Research Paper Volume 15, Issue 7 pp 2554—2581
A novel inflammation-related signature for predicting prognosis and characterizing the tumor microenvironment in colorectal cancer
- 1 Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, China
- 2 Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, China
Received: April 20, 2022 Accepted: March 17, 2023 Published: April 2, 2023
https://doi.org/10.18632/aging.204630How to Cite
Copyright: © 2023 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Inflammation is a critical component of tumor progression, and it modifies the tumor microenvironment by various mechanisms. Here, we explore the effect of the inflammatory response on the tumor microenvironment in colorectal cancer (CRC). A prognostic signature consisting of inflammation-related genes (IRGs) was constructed and verified based on the inflammatory response by bioinformatics analysis. IRG risk model was identified as an independent prognostic factor in CRC, and was related to biological processes of extracellular matrix, cell adhesion and angiogenesis. The IRG risk score predicted the clinical benefit of ipilimumab. Weighted correlation network analysis identified TIMP1 as the hub gene of the inflammatory response in the IRG risk model. Coculture experiments with macrophages and CRC cells revealed that TIMP1 promoted macrophage migration, inhibited the expression of M1 markers (CD11C and CD80), and promoted the expression of M2 markers (ARG1 and CD163). TIMP1 promoted the expression of ICAM1 and CCL2 by activating the ERK1/2 signaling pathway to promote macrophage migration and M2-like polarization. These IRGs in the risk model regulated stromal and immune components in the tumor microenvironment and could serve as potential therapeutic targets in CRC. TIMP1 promoted macrophage migration and meditated macrophage M2 polarization by activating ERK1/2/CLAM1 and CCL2.
Abbreviations
CRC: colorectal cancer; IRG: inflammation-related gene; TME: tumor microenvironment; TAMs: tumor-associated macrophages; TIMP1: tissue inhibitor of matrix metalloproteinase-1; MSigDB: Molecular Signatures Database; DEG: differentially expressed gene; LASSO: least absolute shrinkage and selection operator; TCGA: The Cancer Genome Atlas; OS: overall survival; PFS: progress free survival; ROC: receiver operating characteristic; AUC: area under the curve; CNV: copy number variation; TMB: tumor mutation burden; GO: Gene Ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes; GSEA: gene set enrichment analysis; GSVA: gene set variation analysis; MSCs: mesenchymal stem cells; MEPs: megakaryocyte-erythroid progenitors; NK: natural killer; WGCNA: weighted correlation network analysis; TOM: topological overlap matrix; GS: gene significance; MM: module membership; PBMCs: peripheral blood mononuclear cells; CTLA-4: cytotoxic T lymphocyte-associated antigen-4; CAFs: cancer-associated fibroblasts; GEO: Gene Expression Omnibus; DAVID: Database for Annotation, Visualization and Integrated Discovery; FDR: false discovery rate; NES: normalized enrichment score; ME: module eigengene.