Abstract
Kaposi’s sarcoma (KS), a highly disseminated tumor of hyperproliferative spindle endothelial cells, is the most common AIDS-associated malignancy caused by infection of Kaposi’s sarcoma-associated herpesvirus (KSHV). KSHV-encoded viral interferon regulatory factor 1 (vIRF1) is a viral oncogene but its role in KSHV-induced tumor invasiveness and motility remains unknown. Here, we report that vIRF1 promotes endothelial cell migration, invasion and proliferation by down-regulating miR-218-5p to relieve its suppression of downstream targets high mobility group box 2 (HMGB2) and cytidine/uridine monophosphate kinase 1 (CMPK1). Mechanistically, vIRF1 inhibits p53 function to increase the expression of DNA methyltransferase 1 (DNMT1) and DNA methylation of the promoter of pre-miR-218-1, a precursor of miR-218-5p, and increases the expression of a long non-coding RNA OIP5 antisense RNA 1 (lnc-OIP5-AS1), which acts as a competing endogenous RNA (ceRNA) of miR-218-5p to inhibit its function and reduce its stability. Moreover, lnc-OIP5-AS1 increases DNA methylation of the pre-miR-218-1 promoter. Finally, deletion of vIRF1 from the KSHV genome reduces the level of lnc-OIP5-AS1, increases the level of miR-218-5p, and inhibits KSHV-induced invasion. Together, these results define a novel complex lnc-OIP5-AS1/miR-218-5p network hijacked by vIRF1 to promote invasiveness and motility of KSHV-induced tumors.
Highlights
Kaposi’s sarcoma-associated herpesvirus (KSHV), known as human herpesvirus 8 (HHV8), is a double-stranded DNA virus, which belongs to γ-herpesvirus
Kaposi’s sarcoma-associated herpesvirus (KSHV) infection caused Kaposi’s sarcoma (KS), a highly disseminated tumor that frequently occurs in patients with AIDS
KSHVencoded viral interferon regulatory factor 1 is an oncogenic protein, which has been shown to be vital in KSHV evasion of innate antiviral response and induction of tumorigenesis but its role in KS tumor invasiveness and motility remains unclear
Summary
Kaposi’s sarcoma-associated herpesvirus (KSHV), known as human herpesvirus 8 (HHV8), is a double-stranded DNA virus, which belongs to γ-herpesvirus. The life cycle of KSHV consists of two phases, latent and lytic phases, both of which contribute to KSHV-induced pathogenesis, tumorigenesis and angiogenesis [2, 3]. KSHV genome contains over 90 open reading frames [4], some of which are homologous to human genes. To establish a successful persistent infection, KSHV encodes these homologous proteins to regulate cell growth, immune response, inflammatory response and apoptosis, and escape the immune antiviral response of host cells [5]. These homologous proteins are in favor of KSHV-induced tumorigenesis. For examples viral interferon regulatory factors (vIRFs) [6], viral interleukin-6 (vIL-6) [7], viral G proteincoupled receptor (vGPCR) [8], viral Bcl-2 (vBcl-2) [9], viral FLICE inhibitory protein (vFLIP) [10] and viral cyclin (vCyclin) [11] have been shown to be pro-oncogenic or promote tumorigenesis
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