肺腺癌增强子调控miRNA前馈环路的识别与功能分析

Identification and Functional Analysis of miRNA Feed-Forward Loops Regulated by Enhancers in Lung Adenocarcinoma

目的:先前研究表明前馈环路作为重要的调控模式广泛参与肿瘤调控。通过整合多组学数据,阐明肺腺癌转录因子(TF)-增强子-miRNA这一新的前馈环路模式,以期为肺癌的潜在肿瘤标志物识别与相关研究提供理论与方法依据。方法:基于增强子数据库HACER,获取肺腺癌组织特异性增强子并识别TF-增强子、增强子-miRNA、TFmiRNA作用关系,利用超几何检验构建TF-增强子-miRNA前馈环路。通过mirTarBase数据库获取前馈环路的靶基因,分别对靶基因进行GO和KEGG功能富集分析,并对前馈环路的关键基因进行生存分析。筛选前馈环路关键miRNA,并对关键miRNA进行基因调控网络分析。结果:共识别了36条TF-增强子-miRNA前馈环路,功能富集结果显示肺腺癌前馈环路涉及的高表达miRNA(hsa-miR-6734、hsa-miR-210、hsa-miR-4677和hsa-let-7i)在细胞周期、细胞分化、能量代谢和糖代谢等方面具有重要功能,并显著富集于细胞增殖相关的糖代谢与氨基酸代谢通路中。生存分析结果表明前馈环路的多效靶基因TP53、CREB1、STAT5B、TPR的表达差异显著影响肺癌患者的生存时间。结论:TF-增强子-miRNA前馈环路靶基因广泛参与肺癌发生发展相关生物学功能和代谢通路,其调控的多效靶基因TP53、CREB1、STAT5B、TPR表达差异对肺癌患者的生存发展有显著影响。

Objective:Previous studies have shown that feed-forward loops(FFLs)can be widely involved in tumor regulation as an important regulatory pattern.We clarify the new transcription factor(TF)-enhancer-miRNA FFL model of lung adenocarcinoma by integrating multi-omics data,in order to provide theory and method for potential tumor marker recognition and related research of lung cancer.Methods:Based on the enhancer database HACER,the lung adenocarcinoma tissue-specific enhancer was obtained and the relationship between TF-enhancer,enhancer-miRNA and TF-miRNA was identified,and the TF-enhancer-miRNA FFL was constructed by hypergeometric test.The target genes of the FFL being obtained from the mirTarBase database,the GO and KEGG functional enrichment analysis was performed on the target genes,and the survival analysis of key genes in the FFL was performed.We screened for key miRNAs in the FFL and perform gene regulatory network analysis on key miRNAs.Results:A total of 36 TF-enhancer-miRNA FFLs were identified,and functional enrichment results revealed high expression of miRNAs(hsa-miR-6734,hsa-miR-210,hsa-miR-4677,and hsa-let-7i)involved in lung adenocarcinoma FFLs has important functions in cell cycle,cell differentiation,energy metabolism and glucose metabolism,and is significantly enriched in cell metabolism-related glucose metabolism and amino acid metabolism pathways.Survival analysis showed that the differential expression of the multi-effect target genes TP53,CREB1,STAT5B and TPR in the FFL significantly affected the survival time of lung cancer patients.Conclusion:The TF-enhancer-miRNA FFL target gene is widely involved in the biological functions and metabolic pathways involved in the development of lung cancer.The expression difference of regulated multi-effect target gene TP53,CREB1,STAT5B and TPR has a significant impact on the survival and development of lung cancer patients.