Identification of a functional polymorphism within the 3 '-untranslated region of denticleless E3 ubiquitin protein ligase homolog associated with survival in acral melanoma
Identification of a functional polymorphism within the 3 '-untranslated region of denticleless E3 ubiquitin protein ligase homolog associated with survival in acral melanoma
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DOI：
10.1016/j.ejca.2019.06.006
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发表时间：
2019
影响因子：
8.4
通讯作者：
Guo Jun
中科院分区：
文献类型：
--
作者：
Yang Lu;Dai Jie;Ma Meng;Mao Lili;Si Lu;Cui Chuanliang;Sheng Xinan;Chi Zhihong;Yu Sifan;Xu Tianxiao;Yu Jinyu;Kong Yan;Guo Jun
Backgroundless E3泛素蛋白连接酶同源物（DTL）的高表达与皮肤黑色素瘤的无病生存率和总生存率相关，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。在发现队列（n = 570）中对AM患者DTLin的3′-非翻译区（3′UTR）中的两个候选标签单核苷酸多态性（SNP）进行测序并分析其与生存的相关性，并对显著SNP进行复制队列（n = 201）。免疫组化法检测DTL的表达。结果与良性黑素细胞痣相比，AM中DTL过表达。在两个队列和联合队列中，发现rs 11275300：C > G与AM患者的无进展生存期和总生存期显著相关。体外分析表明，DTL是hsa-miR-4672的直接靶点，rs 11275300：G等位基因干扰了hsa-miR-4672与DTL基因3′UTR的结合亲和力，从而增加了DTL的表达。结论位于DTL基因3 ′ UTR的rs 11275300：G等位基因可能通过转录后调节导致AM患者的预后不良和DTL表达的等位基因特异性增加。
BackgroundHigh 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.MethodsThe 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) ofDTLin 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 usingin silicotarget prediction tools and validated byin vitroanalysis.ResultsDTL 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 vitroanalysis demonstrated thatDTLwas 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 ofDTLand thereby increasedDTLexpression.ConclusionThe rs11275300:G allele in the 3′UTR ofDTLmay lead to a poor prognosis and allele-specific increase in the expression ofDTLby post-transcriptional regulation in AM.