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.
Eur J Cancer. 2019 Sep;118:70-81. doi: 10.1016/j.ejca.2019.06.006. Epub 2019 Jul 17.
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.
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.
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.
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.
牙本质生成蛋白 E3 泛素连接酶同源物（DTL）高表达与皮肤黑色素瘤无病生存率和总生存率降低相关，但该基因在肢端黑色素瘤（AM）中的分子特征和临床意义尚不清楚。
利用现有基因表达综合数据库（GEO）数据比较 AM 和良性黑色素痣中 DTL 的表达水平，并在新鲜冷冻组织中进行验证。对 AM 患者 DTL 3′非翻译区（UTR）中的两个候选标签单核苷酸多态性（SNP）进行测序，并在发现队列（n=570）中分析其与生存的相关性，对显著 SNP 进行复制队列（n=201）分析。采用免疫组织化学法评估 DTL 的表达。采用计算机目标预测工具预测与 rs11275300：C>G 相互作用的 microRNA，并通过体外分析进行验证。
与良性黑色素痣相比，AM 中 DTL 表达上调。在两个队列和联合队列中，均发现 rs11275300：C>G 与 AM 患者的无进展生存率和总生存率显著相关。此外，携带 rs11275300：G 等位基因的患者 DTL 表达水平高于携带 CC 基因型的患者。体外分析表明 DTL 是 hsa-miR-4672 的直接靶基因，rs11275300：G 等位基因干扰了 hsa-miR-4672 与 DTL 3′UTR 的结合亲和力，从而增加了 DTL 的表达。
DTL 3′UTR 中的 rs11275300：G 等位基因可能导致 AM 预后不良，并通过转录后调控特异性增加 DTL 的表达。
