Identification of key genes involved in tumor immune cell infiltration and cetuximab resistance in colorectal cancer.
Identification of key genes involved in tumor immune cell infiltration and cetuximab resistance in colorectal cancer.
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结直肠癌肿瘤免疫细胞浸润和西妥昔单抗耐药相关关键基因的鉴定
DOI：
10.1186/s12935-021-01829-8
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发表时间：
2021-02-25
影响因子：
5.8
通讯作者：
Liu T
中科院分区：
文献类型：
--
作者：
Liang L;Liu M;Sun X;Yuan Y;Peng K;Rashid K;Yu Y;Cui Y;Chen Y;Liu T
背景抗表皮生长因子受体（EGFR）抗体向转录组引入适应性变异并触发肿瘤免疫浸润，导致结直肠癌（CRC）治疗耐药。我们的目的是鉴定在西妥昔单抗耐药和肿瘤免疫细胞浸润中起重要作用的基因。方法建立西妥昔单抗耐药CACO2细胞模型，并通过微阵列检测其转录组变异。同时，还下载了基因表达综合数据库和癌症基因组图谱（TCGA）数据库的公共数据。应用综合生物信息学分析来检测西妥昔单抗耐药组和西妥昔单抗敏感组之间的差异表达基因（DEG）。然后，我们研究了 DEG 与免疫细胞浸润之间的相关性。生物信息学分析的 DEG 在体外和临床样本中得到进一步验证。结果我们在诱导细胞模型中鉴定出 732 个上调的 DEG 和 1259 个下调的 DEG。基因本体论和京都基因和基因组百科全书途径富集分析，以及基因集富集分析和基因集变异分析，表明了 DEG 的功能。与 GSE59857 和 GSE5841 一起，鉴定了 12 个常见 DEG（SATB-2、AKR1B10、ADH1A、ADH1C、MYB、ATP10B、CDX-2、FAR2、EPHB2、SLC26A3、ORP-1、VAV3），并在 GSE56386 中验证了它们对西妥昔单抗治疗的预测价值。在在线癌症药物敏感性基因组学 (GDSC) 数据库中，十二个 DEG 中有九个在蛋白质-蛋白质 (PPI) 网络中得到识别。基于TCGA中CRC样本的转录组图谱并使用肿瘤免疫估计资源2.0版，我们通过生物信息学方法确定了SATB-2、ORP-1、MYB和CDX-2的表达与B细胞、CD4+T细胞、CD8+T细胞和巨噬细胞的密集浸润相关，然后通过免疫组织化学在临床样本中验证了相关性。我们发现西妥昔单抗治疗在体外下调了SATB-2、ORP-1、MYB和CDX-2。临床上，ORP-1高表达的晚期CRC患者接受抗EGFR治疗比ORP-1低表达的患者表现出更长的无进展生存时间。结论SATB-2、ORP-1、MYB和CDX-2与CRC患者对西妥昔单抗的敏感性以及增强的肿瘤免疫细胞浸润有关。
BackgroundThe anti-epidermal growth factor receptor (EGFR) antibody introduces adaptable variations to the transcriptome and triggers tumor immune infiltration, resulting in colorectal cancer (CRC) treatment resistance. We intended to identify genes that play essential roles in cetuximab resistance and tumor immune cell infiltration.MethodsA cetuximab-resistant CACO2 cellular model was established, and its transcriptome variations were detected by microarray. Meanwhile, public data from the Gene Expression Omnibus and The Cancer Genome Atlas (TCGA) database were downloaded. Integrated bioinformatics analysis was applied to detect differentially expressed genes (DEGs) between the cetuximab-resistant and the cetuximab-sensitive groups. Then, we investigated correlations between DEGs and immune cell infiltration. The DEGs from bioinformatics analysis were further validated in vitro and in clinical samples.ResultsWe identified 732 upregulated and 1259 downregulated DEGs in the induced cellular model. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, along with Gene Set Enrichment Analysis and Gene Set Variation Analysis, indicated the functions of the DEGs. Together with GSE59857 and GSE5841, 12 common DEGs (SATB-2,AKR1B10,ADH1A,ADH1C,MYB,ATP10B,CDX-2,FAR2,EPHB2,SLC26A3,ORP-1,VAV3) were identified and their predictive values of cetuximab treatment were validated in GSE56386. In online Genomics of Drug Sensitivity in Cancer (GDSC) database, nine of twelve DEGs were recognized in the protein-protein (PPI) network. Based on the transcriptome profiles of CRC samples in TCGA and using Tumor Immune Estimation Resource Version 2.0, we bioinformatically determined thatSATB-2, ORP-1, MYB, andCDX-2expressions were associated with intensive infiltration of B cell, CD4+T cell, CD8+T cell and macrophage, which was then validated the correlation in clinical samples by immunohistochemistry. We found thatSATB-2,ORP-1, MYB, andCDX-2were downregulated in vitro with cetuximab treatment. Clinically, patients with advanced CRC and highORP-1expression exhibited a longer progression-free survival time when they were treated with anti-EGFR therapy than those with lowORP-1expression.ConclusionsSATB-2, ORP-1, MYB, andCDX-2were related to cetuximab sensitivity as well as enhanced tumor immune cell infiltration in patients with CRC.
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影响因子：
14.9
作者：
Ritchie ME;Phipson B;Wu D;Hu Y;Law CW;Shi W;Smyth GK
通讯作者：
Smyth GK
影响因子：
51.1
作者：
Primrose, John;Falk, Stephen;Bridgewater, John
通讯作者：
Bridgewater, John
影响因子：
5.3
作者：
Motazacker, Mahdi M.;Pirhonen, Juho;Olkkonen, Vesa M.
通讯作者：
Olkkonen, Vesa M.
影响因子：
11.2
作者：
Li T;Fan J;Wang B;Traugh N;Chen Q;Liu JS;Li B;Liu XS
通讯作者：
Liu XS
影响因子：
5.4
作者：
Mansour, Mohammed A.;Hyodo, Toshinori;Senga, Takeshi
通讯作者：
Senga, Takeshi