Zhou Jinsong, Liu Shuang, Zhang Juwei, Zeng Qiaoyan, Lin Zheng, Fu Rong, Lin Yulan, Hu Zhijian
Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, 1 Xue Yuan Road, University Town, Fuzhou, 350122, China.
Sun Yat-Sen University Cancer Center/Cancer Hospital, Guangzhou, 510060, China.
Int J Clin Oncol. 2025 Feb;30(2):309-319. doi: 10.1007/s10147-024-02656-3. Epub 2024 Dec 4.
Methylation of microRNA (miRNA) promoters associated with diseases is a common epigenetic mechanism in the development of various human cancers. However, its relationship with prognosis in esophageal squamous cell carcinoma (ESCC) remains unclear. This study aims to explore the association between the methylation level of has-miR-3665 promoter and prognosis in ESCC.
Human miRNA data were downloaded from miRbase, and we identified CpG islands of these human miRNAs by genomics browser analysis. MiRNA methylation levels were detected by methylation-specific high-resolution melting. Gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to explore the molecular mechanism of hsa-miR-3665. Cox regression analysis was used to investigate prognostic factors. The overall survival rate was predicted by a nomogram.
We found that 88 human miRNAs had promoter methylatio, of which 15 miRNAs were found to be epigenetically regulated in ESCC cells compared with their normal counterparts, including hsa-miR-3665. Meanwhile, hsa-miR-3665 expression was significantly lower in ESCC tumour tissue than in adjacent tissue (P = 0.03). GO and KEGG analyses demonstrated that the target genes are involved in protein transport, transcription regulator activity, MAPK and RAS signaling pathway. High hsa-miR-3665 promoter methylation levels were associated with a poor prognosis (HR = 3.89, 95% CI 1.11 ~ 13.55). Moreover, a nomogram incorporating the hsa-miR-3665 methylation level and clinical factors presented a good performance for predicting survival in the training and validation tests, with C-indices of 0.748 and 0.751, respectively.
High hsa-miR-3665 promoter methylation levels may be a potential biomarker for the progression of ESCC.
与疾病相关的微小RNA（miRNA）启动子甲基化是多种人类癌症发生发展中常见的表观遗传机制。然而，其与食管鳞状细胞癌（ESCC）预后的关系仍不清楚。本研究旨在探讨hsa-miR-3665启动子甲基化水平与ESCC预后之间的关联。
从miRbase下载人类miRNA数据，并通过基因组浏览器分析确定这些人类miRNA的CpG岛。采用甲基化特异性高分辨率熔解检测miRNA甲基化水平。利用基因本体（GO）和京都基因与基因组百科全书（KEGG）分析探索hsa-miR-3665的分子机制。采用Cox回归分析研究预后因素。通过列线图预测总生存率。
我们发现88个人类miRNA存在启动子甲基化，其中15个miRNA在ESCC细胞中与其正常对应物相比存在表观遗传调控，包括hsa-miR-3665。同时，hsa-miR-3665在ESCC肿瘤组织中的表达明显低于相邻组织（P = 0.03）。GO和KEGG分析表明，靶基因参与蛋白质转运、转录调节活性、MAPK和RAS信号通路。hsa-miR-3665启动子高甲基化水平与预后不良相关（HR = 3.89，95%CI 1.11～13.55）。此外，纳入hsa-miR-3665甲基化水平和临床因素的列线图在训练和验证试验中对生存预测表现良好，C指数分别为0.748和0.751。
hsa-miR-3665启动子高甲基化水平可能是ESCC进展的潜在生物标志物。
