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Follistatin-Like 3 Correlates With Lymph Node Metastasis and Serves as a Biomarker of Extracellular Matrix Remodeling in Colorectal Cancer
BACKGROUND: As a heterogeneous disease, colorectal cancer (CRC) presents a great challenge to individualized treatment due to its lymph node metastasis (LNM). Existing studies have shown that immune and stromal components in extracellular matrix (ECM) act as important part in tumorigenicity and prog...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322704/ https://www.ncbi.nlm.nih.gov/pubmed/34335633 http://dx.doi.org/10.3389/fimmu.2021.717505 |
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author | Yang, Chao Cao, Fengyu Huang, Shuoyang Zheng, Yongbin |
author_facet | Yang, Chao Cao, Fengyu Huang, Shuoyang Zheng, Yongbin |
author_sort | Yang, Chao |
collection | PubMed |
description | BACKGROUND: As a heterogeneous disease, colorectal cancer (CRC) presents a great challenge to individualized treatment due to its lymph node metastasis (LNM). Existing studies have shown that immune and stromal components in extracellular matrix (ECM) act as important part in tumorigenicity and progression, while their roles in LNM have not been fully elucidated. Here, crucial ECM-related genes responsible for LNM in CRC were selected by multi-omics analysis. METHODS: Firstly, we characterized the immune infiltration landscape of CRC samples from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases by using ssGSEA algorithm. The CRC patients were divided into several immune subgroups by hierarchical clustering analyses. Then, differential genes were identified among immune subgroups and CRC vs. normal tissues in TCGA and GEO GSE39582 cohorts, respectively. Next, weighted correlation network analysis (WGCNA) was employed to construct a co-expression network to find LNM-related modules and hub genes. Subsequently, we evaluated the clinical value of hub gene in prognostic prediction and chemotherapy/immunotherapy. Besides, the protein level of key gene was verified in an external cohort from our center. Finally, we explored the underlying mechanism of FSTL3-mediated LNM by Gene function annotation and correlation analysis. RESULTS: Two immune subgroups, namely Immunity_High and Immunity_Low, were defined among the two CRC cohorts using ssGSEA algorithm, respectively. Based on the two immune subgroups, 2,635 overlapping differentially expressed genes were obtained from two cohorts, which were sequentially subjected to WGCNA and univariate Cox regression analysis. Ultimately, FSTL3 was selected as the key gene. Here, we first confirmed that overexpression of FSTL3 correlated with LNM and worse prognosis in CRC and was verified at the protein level in the external validation cohort. Moreover, FSTL3 expression showed strongly positive correlation with immune and stromal components in ECM. We furthermore found that FSTL3 may accelerate LNM through the formation of inhibitory immune microenvironment via promoting macrophage and fibroblast polarization and T cell exhaustion. Interestingly, high FSTL3 expression is linked to chemoresistance, but immunotherapy-sensitive. CONCLUSION: FSTL3 is identified as a biomarker for ECM remodeling and worse clinical outcomes for the first time in CRC and is also a potential immunotherapeutic target to block LNM for CRC. |
format | Online Article Text |
id | pubmed-8322704 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-83227042021-07-31 Follistatin-Like 3 Correlates With Lymph Node Metastasis and Serves as a Biomarker of Extracellular Matrix Remodeling in Colorectal Cancer Yang, Chao Cao, Fengyu Huang, Shuoyang Zheng, Yongbin Front Immunol Immunology BACKGROUND: As a heterogeneous disease, colorectal cancer (CRC) presents a great challenge to individualized treatment due to its lymph node metastasis (LNM). Existing studies have shown that immune and stromal components in extracellular matrix (ECM) act as important part in tumorigenicity and progression, while their roles in LNM have not been fully elucidated. Here, crucial ECM-related genes responsible for LNM in CRC were selected by multi-omics analysis. METHODS: Firstly, we characterized the immune infiltration landscape of CRC samples from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases by using ssGSEA algorithm. The CRC patients were divided into several immune subgroups by hierarchical clustering analyses. Then, differential genes were identified among immune subgroups and CRC vs. normal tissues in TCGA and GEO GSE39582 cohorts, respectively. Next, weighted correlation network analysis (WGCNA) was employed to construct a co-expression network to find LNM-related modules and hub genes. Subsequently, we evaluated the clinical value of hub gene in prognostic prediction and chemotherapy/immunotherapy. Besides, the protein level of key gene was verified in an external cohort from our center. Finally, we explored the underlying mechanism of FSTL3-mediated LNM by Gene function annotation and correlation analysis. RESULTS: Two immune subgroups, namely Immunity_High and Immunity_Low, were defined among the two CRC cohorts using ssGSEA algorithm, respectively. Based on the two immune subgroups, 2,635 overlapping differentially expressed genes were obtained from two cohorts, which were sequentially subjected to WGCNA and univariate Cox regression analysis. Ultimately, FSTL3 was selected as the key gene. Here, we first confirmed that overexpression of FSTL3 correlated with LNM and worse prognosis in CRC and was verified at the protein level in the external validation cohort. Moreover, FSTL3 expression showed strongly positive correlation with immune and stromal components in ECM. We furthermore found that FSTL3 may accelerate LNM through the formation of inhibitory immune microenvironment via promoting macrophage and fibroblast polarization and T cell exhaustion. Interestingly, high FSTL3 expression is linked to chemoresistance, but immunotherapy-sensitive. CONCLUSION: FSTL3 is identified as a biomarker for ECM remodeling and worse clinical outcomes for the first time in CRC and is also a potential immunotherapeutic target to block LNM for CRC. Frontiers Media S.A. 2021-07-16 /pmc/articles/PMC8322704/ /pubmed/34335633 http://dx.doi.org/10.3389/fimmu.2021.717505 Text en Copyright © 2021 Yang, Cao, Huang and Zheng https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Yang, Chao Cao, Fengyu Huang, Shuoyang Zheng, Yongbin Follistatin-Like 3 Correlates With Lymph Node Metastasis and Serves as a Biomarker of Extracellular Matrix Remodeling in Colorectal Cancer |
title | Follistatin-Like 3 Correlates With Lymph Node Metastasis and Serves as a Biomarker of Extracellular Matrix Remodeling in Colorectal Cancer |
title_full | Follistatin-Like 3 Correlates With Lymph Node Metastasis and Serves as a Biomarker of Extracellular Matrix Remodeling in Colorectal Cancer |
title_fullStr | Follistatin-Like 3 Correlates With Lymph Node Metastasis and Serves as a Biomarker of Extracellular Matrix Remodeling in Colorectal Cancer |
title_full_unstemmed | Follistatin-Like 3 Correlates With Lymph Node Metastasis and Serves as a Biomarker of Extracellular Matrix Remodeling in Colorectal Cancer |
title_short | Follistatin-Like 3 Correlates With Lymph Node Metastasis and Serves as a Biomarker of Extracellular Matrix Remodeling in Colorectal Cancer |
title_sort | follistatin-like 3 correlates with lymph node metastasis and serves as a biomarker of extracellular matrix remodeling in colorectal cancer |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322704/ https://www.ncbi.nlm.nih.gov/pubmed/34335633 http://dx.doi.org/10.3389/fimmu.2021.717505 |
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