Clinical Implications•MicroRNAs (miRNAs) are noncoding RNAs that regulate both transcription and translation.•miRNA dysregulation is implicated in melanoma development, growth, and metastatic spreading.•Specific miRNAs can be isolated and quantified in serum and can play a role in predicting response to target and immunotherapy. •MicroRNAs (miRNAs) are noncoding RNAs that regulate both transcription and translation.•miRNA dysregulation is implicated in melanoma development, growth, and metastatic spreading.•Specific miRNAs can be isolated and quantified in serum and can play a role in predicting response to target and immunotherapy. Cutaneous melanoma (cM) incidence is still rising, mainly because of screening campaigns, which have increased the number of reported melanomas (Ribero et al., 2016Ribero S. Glass D. Bataille V. Genetic epidemiology of melanoma.Eur J Dermatol. 2016; 26: 335-339Crossref PubMed Scopus (36) Google Scholar). The field of melanoma molecular investigations is also increasing, with the widespread use of technologies for SNP analysis, genome sequencing, gene and noncoding RNA expression, and methylation analysis (DiVincenzo et al., 2022DiVincenzo M.J. Schwarz E. Ren C. Barricklow Z. Moufawad M. Yu L. et al.Expression patterns of microRNAs and associated target genes in ulcerated primary cutaneous melanoma.J Invest Dermatol. 2023; 143: 630-638.e3Abstract Full Text Full Text PDF Google Scholar). The final goal of these extensive molecular investigations is the identification of novel molecules that could be used as predictive or prognostic biomarkers. In the last two decades, great attention has been shown to the evaluation of noncoding RNA (ncRNA) role in cancer development and progression. ncRNAs consist of functional RNA molecules with no protein-coding functions: they are categorized on the basis of their length as small medium- or long-size ncRNAs. MicroRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNA have been investigated in melanoma. miRNAs are ncRNAs that regulate both transcription and translation. miRNAs (18–22 nucleotides in length) modulate the expression of mRNAs by binding to complementary sequences in the 3′ untranslated regions of the target mRNAs. miRNA dysregulation is implicated in cM development, growth (cell proliferation or apoptosis), and metastatic spreading (Riefolo et al., 2019Riefolo M. Porcellini E. Dika E. Broseghini E. Ferracin M. Interplay between small and long non-coding RNAs in cutaneous melanoma: a complex jigsaw puzzle with missing pieces.Mol Oncol. 2019; 13: 74-98Crossref PubMed Scopus (25) Google Scholar). Oncogenic miRNAs target and downregulate tumor suppressor genes, whereas a number of miRNAs exert a protective role in downregulating genes related to the neoplastic process: the imbalance of these two groups has a key role in the neoplastic process. Globally, miR-211-5p has shown the most distinctive expression in cM than in normal melanocytes, TRPM1/miR-211 being frequently downregulated or lost. The upregulation of several miRNAs, including miR-21-5p, miR-135a, and miR-155, has been detected in tumor cells and metastatic cMs compared with that in healthy samples. Conversely, specific miRNAs are known to be downregulated, including miR-125b, miR-126/126∗, miR-136, miR-145, miR-194, miR-203, miR-205, miR-206, miR-365, and miR-485-5p14–18. Regarding cM progression and development of distant metastases, the upregulation of miR-150, miR-182, miR-182, and miR-200 family was associated with neoplastic spreading, as opposed to that of miR-203, miR-34a, miR-7-5p, and miR-9 or miR-211 (Riefolo et al., 2019Riefolo M. Porcellini E. Dika E. Broseghini E. Ferracin M. Interplay between small and long non-coding RNAs in cutaneous melanoma: a complex jigsaw puzzle with missing pieces.Mol Oncol. 2019; 13: 74-98Crossref PubMed Scopus (25) Google Scholar). As for the role of lncRNAs in melanomagenesis, HOX Transcript Antisense RNA is supposed to be one of the most relevant, being upregulated in metastatic lymph nodes. MALAT1 has oncogenic properties enhancing neoplastic proliferation and invasion, whereas SPRY4-IT1 is implicated in the induction of lipid synthesis. Other specific lncRNAs related to cM include BRAF-activated ncRNA, whose expression increases with tumor stage, and SAMMSON that resulted to be coamplified with MITF intensifying the clonogenicity of cM cells influencing mitochondrial metabolism (Dika et al., 2020Dika E. Riefolo M. Porcellini E. Broseghini E. Ribero S. Senetta R. et al.Defining the prognostic role of microRNAs in cutaneous melanoma.J Invest Dermatol. 