Circulating MicroRNAs: functional biomarkers for melanoma prognosis and treatment

Abstract

MicroRNAs (miRNAs) hold significant promise as circulating cancer biomarkers and unlike many other molecular markers, they can provide valuable insights that extend beyond tumour biology. The expression of circulating miRNAs may parallel the cellular composition and dynamic activity within the tumour microenvironment and reveal systemic immune responses. The functional complexity of miRNAs-where a single miRNA can regulate multiple messenger RNAs (mRNAs) to fine tune fundamental processes, and a single mRNA can be targeted by multiple miRNAs-underscores their broad significance and impact. However, this complexity poses significant challenges for translating miRNA research into clinical practice. In melanoma, specific miRNA signatures have shown notable diagnostic, prognostic and predictive value, with lineage-specific and immune-related miRNAs frequently identified as valuable markers. In this review, we explore the role of circulating miRNAs as potential biomarkers in melanoma, and highlight the current status and advances required to translate miRNA research into therapeutic opportunities.

Keywords: Biomarkers; Immune checkpoint inhibitors; Melanoma; MicroRNA; Targeted therapies; Treatment prediction.

Fig. 1

Canonical miRNA biosynthesis and miRNA function. Following transcription by RNA polymerase II/III (RNA pol II/III), primary miRNAs (pri-miRNAs) are cleaved at the base of a hairpin structure by the nuclear DROSHA RNase III to yield ~ 60–70 nucleotide precursor miRNAs (pre-miRNAs). Pre-miRNAs are exported to the cytoplasm via an Exportin-5 receptor-dependent process where they undergo further cleavage by the Dicer RNase III bound to RNA-binding proteins, such as TRBP. The resulting miRNA duplex associates with an AGO protein, where one miRNA strand (the guide strand) is selected to form the functional miRISC. The miRNA may originate from the 5’ end of the pre-miRNA or the 3’ end of the pre-miRNA giving rise to the -5p or -3p miRNAs, respectively. The unbound strand of the miRNA duplex is ejected from the AGO protein and degraded. Once formed, miRISC binds to target mRNAs and inhibits translation by competing with eIF4F recognition of the 7-methyl-G (m7G) cap, inhibiting cap-dependent translation initiation and destabilizing the target mRNA through the recruitment of de-adenylation complexes, which remove the stabilizing 3’ poly(A) tail

Fig. 2

miRNA regulators of the MITF gene. Multiple miRNAs can bind to identical and overlapping regions within the 3’ UTR of the target human MITF mRNA. miRNAs with 8mer or 7mer seed sites are highlighted in red and blue, respectively. Data are derived from TargetScanHuman (release 7.2) [181]. The hg19 chromosome coordinates of the MITF mRNA and the miRNA binding sites are shown

Fig. 3

miRNAs modulating components of the MAPK pathway in melanoma. Several miRNAs have been shown to regulate the MAPK pathway in melanoma by binding to the 3’ or 5’ UTR of various MAPK pathway components. These include miR-7 (targets EGFR, IGF-1R and CRAF [122]), miR-199b-5p (targets VEGFA and HIF1α [107]), miR-204-5p (targets VEGFA [182]), miR-126-3p (targets VEGFA and BRAF [182]), miR-579-3p (targets BRAF [123]), miR-524-5p (targets BRAF and ERK [183]), and miR-876-3p (targets ERK2 [184])

Fig. 4

Strategies and delivery systems for miRNA-based therapies. miRNA constructs can be designed to either inhibit (antagomiRs, BlockmiRs, miRNA masking, miRNA sponges) or overexpress (miRNA mimics) target miRNAs. To maximise stability of miRNAs and minimise off-target effects, miRNA constructs can be packaged within viral or non-viral delivery systems for transport to specific tumour sites