LncRNA LINC00518 Acts as an Oncogene in Uveal Melanoma by Regulating an RNA-Based Network

SIMPLE SUMMARY: Uveal melanoma (UM) is the most frequent primary tumor of the eye in adults. Although molecular alterations on protein-coding genes have been associated with the development of UM, the role of non-coding RNAs and their competitive endogenous networks remain poorly investigated. Starting from a computational analysis on UM expression dataset deposited in The Cancer Genome Atlas, we identified the long non-coding RNA LINC00518 as a potential oncogene. We then experimentally evaluated LINC00518 and its supposed RNA signaling in human biopsies and in vitro functional assays. The results obtained suggest that LINC00518, under potential transcriptional control by MITF, regulates an RNA–RNA network promoting cancer-related processes (i.e., cell proliferation and migration). These findings open the way to the characterization of the unknown RNA signaling associated with UM and pave the way to the exploitation of a potential target for RNA-based therapeutics. ABSTRACT: Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults; little is known about the contribution of non-coding RNAs (ncRNAs) to UM pathogenesis. Competitive endogenous RNA (ceRNA) networks based on RNA–RNA interactions regulate physiological and pathological processes. Through a combined approach of in silico and experimental biology, we investigated the expression of a set of long non-coding RNAs (lncRNAs) in patient biopsies, identifying LINC00518 as a potential oncogene in UM. The detection of LINC00518 dysregulation associated with several in vitro functional assays allowed us to investigate its ceRNA regulatory network and shed light on its potential involvement in cancer-related processes, such as epithelial to mesenchymal transition (EMT) and CoCl(2)-induced hypoxia-like response. In vitro transient silencing of LINC00518 impaired cell proliferation and migration, and affected mRNA expression of LINGO2, NFIA, OTUD7B, SEC22C, and VAMP3. A “miRNA sponge” and “miRNA protector” model have been hypothesized for LINC00518-induced regulation of mRNAs. In vitro inhibition of MITF suggested its role as a potential activator of LINC00518 expression. Comprehensively, LINC00518 may be considered a new oncogene in UM and a potential target for RNA-based therapeutic approaches.