Regulatory pathways involving non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNA), have gained great relevance due to their role in the control of gene expression modulation. Using RNA sequencing of KSHV Bac36 transfected mouse endothelial cells (mECK36) and tumors, we have analyzed the host and viral transcriptome to uncover the role lncRNA-miRNA-mRNA driven networks in KSHV tumorigenesis. The integration of the differentially expressed ncRNAs, with an exhaustive computational analysis of their experimentally supported targets, led us to dissect complex networks integrated by the cancer-related lncRNAs Malat1, Neat1, H19, Meg3, and their associated miRNA-target pairs. These networks would modulate pathways related to KSHV pathogenesis, such as viral carcinogenesis, p53 signaling, RNA surveillance, and cell cycle control. Finally, the ncRNA-mRNA analysis allowed us to develop signatures that can be used to an appropriate identification of druggable gene or networks defining relevant AIDS-KS therapeutic targets.El material suplementario incluye: DataSheet_1_A Non-Coding RNA Network Involved in KSHV Tumorigenesis Supplementary Table 1 | DE lncRNAs in key biological comparisons detected by RNA-sequencing. Results were obtained after DeSeq2 analysis of: two KSHV (+) cells, two KSHV (−) cells, six KSHV (+) tumors, two KSHV (−) tumor cells and three KSHV (−) tumors. Supplementary Table 2 | Pathway analysis of the lncRNAs EVT. Supplementary Table 3 | Pathway analysis of the selected lncRNAs and their EVT genes DE in the corresponding comparisons. Supplementary Table 4 | DE miRNAs in key biological comparisons detected by small RNA-sequencing. Supplementary Table 5 | Pathway analysis of DE miRNAs and their EVT genes DE in the corresponding comparisons. Supplementary Table 6 | KSHV miRNAs analysis in KSHV (+) tumors and pathway analysis of their EVT. Supplementary Table 7 | lncRNA-miRNA-mRNA-Pathway networks. Supplementary Table 8 | Drugs associated with miRNA-gene pairs obtained from network analysis.Centro de Investigaciones Inmunológicas Básicas y Aplicadas