title: The Response of microRNAs to Solar UVR in Skin-Resident Melanocytes Differs between Melanoma Patients and Healthy Persons.
abstract: The conversion of melanocytes into cutaneous melanoma is largely dictated by the effects of solar ultraviolet radiation (UVR). Yet to be described, however, is exactly how these cells are affected by intense solar UVR while residing in their natural microenvironment, and whether their response differs in persons with a history of melanoma when compared to that of healthy individuals. By using laser capture microdissection (LCM) to isolate a pure population of melanocytes from a small area of skin that had been intermittingly exposed or un-exposed to physiological doses of solar UVR, we can now report for the first time that the majority of UV-responsive microRNAs (miRNAs) in the melanocytes of a group of women with a history of melanoma are down-regulated when compared to those in the melanocytes of healthy controls. Among the miRNAs that were commonly and significantly down-regulated in each of these women were miR-193b (P<0.003), miR-342-3p (P<0.003), miR186 (P<0.007), miR-130a (P<0.007), and miR-146a (P<0.007). To identify genes potentially released from inhibition by these repressed UV-miRNAs, we analyzed databases (e.g., DIANA-TarBase) containing experimentally validated microRNA-gene interactions. In the end, this enabled us to construct UV-miRNA-gene regulatory networks consisting of individual genes with a probable gain-of-function being intersected not by one, but by several down-regulated UV-miRNAs. Most striking, however, was that these networks typified well-known regulatory modules involved in controlling the epithelial-to-mesenchymal transition and processes associated with the regulation of immune-evasion. We speculate that these pathways become activated by UVR resulting in miRNA down regulation only in melanocytes susceptible to melanoma, and that these changes could be partially responsible for empowering these cells toward tumor progression.
authors.affiliation: Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, United States of America.
authors.forename: Jingfeng
authors.initials: J
authors.lastname: Sha
authors.affiliation: Department of Immunology, Cleveland Clinic, Cleveland, OH, 44195, United States of America.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Gastman
authors.affiliation: Statistical Science Core in the Center for Clinical Investigation, Case Western Reserve University, Cleveland, OH, 44106, United States of America.
authors.forename: Nathan
authors.initials: N
authors.lastname: Morris
authors.affiliation: Department of Dermatology, Cleveland Clinic, Cleveland, OH, 44195, United States of America.
authors.forename: Natasha A
authors.initials: NA
authors.lastname: Mesinkovska
authors.affiliation: Department of Dermatology, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, OH, 44106, United States of America.
authors.forename: Elma D
authors.initials: ED
authors.lastname: Baron
authors.affiliation: Department of Dermatology, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, OH, 44106, United States of America.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Cooper
authors.affiliation: Department of Dermatology, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, OH, 44106, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: McCormick
authors.affiliation: Department of Dermatology, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, OH, 44106, United States of America.
authors.forename: Joshua
authors.initials: J
authors.lastname: Arbesman
authors.affiliation: Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, United States of America.|Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, United States of America.
authors.forename: Marian L
authors.initials: ML
authors.lastname: Harter
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D061346:Laser Capture Microdissection; D008544:Melanocytes / Q000378:metabolism / Q000528:radiation effects*; D008545:Melanoma / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012878:Skin Neoplasms / Q000378:metabolism*; D013472:Sunlight; D014466:Ultraviolet Rays
chemical_list: D035683:MicroRNAs