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.
Highlights
Colorectal cancer (CRC) is one of the most common malignant gastrointestinal cancers [1] and ranks the fifth leading cause of cancer-related death in China [2]
According to the clinical data extracted from The Cancer Genome Atlas (TCGA) (Supplementary Table S1), we observed that there was no significant difference among different stages in the StromalScore (P = 0.053; Figure 1A)
The StromalScore ranged from -2,286.02 to 1,695.44, ImmuneScore ranged from -741.19 to 2,489.81, and ESTIMATEScore ranged from -3,027.21 to 4,185.25
Summary
Colorectal cancer (CRC) is one of the most common malignant gastrointestinal cancers [1] and ranks the fifth leading cause of cancer-related death in China [2]. The Estimation of STromal and Immune cells in MAlignant Tumours using Expression data (ESTIMATE) algorithm is an accurate method to calculate the specific gene data expression signature to evaluate the infiltration of stromal and immune cells and tumor purity. It is a broad, novel, and reliable algorithm that has been administered in data mining of several cancers, and this method has been proven effective in several large independent databases [20,21,22,23,24]. Several studies have confirmed that the scores are associated with the clinicopathological characteristics and chemotherapeutic drug resistance in various types of tumors, and that ESTIMATE could be used as an indicator for patient prognosis assessment [27,28,29]
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