Identification and validation of methylated differentially expressed miRNAs and immune infiltrate profile in EBV-associated gastric cancer.
Identification and validation of methylated differentially expressed miRNAs and immune infiltrate profile in EBV-associated gastric cancer.
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EBV 相关胃癌甲基化差异表达 miRNA 和免疫浸润谱的鉴定和验证
DOI：
10.1186/s13148-020-00989-0
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发表时间：
2021-01-29
影响因子：
5.7
通讯作者：
Li G
中科院分区：
文献类型：
--
作者：
Zhu M;Liang Q;Chen T;Kong Q;Ye G;Yu S;Li X;He Q;Liu H;Hu Y;Yu J;Li G
最近发现的miRNA的癌症/组织特异性表明其作为治疗靶点的巨大潜力。在eb病毒相关胃癌（EBVaGC）中，宿主基因受到广泛的DNA甲基化，包括mirna的影响。然而，甲基化miRNA在EBVaGC的发展和免疫细胞浸润中的作用在很大程度上仍然是未知的。在基因表达图谱（Gene expression Omnibus， GEO）和癌症基因组图谱研究网络（Cancer Genome Atlas Research Network， TCGA）中交叉匹配miRNA和mRNA的DNA甲基化和表达谱后，我们发现miR-129-2-3p在EBVaGC中由于其增强子的超甲基化而被显著抑制。差异表达基因（DEGs）共计30个，其中预测AKAP12和LARP6是miR-129-2-3p的靶基因，与患者生存率呈负相关。因此，在我们的队列中，40例病例中有26例（65%）的肿瘤样本中miR-129-2-3p显著下调（P < 0.0001）。转染miR-129-2-3p抑制剂可显著促进GC细胞的增殖、迁移和侵袭功能，转染模拟物或5-aza-2 ' -脱氧胞苷可抑制GC细胞的增殖、迁移和侵袭功能。此外，结合推测的转录因子、miRNA-mRNA和蛋白-蛋白相互作用（PPI）分析，建立了一个全面的调控网络。途径富集分析表明，细胞因子活性，尤其是CCL20，是EBVaGC发育过程中最突出的生物学过程。免疫细胞浸润分析显示CD4+ T细胞、巨噬细胞和树突状细胞浸润显著富集预示预后的枢纽基因。本研究通过整合GEO和TCGA的转录组、甲基组和临床数据、肿瘤样本的QPCR和细胞功能分析等多源数据，对与全基因组DNA甲基化相关的差异表达miRNAs和mrna进行了全面分析。这也提示了甲基化miRNA、DEGs与免疫浸润之间的关系。需要进一步的实验和临床研究来探索潜在的机制并验证我们的发现。
The recent discovery of cancer/tissue specificity of miRNA has indicated its great potential as a therapeutic target. In Epstein–Barr virus-associated gastric cancer (EBVaGC), host genes are affected by extensive DNA methylation, including miRNAs. However, the role of methylated miRNA in the development of EBVaGC and immune cell infiltration has largely remained elusive. After crossmatching the DNA methylation and expression profile of miRNA and mRNA in the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas Research Network (TCGA), we discovered that miR-129-2-3p was significantly suppressed due to hypermethylation on its enhancer in EBVaGC. The differentially expressed genes (DEGs) added up to 30, among which AKAP12 and LARP6 were predicted to be the target genes of miR-129-2-3p and negatively correlated with patients’ survival. Accordingly, miR-129-2-3p was significantly down-regulated in tumor samples in 26 (65%) out of 40 cases in our cohort (P < 0.0001). The proliferation, migration and invasion functions of GC cells were significantly promoted when transfected with miR-129-2-3p inhibitor and suppressed when transfected with mimics or treated with 5-aza-2′-deoxycytidine. Moreover, a comprehensive regulation network was established by combining the putative transcription factors, miRNA-mRNA and protein–protein interaction (PPI) analysis. Pathway enrichment analysis showed that cytokine activity, especially CCL20, was the most prominent biological process in EBVaGC development. Immune cell infiltration analysis demonstrated CD4+ T cell, macrophage and dendritic cell infiltrates were significantly enriched for the prognostic-indicated hub genes. This study has provided a comprehensive analysis of differentially expressed miRNAs and mRNAs associated with genome-wide DNA methylation by integrating multi-source data including transcriptome, methylome and clinical data from GEO and TCGA, QPCR of tumor samples and cell function assays. It also gives a hint on the relationships between methylated miRNA, DEGs and the immune infiltration. Further experimental and clinical investigations are warranted to explore the underlying mechanism and validate our findings.
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