The pleiotropic roles of circular and long noncoding RNAs in cutaneous melanoma

Abstract

Cutaneous melanoma (CM) is a very aggressive disease, often characterized by unresponsiveness to conventional therapies and high mortality rates worldwide. The identification of the activating BRAF^V600 mutations in approximately 50% of CM patients has recently fueled the development of novel small-molecule inhibitors that specifically target BRAF^V600 -mutant CM. In addition, a major progress in CM treatment has been made by monoclonal antibodies that regulate the immune checkpoint inhibitors. However, although target-based therapies and immunotherapeutic strategies have yielded promising results, CM treatment remains a major challenge. In the last decade, accumulating evidence points to the aberrant expression of different types of noncoding RNAs (ncRNAs) in CM. While studies on microRNAs have grown exponentially leading to significant insights on CM biology, the role of circular RNAs (circRNAs) and long noncoding RNAs (lncRNAs) in this tumor is less understood, and much remains to be discovered. Here, we summarize and critically review the available evidence on the molecular functions of circRNAs and lncRNAs in BRAF^V600 -mutant CM and CM immunogenicity, providing recent updates on their functional role in targeted therapy and immunotherapy resistance. In addition, we also include an evaluation of several algorithms and databases for prediction and validation of circRNA and lncRNA functional interactions.

Keywords: circular RNAs; cutaneous melanoma; immunotherapy; long noncoding RNAs; targeted therapy.

Fig. 1

Biogenesis of circRNAs. During mRNA maturation, competition between linear splicing and backsplicing can lead to the formation of intron lariats, which can be further processed into circRNAs. Alternatively, the presence across flanking introns or within them of repeated sequences (i.e., Alu repeats with opposite directions) can produce intron‐driven circularization of RNA. In both lariat‐pairing‐driven circularization and intron‐pairing‐driven circularization, introns can be removed to originate an exonic circRNA (ecircRNA), or retained to form an intron‐containing circRNA (ciRNA or EIciRNA). CiRNA biogenesis relies on a consensus motif of a 7 nucleotide GU‐rich element near the 5′ spliced site and an 11 nucleotide C‐rich element adjacent to the branchpoint site. RNA‐binding proteins (RBPs) may actively participate in this process. EcircRNAs (exonic circRNAs) are mainly distributed in the cytoplasm, whereas ciRNAs (circular intronic RNAs) and EIciRNAs (exon‐ and intron‐containing circular RNAs) are primarily located in the nucleus.

Fig. 2

CircRNA (A) and lncRNA (B) functions. CircRNAs can modulate gene expression at different levels: by competitive miRNA sponging and sequestration, thus indirectly enabling the transcription of downstream genes, or by direct interaction with target mRNAs. In rare cases, circRNAs can be translated into proteins. Lastly, circRNAs can interact with RNA‐binding proteins (RBPs) to regulate multiple signaling pathways. LncRNAs are involved in transcriptional and post‐transcriptional regulation of gene expression. In particular, lncRNAs have been implied in different regulatory mechanisms: by competitively binding to miRNAs, by binding and redirecting chromatin remodeling proteins or transcription factors to alternatively modulate transcription of target genes, and by regulating mRNA splicing and degradation. In addition, lncRNAs can serve as scaffold for the formation of multiprotein complexes.

Fig. 3

LncRNAs associated with the MAPK pathways in CM. Red arrows and green blocking bars indicate a positive or negative regulation, respectively.

Fig. 4

Roles of ncRNAs in CM‐immune system interaction. NcRNAs can impact on immune cell differentiation, function, and interaction with CM by acting either in cancer cells or in immune cells. In CM cells, the expression of ncRNAs could be both immunosuppressive and immunostimulating. Indeed, an impaired CTL (cytotoxic lymphocyte) infiltration can be observed in tumors expressing circ_020710, whereas the translation of lncRNA MELOE into the MELOE‐1 protein can improve CM immunogenicity. Immune cells, as well, express plenty of lncRNA. The mechanistic activity of lncRNA was studied more in detail in myeloid‐derived suppressor cells (MDSCs), where Olfr29‐ps1 and Lnc‐CHOP, with the possible contribution of tumor factors, are involved in MDSC differentiation and function. In line with the role of lncRNA in immune cell functions and with notion that the immune system is altered in cancer, CD4, CD8, and CD14 circulating cells from patients with stage IV CM were demonstrated to have different lncRNA profiles than those in healthy people. Green arrows and blocking bars indicate, respectively, the positive or negative regulation.