2020; 140: 2260-2267Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). Breslow thickness is the main histopathologic prognostic factor in cM; it was proposed in 1970 and is still used nowadays. Tumor ulceration and sentinel lymph node biopsy prognostic roles have been also validated in large cohorts and multicenter studies and are now included in the latest melanoma staging system (American Joint Committee on Cancer [AJCC] VIII edition). The association of these histopathologic prognostic factors with novel molecular biomarkers is crucial in the era of precision medicine to further improve patient prognostication and implement standard histopathologic biomarkers performance. The determination of Breslow thickness has important implications in patient management. The quantification of specific molecules in the tumor can re-evaluate and confirm the pathologist’s ocular micrometer measurement; they could be an adjunct value to overcome interobserver variability, which is reported in cM pathologic diagnosis, and undeterminable or uncertain cases. Indeed, we recently showed the precise correlation of the combined assessment of miR-21-5p and miR-146a-5p expression with Breslow thickness in superficially spreading cM (Dika et al., 2020Dika E. Riefolo M. Porcellini E. Broseghini E. Ribero S. Senetta R. et al.Defining the prognostic role of microRNAs in cutaneous melanoma.J Invest Dermatol. 2020; 140: 2260-2267Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). Ulceration is currently recognized as a negative prognostic factor, and it has been classified as a T-category criterion staging system of the AJCC VIII edition. Moreover, ulceration extent has been recently proven as an independent prognostic factor in melanoma ≤2 mm (Portelli et al., 2021Portelli F. Galli F. Cattaneo L. Cossa M. De Giorgi V. Forte G. et al.The prognostic impact of the extent of ulceration in patients with clinical stage I– II melanoma: a multicentre study of the Italian Melanoma Intergroup (IMI).Br J Dermatol. 2021; 184: 281-288Crossref PubMed Scopus (9) Google Scholar). In their new article in the Journal of Investigative Dermatology, DiVincenzo et al., 2022DiVincenzo M.J. Schwarz E. Ren C. Barricklow Z. Moufawad M. Yu L. et al.Expression patterns of microRNAs and associated target genes in ulcerated primary cutaneous melanoma.J Invest Dermatol. 2023; 143: 630-638.e3Abstract Full Text Full Text PDF Google Scholar studied the expression pattern of miRNAs and associated target genes in ulcerated primary cM. The authors reported that ulcerated cM samples showed a differential expression of 24 miRNAs when compared with melanoma without ulceration. Despite the relatively small sample size and the lack of validation of protein expression, these results are interesting because there is still an open debate on the prognostic role of melanoma ulceration. Moreover, it should be noted that the described case series mainly consists of cMs with a high Breslow thickness, which is the same for all cases except two that are ≥1.5 mm, which can represent a possible bias because some miRNAs change very precisely with Breslow thickness. Among the most significantly upregulated miRNAs in ulcerated cMs, there were miR-363-3p, miR-146a-5p, miR-130b-3p, miR-320b, miR-21-5p, and miR-196b-5p (>1.5 fold change, P < 0.05). The increased expression of miR-146a-5p in ulcerated samples (2.64 fold change) is likely related to greater and faster neoplastic growth because these miRNAs are known to increase cM growth (Raimo et al., 2016Raimo M. Orso F. Grassi E. Cimino D. Penna E. De Pittà C. et al.miR-146a exerts differential effects on melanoma growth and metastatization.Mol Cancer Res. 2016; 14: 548-562Crossref PubMed Scopus (35) Google Scholar). miR-146a-5p plays an oncogenic role and targets the NUMB gene, a repressor of NOTCH signaling (Raimo et al., 2016Raimo M. Orso F. Grassi E. Cimino D. Penna E. De Pittà C. et al.miR-146a exerts differential effects on melanoma growth and metastatization.Mol Cancer Res. 2016; 14: 548-562Crossref PubMed Scopus (35) Google Scholar). Furthermore, miR-146a-5p enhances cell migration and invasion targeting SMAD4 and controls the MAPK signaling pathway, which has a pivotal role in cM (Dika et al., 2020Dika E. Riefolo M. Porcellini E. Broseghini E. Ribero S. Senetta R. et al.Defining the prognostic role of microRNAs in cutaneous melanoma.J Invest Dermatol. 