, inflammatory infiltration and tumor dissemination through autocrine and paracrine mechanisms [8]
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