miRNAs as Key Players in the Management of Cutaneous Melanoma

Abstract

The number of treatment options for melanoma patients has grown in the past few years, leading to considerable improvements in both overall and progression-free survival. Targeted therapies and immune checkpoint inhibitors have opened a new era in the management of melanoma patients. Despite the clinical advances, further research efforts are needed to identify other "druggable" targets and new biomarkers to improve the stratification of melanoma patients who could really benefit from targeted and immunotherapies. To this end, many studies have focused on the role of microRNAs (miRNAs) that are small non-coding RNAs (18-25 nucleotides in length), which post-transcriptionally regulate the expression of their targets. In cancer, they can behave either as oncogenes or oncosuppressive genes and play a central role in many intracellular pathways involved in proliferation and invasion. Given their modulating activity on the transcriptional landscape, their biological role is under investigation to study resistance mechanisms. They are able to mediate the communication between tumor cells and their microenvironment and regulate tumor immunity through direct regulation of the genes involved in immune activation or suppression. To date, a very promising miRNA-based strategy is to use them as prognosis and diagnosis biomarkers both as cell-free miRNAs and extracellular-vesicle miRNAs. However, miRNAs have a complex role since they target different genes in different cellular conditions. Thus, the ultimate aim of studies has been to recapitulate their role in melanoma in biological networks that account for miRNA/gene expression and mutational state. In this review, we will provide an overview of current scientific knowledge regarding the oncogenic or oncosuppressive role of miRNAs in melanoma and their use as biomarkers, with respect to approved therapies for melanoma treatment.

MicroRNA-21-Enriched Exosomes as Epigenetic Regulators in Melanomagenesis and Melanoma Progression: The Impact of Western Lifestyle Factors

“…Therefore, therapeutic agents that attenuate miR-21 expression such as metformin, beta-blockers, vitamin D, curcumin, EGCG and SFN may have beneficial effects in MM prevention and treatment. The anti-proliferative effects of miR-21-antagonizing agents, its catalytic knockdown of miR-21 by artificial ribonuclease, and miR-21 expression lowering agents may synergistically improve MM therapy [ 365 , 366 , 367 , 368 , 369 , 370 , 371 , 413 ]. Delivery of exosomal anti-miR-21 may be a promising new option for MM treatment [ 367 , 368 , 369 , 370 ].…”

The Non-Coding Landscape of Cutaneous Malignant Melanoma: A Possible Route to Efficient Targeted Therapy

“…To date, results regarding the effect of ncRNAs on melanoma response to immune checkpoint blockers are sparse [ 128 , 129 ]. In order for studies to gain momentum in this area, some suggested the use of single-cell RNAseq approach to distinguish between the expression of cancer cells and that of the immune components [ 90 ]. Nevertheless, some miRNAs have been recognised as being involved in the conversion of monocytes into immunosuppressive MDSCs (let-7e, miR-99b, miR-100, miR-125a, miR-125b, miR-146a, miR-146b, miR-155) [ 130 ], while some interfere with PD-1 (miR-28) or PD-L1 (miR-17-5p) at a post-transcriptional level [ 131 , 132 ], facilitating resistance to immunotherapy ( Table 2 ).…”

“…The clinical utilities and implications of ncRNAs in melanoma management are not fully established and future investigations are needed to clarify this aspect [ 29 , 90 ], however some promising results that recommend miRNAs and lncRNAs as tools for diagnosing, monitoring and treating cutaneous melanoma are presented in the following sections.…”

“…The potential of targeting ncRNAs to develop novel anticancer therapeutic strategies or to increase the efficacy of already existing ones has been pointed out in several studies [ 90 , 150 , 151 ].…”

MicroRNAs as Key Players in Melanoma Cell Resistance to MAPK and Immune Checkpoint Inhibitors

“…In a recent study, 11 miRNAs were identified as differentially expressed between healthy controls and plasma samples from different melanoma stages [ 43 ]. Therefore, miRNAs, especially those being part of the circulating transcriptome, may be useful as biomarkers for early melanoma detection and response to treatments [ 44 ]. Numerous miRNAs have been found to regulate melanoma cell behavior and gene expression acting on the MAPK signaling pathway [ 45 ], while some miRNAs have been found to regulate the expression of immune checkpoints, acting on melanoma cells or immune cells [ 46 ].…”