2020; 140: 2260-2267Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). miR-146a-5p expression is significantly correlated with Breslow thickness in superficially spreading cMs, and increased expression was found in those cases with high mitotic rates (Raimo et al., 2016Raimo M. Orso F. Grassi E. Cimino D. Penna E. De Pittà C. et al.miR-146a exerts differential effects on melanoma growth and metastatization.Mol Cancer Res. 2016; 14: 548-562Crossref PubMed Scopus (35) Google Scholar). Regarding miR-363-3p, it was reported to be induced by HIF-2α, having a positive role in stemness and an upregulation in cM cells: HIF-2α knockdown and miR-363-3p downregulation were shown to inhibit the levels of the stemness markers (CD133, CD271, Jarid1B, and Nanog) (Murria Estal et al., 2021Murria Estal R. de Unamuno Bustos B. Pérez Simó G. Simarro Farinos J. Torres Navarro I. Alegre de Miquel V. et al.MicroRNAs expression associated with aggressive clinicopathological features and poor prognosis in primary cutaneous melanomas.Melanoma Res. 2021; 31: 18-26Crossref PubMed Scopus (4) Google Scholar). Other studies reported that miR-106b expression is correlated with Breslow thickness (P = 0.002), tumor ulceration (P = 0.002), and advanced clinical stage (P < 0.001) (Li, 2016Li N. Low expression of Mir-137 predicts poor prognosis in cutaneous melanoma patients.Med Sci Monit. 2016; 22: 140-144Crossref PubMed Scopus (20) Google Scholar). However, lower miR-137 expression was described as related to TNM stage, ulceration and occurrence site, and a worse prognosis (Li, 2016Li N. Low expression of Mir-137 predicts poor prognosis in cutaneous melanoma patients.Med Sci Monit. 2016; 22: 140-144Crossref PubMed Scopus (20) Google Scholar). These latter two miRNAs were not confirmed in the study by DiVincenzo et al., 2022DiVincenzo M.J. Schwarz E. Ren C. Barricklow Z. Moufawad M. Yu L. et al.Expression patterns of microRNAs and associated target genes in ulcerated primary cutaneous melanoma.J Invest Dermatol. 2023; 143: 630-638.e3Abstract Full Text Full Text PDF Google Scholar. Another interesting topic of research is the evaluation of cell-free miRNAs in the blood as disease biomarkers. Indeed, specific miRNAs can be isolated and quantified in serum or plasma fractions because they show good stability. Currently, methodological guidelines and standardized protocols for circulating miRNA quantification in clinical settings are still missing, and they represent an active and intriguing field of research in patients with melanoma. Evaluation of miR-1246 and miR-485-3p baseline plasma levels might help clinicians to identify patients with melanoma most likely to be unresponsive to targeted therapy or at higher risk for short-term progression-free survival and mortality, thus improving their management (Levati et al., 2022Levati L. Bassi C. Mastroeni S. Lupini L. Antonini Cappellini G.C. Bonmassar L. et al.Circulating miR-1246 and miR-485-3p as promising biomarkers of clinical response and outcome in melanoma patients treated with targeted therapy.Cancers (Basel). 2022; 14: 3706Crossref PubMed Scopus (1) Google Scholar). In addition, miRNAs play a major role in the regulation of both the innate and adaptive immune systems. Therefore, it is possible to investigate miRNA-based biomarkers in response to immunotherapy. The detection levels of five miRNAs, including let-7e, miR-99b, miR-125a, miR-125b, and miR-146b, in plasma could be predictive markers of the response of patients with melanoma to ipilimumab and nivolumab (Nguyen et al., 2021Nguyen M.H.T. Luo Y.H. Li A.L. Tsai J.C. Wu K.L. Chung P.J. et al.miRNA as a modulator of immunotherapy and immune response in melanoma.Biomolecules. 2021; 11: 1648Crossref PubMed Scopus (9) Google Scholar). Studies on miRNA expression can help in providing insight regarding how they target gene mRNA expression, thus impacting cM development and progression. The authors state no conflict of interest. Expression Patterns of microRNAs and Associated Target Genes in Ulcerated Primary Cutaneous MelanomaJournal of Investigative DermatologyVol. 143Issue 4PreviewUlcerated cutaneous melanoma carries a poor prognosis, and the underlying biology driving its aggressive behavior is largely unexplored. MicroRNAs (miRs) are small, noncoding RNAs that inhibit the expression of specific genes and exhibit dysregulated expression patterns in cancer. We hypothesized that a unique miR profile exists in ulcerated relative to nonulcerated melanoma and that miR expression inversely correlates with target genes of biologic importance. Expression of miRs and mRNAs was assessed in ulcerated and nonulcerated cutaneous melanomas using the NanoString Human miRNA and Tumor Signaling 360 mRNA assays and validated in an independent cohort. Full-Text PDF Open Access