Activating miRNA-mRNA network in gemcitabine-resistant pancreatic cancer cell associates with alteration of memory CD4+ T cells
Activating miRNA-mRNA network in gemcitabine-resistant pancreatic cancer cell associates with alteration of memory CD4+ T cells
复制标题
激活吉西他滨耐药胰腺癌细胞中的 miRNA-mRNA 网络与记忆 CD4( ) T 细胞的改变相关
DOI：
10.21037/atm.2020.03.53
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发表时间：
2020-03-01
影响因子：
--
通讯作者：
Wang, Huaizhi
中科院分区：
文献类型：
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作者：
Gu, Jianyou;Zhang, Junfeng;Wang, Huaizhi
背景资料：目的：筛选与胰腺癌吉西他滨耐药相关的关键microRNAs（miRNAs）及其靶mRNA，并探讨其与胰腺癌吉西他滨耐药的关系。在吉西他滨抗性PC细胞和其亲本细胞之间区分差异表达的miRNA和mRNA（分别称为“DEmiRNA”和“DEmRNA”）。使用miRDB、microT和Targetscan检索DEmiRNA靶向的DEmRNA。此外，进行GO和KEGG途径富集分析和GSEA。采用Kaplan-Meier逐步回归分析关键DEmiRNAs和DEmRNAs对PC患者预后的影响。使用CIBERSORT方法，使用LM 22标签作为参考，研究PC中关键DEmRNA与肿瘤浸润免疫细胞之间的关系。进一步分析关键浸润免疫细胞与TCGA PAAD患者预后的相关性。四种DEmiRNA，包括hsa-miR-3178、hsa-miR-485- 3 p、hsa-miR-574- 5 p和hsa-miR-584- 5 p，被鉴定为分别靶向七种DEmRNA，包括MSI 2、TEAD 1、GNPDA 1、RND 3、PRKACB、TRIM 68和YKT 6，在吉西他滨耐药PC细胞与亲本细胞中。吉西他滨耐药PC细胞富含蛋白酶体相关、免疫相关和记忆性CD 4（+）T细胞相关途径，表明吉西他滨对PC细胞具有治疗作用。所有四种DEmiRNAs和几乎所有的DEmRNAs都对PC患者的预后有影响。所有7种DEmRNAs对CD 4（+）记忆T细胞均有显著影响，这受到吉西他滨治疗效果的影响。根据TCGA PAAD数据集，效应记忆性CD 4（+）T细胞而非中枢记忆性CD 4（+）T细胞预测预后良好。吉西他滨抗性可通过hsa-miR-3178、hsa-miR-485- 3 p、hsa-miR-574- 5 p和hsa-miR-584- 5 p靶向的MSI 2、TEAD 1、GNPDA 1、RND 3、PRKACB、TRIM 68、和YKT 6网络。
Background: To identify key microRNAs (miRNAs) and their target mRNAs related to gemcitabine-resistant pancreatic cancer (PC) and investigate the association between gemcitabine-resistant-related miRNAs and mRNAs and immune infiltration.Methods: Expression profiles of miRNAs and mRNAs were obtained from the Gene Expression Omnibus (GEO) database. The differentially expressed miRNAs and mRNAs (referred to as "DEmiRNAs" and "DEmRNAs", respectively) were distinguished between gemcitabine-resistant PC cells and its parental cells. The DEmRNAs targeted by the DEmiRNAs were retrieved using miRDB, microT, and Targetscan. Furthermore, GO and KEGG pathway enrichment analysis and GSEA were performed. The Kaplan-Meier plotter was used to analyze the prognosis of key DEmiRNAs and DEmRNAs on PC patients. The relationship between the key DEmRNAs and tumor-infiltrating immune cells in PC was investigated using CIBERSORT method using the LM22 signature as reference. Key infiltrating immune cells were further analyzed for the associations with prognosis of TCGA PAAD patients.Results: Four DEmiRNAs, including hsa-miR-3178, hsa-miR-485-3p, hsa-miR-574-5p, and hsa-miR-584-5p, were identified to target seven DEmRNAs, including MSI2, TEAD1, GNPDA1, RND3, PRKACB, TRIM68, and YKT6, individually, in gemcitabine-resistant PC cells versus parental cells. Gemcitabine-resistant PC cells were enriched in proteasome-related, immune-related, and memory CD4(+) T cell-related pathways, indicating a gemcitabine therapeutic effect on PC cells. All four DEmiRNAs and almost all DEmRNAs had an impact on the prognosis of PC patients. All seven DEmRNAs had remarkable effects on CD4(+) memory T cells, which were affected by the gemcitabine therapeutic effect. Effector memory CD4(+) T cells rather than central memory CD4(+) T cells predicted a good prognosis according to the TCGA PAAD dataset.Conclusions: Gemcitabine resistance can alter the fraction of memory CD4(+) T cells via hsa-miR-3178, hsa-miR-485-3p, hsa-miR-574-5p and hsa-miR-584-5p targeted MSI2, TEAD1, GNPDA1, RND3, PRKACB, TRIM68, and YKT6 network in PC.