Background Pigmentation could be a relevant prognostic factor in uveal melanoma (UM) development. Microphthalmia-associated transcription factor (MITF) regulates melanin synthesis by activating tyrosinase-related protein 2 (TYRP2) and silver protein (SILV) that induce the melanogenesis pathway. Although their oncogenic potential has been observed in various malignancies but has not been investigated in UM Asian population. Our aim is to study the ultrastructure of melanosomes and the prognostic significance of pigmentation markers such as TYRP2, MITF and SILV in UM.
Methods Transmission electron microscopy was performed to compare the ultrastructure of melanosomes in the normal choroid and UM cases. Immunoexpression of TYRP2, SILV and MITF was analysed in 82 UM samples. The mRNA expression level of all genes was measured in 70 UM cases. A statistical correlation was performed to determine the prognostic significance of all markers.
Results Premelanosomes and mature melanosomes undergoing dedifferentiation were observed in high-pigmented UM cases as compared with low-pigmented UM cases. Seventy per cent of UM cases showed high SILV expression while TYRP2 and MITF expression was present in 58% and 56% of cases, respectively. At the mRNA level, upregulation of TYRP2, SILV and MITF markers was seen in around 50% of UM cases, which was statistically significant with high pigmentation. Reduced metastatic-free survival was statistically significant with the MITF protein expression.
Conclusion Our results demonstrated that ultrastructural changes in melanosomes and high expression of TYRP2, MITF and SILV could dysregulate the melanogenesis pathway and might be responsible for the aggressive behaviour of UM.
Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information. Not applicable.
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Contributors JJ executed the study and data analysis in association with SK. SK is responsible for the overall content as guarantor.The guarantor accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish. MKS and LS contributed to the design and draft of the manuscript. TCN and KC helped in the experiments and coordination of the manuscript. NP, NL and RM provided the enucleated specimens. SS and SK were responsible for histopathological examination. SB provided the follow-up of the patients. All authors read and approved the final manuscript.
Funding Indian Council of Medical Research (ICMR), New Delhi. Senior Research Fellowship (Grant no. 3/1/2(7)/OPH/2019-NCD-11). The funding organisation participated in conducting the study of the manuscript.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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