Value of dopachrome tautomerase detection in the assessment of melanocytic tumors.
Dopachrome tautomerase (DCT) and tyrosinase (Tyr) are melanogenic enzymes and structurally related melanosomal proteins. The present study investigates DCT expression comparatively with Tyr, the most tested melanoma biomarker, aiming to evaluate DCT potential in the assessment of melanocytic tumors and gain insights into the molecular and pathological characterization of DCT-phenotype in tumor progression. DCT and Tyr are simultaneously analyzed in melanoma cell lines by semiquantitative RT-PCR, western blot, and N-glycan analysis, and in cell populations of melanocytic tumors by immunohistofluorescence using a novel anti-hDCT antibody against an extended sequence within DCT luminal domain. DCT, unlike Tyr, is fully processed along the secretory pathway in both pigmented and amelanotic melanoma cells. In 53 nevi and 116 primary malignant melanomas, 81% and 52%, respectively, are DCT+/Tyr+, showing that DCT is a stable antigen, retained by most tumors and partially expressed in Tyr-negative cell populations. The DCT/Tyr disjunction is a process correlated with melanocyte neoplastic transformation and malignant progression. A tumor architecture--DCT-phenotype-containing DCT+/Tyr- cell populations selected into the innermost dermis from double-positive cells is detected in 35% of DCT+/Tyr+ specimens. The DCT-phenotype is associated with enhanced neurotization in benign nevi and with ulceration in thin malignant melanomas. The intradermal DCT+/Tyr- clones in superficial melanomas acquire the expression and specific subcellular distribution of unfavorable prognostic markers. DCT assessment shows specific antigen patterns with potential significance in the outcome of melanocytic lesions, connecting DCT, a mediator of a melanoma stress-resistant pathway, and an antiapoptotic molecule to DCT- phenotypes that are possibly more stable and stress resistant.
Departments of aMolecular Cell Biology bBioinformatics and Structural Biochemistry, Institute of Biochemistry, Romanian Academy cDepartment of Pathology, Colentina University Hospital, Bucharest, Romania.
Anca
A
Filimon
Sabina A
SA
Zurac
Adina L
AL
Milac
Livia E
LE
Sima
Stefana M
SM
Petrescu
Gabriela
G
Negroiu
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D008544:Melanocytes / Q000201:enzymology* / Q000473:pathology; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D014442:Monophenol Monooxygenase / Q000378:metabolism; D009508:Nevus, Pigmented / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D034622:RNA Interference; D012878:Skin Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D014162:Transfection
D014408:Biomarkers, Tumor; D014442:Monophenol Monooxygenase; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase