title: Loss of microRNA-200a and c, and microRNA-203 expression at the invasive front of primary cutaneous melanoma is associated with increased thickness and disease progression.
abstract: Loss of E-cadherin expression in melanoma correlates with increased tumor thickness and reduced disease-free survival. The molecular mechanisms underpinning its differential expression in melanoma tissue remain elusive. MicroRNAs (miRNAs) have been implicated in tumor progression and regulation of E-cadherin expression. Here, we demonstrate a significant correlation between tumor thickness and loss of expression of miR-200a, miR-200c, and miR-203 in a series of 23 frozen primary melanomas, where it was confirmed in two subsequent validation series (series 1: six nevi, 15 primary melanomas, and 16 metastases; series 2: 11 matched pairs of primary melanomas and metastases). Decreased levels of miR-200a, miR-200c, and miR-203 correlated with increasing thickness in the combined validation series (P = 0.024, 0.033, and 0.031, respectively). In addition, progressive loss of miR-200a expression with disease progression was observed in series 1 (P < 0.001) and in series 2 (P = 0.029). MiR-200 in situ hybridization and E-cadherin immunohistochemistry demonstrated reduced expression of both at the deep invasive margin of the tumor. Furthermore, a functional validation study using an anti-miR200 strategy demonstrated that loss of miR-200 expression in melanoma cell lines reduced E-cadherin expression. Collectively, our data point towards an important role for miR-200 and miR203 expression in regulating E-cadherin during melanoma progression.
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, LDI-E447, 3755 Cote Ste-Catherine, Montreal, QC, Canada H3T 1E2. leon.vankempen@mcgill.ca
authors.forename: Léon C
authors.initials: LC
authors.lastname: van Kempen
authors.forename: Karin
authors.initials: K
authors.lastname: van den Hurk
authors.forename: Vladimir
authors.initials: V
authors.lastname: Lazar
authors.forename: Stefan
authors.initials: S
authors.lastname: Michiels
authors.forename: Véronique
authors.initials: V
authors.lastname: Winnepenninckx
authors.forename: Marguerite
authors.initials: M
authors.lastname: Stas
authors.forename: Alan
authors.initials: A
authors.lastname: Spatz
authors.forename: Joost J
authors.initials: JJ
authors.lastname: van den Oord
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011237:Predictive Value of Tests; D011379:Prognosis; D012189:Retrospective Studies; D012878:Skin Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; C533896:MIRN200 microRNA, human; C546703:MIRN203 microRNA, human; D035683:MicroRNAs