Oncogenic KSHV-encoded interferon regulatory factor upregulates HMGB2 and CMPK1 expression to promote cell invasion by disrupting a complex lncRNA-OIP5-AS1/miR-218-5p network

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. Author summary Kaposi's sarcoma-associated herpesvirus (KSHV) infection caused Kaposi's sarcoma (KS), a highly disseminated tumor that frequently occurs in patients with AIDS. KSHV-encoded viral interferon regulatory factor 1 (vIRF1) 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. A growing volume of literatures has proposed that lncRNAs could function as tumor suppressors or oncogenes, and numerous lncRNAs might act as competing endogenous RNAs (ceRNAs) that competitively bind to microRNAs (miRNAs), hence exerting influence on posttranscriptional regulation. However, whether cellular lncRNAs are involved in the progression of KS is still unknown. Here, we revealed a previously undefined role of vIRF1 in cell motility and proliferation, and described the cross-regulatory network of cellular lncRNAs and miRNAs involved in the pathogenesis of KS. We found that the crosstalk between miR-218-5p and lnc-OIP5-AS1 contributed to vIRF1-induced cell motility and proliferation via increasing HMGB2 and CMPK1 expression. In summary, this study constitutes an important discovery related to KS pathogenesis, particularly in the invasiveness and motility of KS tumors.