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Identification of a functional polymorphism within the 3'-untranslated region of denticleless E3 ubiquitin protein ligase homolog associated with survival in acral melanoma.
Eur J Cancer 2019; 118:70-81EJ

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+Show Affiliations

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, 100142, China.Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, 100142, China.Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, 100142, China; Department of Radiotherapy, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, China.Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, 100142, China.Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, 100142, China.Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, 100142, China.Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, 100142, China.Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, 100142, China.Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, 100142, China.Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, 100142, China.Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, 100142, China.Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, 100142, China. Electronic address: k-yan08@163.com.Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, 100142, China. Electronic address: guoj307@126.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31325875

Citation

Yang, Lu, et al. "Identification of a Functional Polymorphism Within the 3'-untranslated Region of Denticleless E3 Ubiquitin Protein Ligase Homolog Associated With Survival in Acral Melanoma." European Journal of Cancer (Oxford, England : 1990), vol. 118, 2019, pp. 70-81.
Yang L, Dai J, Ma M, et al. Identification of a functional polymorphism within the 3'-untranslated region of denticleless E3 ubiquitin protein ligase homolog associated with survival in acral melanoma. Eur J Cancer. 2019;118:70-81.
Yang, L., Dai, J., Ma, M., Mao, L., Si, L., Cui, C., ... Guo, J. (2019). Identification of a functional polymorphism within the 3'-untranslated region of denticleless E3 ubiquitin protein ligase homolog associated with survival in acral melanoma. European Journal of Cancer (Oxford, England : 1990), 118, pp. 70-81. doi:10.1016/j.ejca.2019.06.006.
Yang L, et al. Identification of a Functional Polymorphism Within the 3'-untranslated Region of Denticleless E3 Ubiquitin Protein Ligase Homolog Associated With Survival in Acral Melanoma. Eur J Cancer. 2019;118:70-81. PubMed PMID: 31325875.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of a functional polymorphism within the 3'-untranslated region of denticleless E3 ubiquitin protein ligase homolog associated with survival in acral melanoma. AU - Yang,Lu, AU - Dai,Jie, AU - Ma,Meng, AU - Mao,Lili, AU - Si,Lu, AU - Cui,Chuanliang, AU - Sheng,Xinan, AU - Chi,Zhihong, AU - Yu,Sifan, AU - Xu,Tianxiao, AU - Yu,Jinyu, AU - Kong,Yan, AU - Guo,Jun, Y1 - 2019/07/17/ PY - 2018/11/28/received PY - 2019/05/07/revised PY - 2019/06/20/accepted PY - 2019/7/22/pubmed PY - 2019/7/22/medline PY - 2019/7/21/entrez KW - Acral melanoma KW - DTL KW - Genetic variants KW - Prognosis KW - hsa-miR-4672 SP - 70 EP - 81 JF - European journal of cancer (Oxford, England : 1990) JO - Eur. J. Cancer VL - 118 N2 - 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. SN - 1879-0852 UR - https://www.unboundmedicine.com/medline/citation/31325875/Identification_of_a_functional_polymorphism_within_the_3'-untranslated_region_of_denticleless_E3_ubiquitin_protein_ligase_homolog_associated_with_survival_in_acral_melanoma L2 - https://linkinghub.elsevier.com/retrieve/pii/S0959-8049(19)30374-0 DB - PRIME DP - Unbound Medicine ER -