Weighted Gene Co-expression Network Analysis Identifies CALD1 as a Biomarker Related to M2 Macrophages Infiltration in Stage III and IV Mismatch Repair-Proficient Colorectal Carcinoma

Author:

Zheng Hang,Bai Yuge,Wang Jingui,Chen Shanwen,Zhang Junling,Zhu Jing,Liu Yucun,Wang Xin

Abstract

Immunotherapy has achieved efficacy for advanced colorectal cancer (CRC) patients with a mismatch-repair-deficient (dMMR) subtype. However, little immunotherapy efficacy was observed in patients with the mismatch repair-proficient (pMMR) subtype, and hence, identifying new immune therapeutic targets is imperative for those patients. In this study, transcriptome data of stage III/IV CRC patients were retrieved from the Gene Expression Omnibus database. The CIBERSORT algorithm was used to quantify immune cellular compositions, and the results revealed that M2 macrophage fractions were higher in pMMR patients as compared with those with the dMMR subtype; moreover, pMMR patients with higher M2 macrophage fractions experienced shorter overall survival (OS). Subsequently, weighted gene co-expression network analysis and protein–protein interaction network analysis identified six hub genes related to M2 macrophage infiltrations in pMMR CRC patients: CALD1, COL6A1, COL1A2, TIMP3, DCN, and SPARC. Univariate and multivariate Cox regression analyses then determined CALD1 as the independent prognostic biomarker for OS. CALD1 was upregulated specifically the in CMS4 CRC subtype, and single-sample Gene Set Enrichment Analysis (ssGSEA) revealed that CALD1 was significantly correlated with angiogenesis and TGF-β signaling gene sets enrichment scores in stage III/IV pMMR CRC samples. The Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm and correlation analysis revealed that CALD1 was significantly associated with multiple immune and stromal components in a tumor microenvironment. In addition, GSEA demonstrated that high expression of CALD1 was significantly correlated with antigen processing and presentation, chemokine signaling, leukocyte transendothelial migration, vascular smooth muscle contraction, cytokine–cytokine receptor interaction, cell adhesion molecules, focal adhesion, MAPK, and TGF-beta signaling pathways. Furthermore, the proliferation, invasion, and migration abilities of cancer cells were suppressed after reducing CALD1 expression in CRC cell lines. Taken together, multiple bioinformatics analyses and cell-level assays demonstrated that CALD1 could serve as a prognostic biomarker and a prospective therapeutic target for stage III/IV pMMR CRCs.

Publisher

Frontiers Media SA

Subject

Biochemistry, Genetics and Molecular Biology (miscellaneous),Molecular Biology,Biochemistry

Reference72 articles.

1. The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages.;Allavena;Crit. Rev. Oncol. Hematol.,2008

2. Multi-omics of 34 colorectal cancer cell lines - a resource for biomedical studies.;Berg;Mol. Cancer,2017

3. Leukocyte infiltrate in gastrointestinal adenocarcinomas is strongly associated with tumor microsatellite instability but not with tumor immunogenicity.;Bernal;Cancer Immunol. Immunother.,2011

4. A National Cancer Institute Workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer.;Boland;Cancer Res.,1998

5. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.;Bray;CA Cancer J. Clin.,2018

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3