Identification of a functional polymorphism within the 3'-untranslated region of denticleless E3 ubiquitin protein ligase homolog associated with survival in acral melanoma.

Abstract

BACKGROUND:

High expression of denticleless E3 ubiquitin protein ligase homologue (DTL) correlates with poor disease-free survival and overall survival in cutaneous melanoma, but the molecular features and clinical significance of this gene in acral melanoma (AM) remain unclear.

METHODS:

The expression levels of DTL were compared between AM and benign melanocytic nevi using existing Gene Expression Omnibus data and validated in fresh frozen tissues. Two candidate tag single-nucleotide polymorphisms (SNPs) in the 3'-untranslated region (3'UTR) of DTL in patients with AM were sequenced and analysed for their association with survival in a discovery cohort (n = 570), and the significant SNP was subjected to a replication cohort (n = 201). The expression of DTL was evaluated by immunohistochemistry. The microRNA interacting with rs11275300:C > G was predicted using in silico target prediction tools and validated by in vitro analysis.

RESULTS:

DTL was overexpressed in AM compared with benign melanocytic nevi. rs11275300:C > G was found to be significantly associated with progression-free survival and overall survival of patients with AM in both cohorts and the combined cohort. Furthermore, the DTL expression level in the patients with the rs11275300:G allele was higher than that in patients with the CC genotype. In vitro analysis demonstrated that DTL was a direct target of hsa-miR-4672, and the rs11275300:G allele interfered with the binding affinity of hsa-miR-4672 with the 3'UTR of DTL and thereby increased DTL expression.

CONCLUSION:

The rs11275300:G allele in the 3'UTR of DTL may lead to a poor prognosis and allele-specific increase in the expression of DTL by post-transcriptional regulation in AM.

• Authors: Lu Yang, Jie Dai, Meng Ma, Lili Mao, Lu Si, Chuanliang Cui, Xinan Sheng, Zhihong Chi, Sifan Yu, Tianxiao Xu, Jinyu Yu, Yan Kong, Jun Guo
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 118 Pg. 70-81 (09 2019) ISSN: 1879-0852 [Electronic] England
• PMID: 31325875 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Chemical References

• 3' Untranslated Regions
• DTL protein, human
• MicroRNAs
• Nuclear Proteins

Topics

• 3' Untranslated Regions
• Adult
• Aged
• Binding Sites
• Female
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Genetic Predisposition to Disease
• HEK293 Cells
• Humans
• Male
• Melanoma (enzymology, genetics, mortality, pathology)
• MicroRNAs (genetics, metabolism)
• Middle Aged
• Nuclear Proteins (genetics, metabolism)
• Phenotype
• Polymorphism, Single Nucleotide
• Progression-Free Survival
• RNA Processing, Post-Transcriptional
• Retrospective Studies
• Risk Assessment
• Risk Factors
• Skin Neoplasms (enzymology, genetics, mortality, pathology)
• Up-Regulation