Detection of a MicroRNA molecular signature of ultraviolet radiation in the superficial regions of melanocytic nevi on sun-exposed skin

Abstract

How melanocytes transform into melanoma cells remains largely unknown. However, prolonged ultraviolet radiation exposure is linked with melanoma, and the DNA of melanomas arising in chronically sun-exposed skin is characterized by an elevated number of pyrimidine transitions, mainly C>T (predominantly caused by ultraviolet B), and transversions of GC>TA or AT>CG (caused by ultraviolet A over indirect mechanisms). Since ultraviolet penetrates mostly only the superficial dermis, we sought to determine the extent to which superficial and deep melanocytes of nevi in sun-exposed skin differ in their miRNA expression and consider the changes as likely secondary to ultraviolet radiation-induced damage. The differentially expressed miRNAs were analyzed for known potential oncomiRs or linked to potential oncogenes or tumor suppressors. Superficial and deep melanocytes were microdissected from the nevi of 14 patients. The suspensions were processed for hybridization to a ribonucleotide protection system with 2280 total probes, including 2256 miRNA probes targeting 2083 human miRNAs. A comprehensive analysis of all human miRNAs registered in miRBase 11.0 was performed using the HTG Molecular Diagnostic database. Statistical analysis of these data yielded for 14 samples a statistically relevant profile of 39 miRNA species at FDR<0.1 that were differentially expressed between superficial and deep melanocytes. Ingenuity Pathway Analysis based on the expression data of these 39 miRNAs suggested the gene transcripts AR, MDM2, SMAD2/3, and YBX1 as the most probable miRNA targets, which were validated at the protein level. Our findings suggest that superficial ultraviolet radiation-damaged melanocytes can be differentiated from deep melanocytes on the basis of the expression of 39 miRNAs, the most probable gene transcript and protein targets of which are AR, MDM2, SMAD2/3, and YBX1, with YBX1 expression validating the best the molecular signature in immunohistochemical analysis.

The Association of Residential Altitude on the Molecular Profile and Survival of Melanoma: Results of an Interreg Study

“…Concerning the TYRP1 gene, it is well-known that the transcription factor Usf-1 activates the tyrosinase promoter by UV exposure [ 21 ]. Additionally, miRNA profiles have been shown to vary in sun-exposed skin [ 22 ] and that oxidative stress [ 23 ] can induce or suppress miRNA expression. Thus, a higher altitude with a hypoxic environment and increased UV intensity may account for the detected differences in the miRNA expression in our cohort.…”

Oxidative-Stress-Sensitive microRNAs in UV-Promoted Development of Melanoma

“…Interestingly, growing evidence also suggests an involvement of UV in the regulation of cutaneous miRNA profiles in both physiological and pathological conditions [63][64][65][66][67][68]. This class of small noncoding RNAs with a length of about 19-24 nucleotides mainly function by regulating gene expression via post-transcriptional mechanisms that include translation inhibition and degradation of target messenger RNAs (mRNAs) [69].…”

Exposomes to Exosomes: Exosomes as Tools to Study Epigenetic Adaptive Mechanisms in High-Altitude Humans

“…Small non-coding mRNAs, such as miRNAs, play important roles in cold acclimation [80], hypoxia stress, and ultraviolet radiation [81] stress. To reveal the potential roles of miRNAs in high-altitude adaptation, high-quality small RNA sequencing data for six tissues (heart, liver, spleen, lung, kidney, muscle) from high-and low-altitude populations of three species, i.e., chicken, sheep, and pig, were generated and several orthologues and some novel miRNAs were found [82].…”