Unraveling the role of microRNA/isomiR network in multiple primary melanoma pathogenesis.
Emi DikaElisabetta BroseghiniElisa PorcelliniMartina LambertiniMattia RiefoloGiorgio DurantePhillipe LoherRoberta RoncaratiCristian BassiCosimo MiscialiMassimo NegriniIsidore RigoutsosEric LondinAnnalisa PatriziManuela FerracinPublished in: Cell death & disease (2021)
Malignant cutaneous melanoma (CM) is a potentially lethal form of skin cancer whose worldwide incidence has been constantly increasing over the past decades. During their lifetime, about 8% of CM patients will develop multiple primary melanomas (MPMs), usually at a young age and within 3 years from the first tumor/diagnosis. With the aim of improving our knowledge on MPM biology and pathogenesis, we explored the miRNome of 24 single and multiple primary melanomas, including multiple tumors from the same patient, using a small RNA-sequencing approach. From a supervised analysis, 22 miRNAs were differentially expressed in MPM compared to single CM, including key miRNAs involved in epithelial-mesenchymal transition. The first and second melanoma from the same patient presented a different miRNA profile. Ten miRNAs, including miR-25-3p, 149-5p, 92b-3p, 211-5p, 125a-5p, 125b-5p, 205-5p, 200b-3p, 21-5p, and 146a-5p, were further validated in 47 single and multiple melanoma samples. Pathway enrichment analysis of miRNA target genes revealed a more differentiated and less invasive status of MPMs compared to CMs. Bioinformatic analyses at the miRNA isoform (isomiR) level detected a panel of highly expressed isomiRs belonging to miRNA families implicated in human tumorigenesis, including miR-200, miR-30, and miR-10 family. Moreover, we identified hsa-miR-125a-5p|0|-2 isoform as tenfold over-represented in melanoma than the canonical form and differentially expressed in MPMs arising in the same patient. Target prediction analysis revealed that the miRNA shortening could change the pattern of target gene regulation, specifically in genes implicated in cell adhesion and neuronal differentiation. Overall, we provided a putative and comprehensive characterization of the miRNA/isomiR regulatory network of MPMs, highlighting mechanisms of tumor development and molecular features differentiating this subtype from single melanomas.
Keyphrases
- skin cancer
- cell proliferation
- long non coding rna
- epithelial mesenchymal transition
- case report
- cell adhesion
- long noncoding rna
- genome wide
- single cell
- end stage renal disease
- endothelial cells
- healthcare
- chronic kidney disease
- peritoneal dialysis
- brain injury
- patient reported outcomes
- middle aged
- subarachnoid hemorrhage
- bioinformatics analysis