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A novel ceRNA axis involves in regulating immune infiltrates and macrophage polarization in gastric cancer.
International Immunopharmacology ( IF 5.6 ) Pub Date : 2020-08-04 , DOI: 10.1016/j.intimp.2020.106845
Kechao Nie 1 , Zhihua Zheng 1 , Yi Wen 1 , Jinglin Pan 2 , Yufeng Liu 3 , Xiaotao Jiang 1 , Yanhua Yan 1 , Kailin Jiang 1 , Peng Liu 1 , Shijie Xu 4 , Fengbin Liu 3 , Peiwu Li 3
Affiliation  

Background

Increasing evidence suggests that the lncRNA-miRNA-mRNA regulatory network is highly correlated with gastric cancer (GC) development. However, a prognosis-associated lncRNA-miRNA-mRNA network remains to be identified in GC.

Methods

Differentially expressed genes (DEGs) were screened by integrating 6 microarray datasets using the RRA method. Hub genes were identified by analysing their degrees in a PPI (protein–protein interaction) network. Upstream miRNAs and lncRNAs of hub genes were predicted by miRTarBase and miRNet, respectively. Key genes, miRNAs and lncRNAs were identified by evaluating their expression and prognosis in GEPIA and Kaplan-Meier plotter, respectively. A key lncRNA-miRNA-mRNA network was constructed in Cytoscape, and the correlations were analysed in the ENCORI database. We also evaluated the mRNA expression of ceRNA axes in the TIMER and Oncomine databases and their correlation with prognosis in GC patients with different clinical features using Kaplan-Meier plotter. In addition, correlations between mRNA and immune infiltrating cells in GC were investigated by the TIMER database. Finally, several experiments were conducted to verify our analyses.

Results

Forty-two upregulated and 86 downregulated DEGs were obtained from the “RRA” integrated analysis. Eight of the 20 hub genes were identified as key genes by analysing their expression and prognosis. Seventeen miRNAs were predicted to target key genes, and low expression of 4 miRNAs suggested poor outcome in GC. Furthermore, 155 lncRNAs were predicted to target 4 key miRNAs, and only 5 lncRNAs were highly expressed, suggesting poor outcomes in patients with GC. Then, the H19-miR-29a-3p-COL1A2 axis was constructed by correlation analysis. In addition, COL1A2 was positively correlated with lymphatic metastasis, immune infiltrating cell levels, markers of monocytes, tumour-associated macrophages (TAMs), and M2 macrophages but not M1 macrophages in GC. The experimental results revealed that the H19-miR-29a-3p-COL1A2 axis may promote macrophage polarization from M1 to M2 in GC.

Conclusions

A novel lncRNA-miRNA-mRNA axis was identified and may be involved in regulating immune cell infiltration and macrophage polarization, which may provide new treatment strategies for GC.



中文翻译:

新型的ceRNA轴涉及在胃癌中调节免疫浸润和巨噬细胞极化。

背景

越来越多的证据表明,lncRNA-miRNA-mRNA调控网络与胃癌(GC)的发展高度相关。然而,与预后相关的lncRNA-miRNA-mRNA网络仍有待在GC中鉴定。

方法

通过使用RRA方法整合6个微阵列数据集来筛选差异表达基因(DEG)。通过分析它们在PPI(蛋白质-蛋白质相互作用)网络中的程度来鉴定轮毂基因。miRTarBase和miRNet分别预测了轮毂基因的上游miRNA和lncRNA。通过分别评估其在GEPIA和Kaplan-Meier绘图仪中的表达和预后来鉴定关键基因,miRNA和lncRNA。在Cytoscape中构建了关键的lncRNA-miRNA-mRNA网络,并在ENCORI数据库中分析了相关性。我们还使用Kaplan-Meier绘图仪评估了TIMER和Oncomine数据库中ceRNA轴的mRNA表达及其与不同临床特征的GC患者预后的相关性。此外,通过TIMER数据库研究了mRNA与GC中免疫浸润细胞之间的相关性。最后,进行了几次实验以验证我们的分析。

结果

从“ RRA”综合分析中获得了42个上调的DEG和86个下调的DEG。通过分析20个中枢基因的表达和预后,将其确定为关键基因。预测有17个miRNA靶向关键基因,而4个miRNA的低表达表明GC的结果较差。此外,预测有155个lncRNA靶向4个关键miRNA,只有5个lncRNA高表达,提示GC患者预后较差。然后,通过相关分析来构建H19-miR-29a-3p-COL1A2轴。另外,COL1A2与GC中的淋巴转移,免疫浸润细胞水平,单核细胞标志物,肿瘤相关巨噬细胞(TAM)和M2巨噬细胞呈正相关。

结论

确定了一个新的lncRNA-miRNA-mRNA轴,并可能参与调节免疫细胞浸润和巨噬细胞极化,这可能为GC提供新的治疗策略。

更新日期:2020-08-04
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