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CX3CR1 在结直肠癌肿瘤微环境中作为一种保护性生物标志物。

CX3CR1 Acts as a Protective Biomarker in the Tumor Microenvironment of Colorectal Cancer.

机构信息

Department of Gastroenterology Medicine, Shengjing Hospital of China Medical University, Shenyang, China.

Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, China.

出版信息

Front Immunol. 2022 Jan 24;12:758040. doi: 10.3389/fimmu.2021.758040. eCollection 2021.

DOI:10.3389/fimmu.2021.758040
PMID:35140706
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8818863/
Abstract

The tumor microenvironment (TME) plays an important role in the pathogenesis of many cancers. We aimed to screen the TME-related hub genes of colorectal adenoma (CRAD) and identify possible prognostic biomarkers. The gene expression profiles and clinical data of 464 CRAD patients in The Cancer Genome Atlas (TCGA) database were downloaded. The Estimation of STromal and Immune cells in MAlignant Tumours using Expression data (ESTIMATE) algorithm was performed to calculate the ImmuneScore, StromalScore, and EstimateScore. Thereafter, differentially expressed genes (DEGs) were screened. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein-protein interaction (PPI) analysis were performed to explore the roles of DEGs. Furthermore, univariate and multivariate Cox analyses were accomplished to identify independent prognostic factors of CRAD. CX3CR1 was selected as a hub gene, and the expression was confirmed in colorectal cancer (CRC) patients and cell lines. The correlations between CX3CR1 and tumor-infiltrating immune cells were estimated by Tumor IMmune Estimation Resource database (TIMER) and CIBERSORT analysis. Besides, we investigated the effects of coculture with THP-1-derived macrophages with HCT8 cells with low CX3CR1 expression on immune marker expression, cell viability, and migration. There were significant differences in the ImmuneScore and EstimateScore among different stages. Patients with low scores presented significantly lower lifetimes than those in the high-score group. Moreover, we recognized 1,578 intersection genes in ImmuneScore and StromalScore, and these genes were mainly enriched in numerous immune-related biological processes. CX3CR1 was found to be associated with immune cell infiltration levels, immune marker expression, and macrophage polarization. Simultaneous silencing of CX3CR1 and coculture with THP-1 cells further regulated macrophage polarization and promoted the cell proliferation and migration of CRC cells. CX3CR1 was decreased in CRAD tissues and cell lines and was related to T and N stages, tumor differentiation, and prognosis. Our results suggest that CX3CR1 contributes to the recruitment and regulation of immune-infiltrating cells and macrophage polarization in CRC and TAM-induced CRC progression. CX3CR1 may act as a prognostic biomarker in CRC.

摘要

肿瘤微环境（TME）在许多癌症的发病机制中起着重要作用。我们旨在筛选结直肠腺瘤（CRAD）的 TME 相关枢纽基因，并确定可能的预后生物标志物。从癌症基因组图谱（TCGA）数据库中下载了 464 例 CRAD 患者的基因表达谱和临床数据。使用表达数据（ESTIMATE）算法计算了免疫评分、基质评分和估计评分，以评估肿瘤间质和免疫细胞。然后筛选差异表达基因（DEGs）。进行基因本体论（GO）、京都基因与基因组百科全书（KEGG）通路和蛋白质-蛋白质相互作用（PPI）分析，以探讨 DEGs 的作用。此外，进行单变量和多变量 Cox 分析以确定 CRAD 的独立预后因素。选择 CX3CR1 作为枢纽基因，并在结直肠癌（CRC）患者和细胞系中验证其表达。通过肿瘤免疫估计资源数据库（TIMER）和 CIBERSORT 分析评估 CX3CR1 与肿瘤浸润免疫细胞之间的相关性。此外，我们研究了与低 CX3CR1 表达的 HCT8 细胞共培养 THP-1 衍生巨噬细胞对免疫标志物表达、细胞活力和迁移的影响。不同分期的免疫评分和估计评分有显著差异。低评分患者的生存期明显短于高评分组。此外，我们在免疫评分和基质评分之间识别出 1578 个交集基因，这些基因主要富集在许多免疫相关的生物学过程中。CX3CR1 与免疫细胞浸润水平、免疫标志物表达和巨噬细胞极化有关。同时沉默 CX3CR1 并与 THP-1 细胞共培养进一步调节巨噬细胞极化，并促进 CRC 细胞的增殖和迁移。CRAD 组织和细胞系中 CX3CR1 降低，与 T 和 N 分期、肿瘤分化和预后有关。我们的结果表明，CX3CR1 有助于 CRC 中免疫浸润细胞的募集和调节以及 TAM 诱导的 CRC 进展中的巨噬细胞极化。CX3CR1 可能是 CRC 的预后生物标志物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7fe7/8818863/51dd2d027b87/fimmu-12-758040-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7fe7/8818863/e79cb019c2fc/fimmu-12-758040-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7fe7/8818863/18be078a350b/fimmu-12-758040-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7fe7/8818863/40a90bd1c347/fimmu-12-758040-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7fe7/8818863/3259b54a93bb/fimmu-12-758040-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7fe7/8818863/51dd2d027b87/fimmu-12-758040-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7fe7/8818863/e79cb019c2fc/fimmu-12-758040-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7fe7/8818863/c5d7d304675f/fimmu-12-758040-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7fe7/8818863/affce5b359fb/fimmu-12-758040-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7fe7/8818863/dfd7f0677eb8/fimmu-12-758040-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7fe7/8818863/18be078a350b/fimmu-12-758040-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7fe7/8818863/40a90bd1c347/fimmu-12-758040-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7fe7/8818863/3259b54a93bb/fimmu-12-758040-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7fe7/8818863/51dd2d027b87/fimmu-12-758040-g008.jpg

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本文引用的文献

[1]
Co-culturing polarized M2 Thp-1-derived macrophages enhance stemness of lung adenocarcinoma A549 cells.

Ann Transl Med. 2021-4

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CX3CR1 is a prerequisite for the development of cardiac hypertrophy and left ventricular dysfunction in mice upon transverse aortic constriction.

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