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Genomic Instability Promotes the Progression of Clear Cell Renal Cell Carcinoma Through Influencing the Immune Microenvironment
Background: Long non-coding RNAs (lncRNAs) are now under discussion as novel promising biomarkers for clear cell renal cell carcinoma (ccRCC). However, the role of genomic instability-associated lncRNA signatures in tumors has not been thoroughly uncovered. The purpose of our study is to probe the r...
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/PMC8546190/ https://www.ncbi.nlm.nih.gov/pubmed/34712264 http://dx.doi.org/10.3389/fgene.2021.706661 |
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author | Wei, Xiyi Wang, Yichun Ji, Chengjian Luan, Jiaocheng Yao, Liangyu Zhang, Xi Wang, Shuai Yao, Bing Qin, Chao Song, Ninghong |
author_facet | Wei, Xiyi Wang, Yichun Ji, Chengjian Luan, Jiaocheng Yao, Liangyu Zhang, Xi Wang, Shuai Yao, Bing Qin, Chao Song, Ninghong |
author_sort | Wei, Xiyi |
collection | PubMed |
description | Background: Long non-coding RNAs (lncRNAs) are now under discussion as novel promising biomarkers for clear cell renal cell carcinoma (ccRCC). However, the role of genomic instability-associated lncRNA signatures in tumors has not been thoroughly uncovered. The purpose of our study is to probe the role of genomic instability-derived lncRNA signature (GILncSig) and to further investigate the mechanism of genomic instability-mediated ccRCC progression. Methods: The transcriptome data and somatic mutation profiles of ccRCC as well as clinical characteristics used in this study were obtained from The Cancer Genome Atlas database and Gene Expression Omnibus database. Lasso regression analysis was performed to construct the GILncSig. Gene set enrichment analysis (GSEA) was performed to elucidate the biological functions and relative pathways. CIBERSORT and EPIC algorithm were applied to calculate the proportion of immune cells in ccRCC. ESTIMATE algorithm was utilized to compute the immune microenvironment scores. Results: In total, 148 novel genomic instability-derived lncRNAs in ccRCC were identified. Immediately, on the basis of univariate cox analysis and lasso analysis, a GILncSig was appraised, through which the patients were allocated into High-Risk and Low-Risk groups with significantly different characteristics and prognoses. In addition, we confirmed that the somatic mutation count, tumor mutation burden, and the expression of UBQLN4, which were ascertainably associated with genomic instability, were significantly correlated with the GILncSig, indicating its reliability as a measurement of the genomic instability. Furthermore, the efficiency of GILncSig in prognostic aspects was better than the single mutation gene in ccRCC. In addition, MNX1-AS1 was defined to be a potential biomarker characterized by strong correlation with clinical features. Moreover, GSEA results indicated that the IL6/JAK/STAT3/SIGNALING pathway could be considered as a potential mechanism of genomic instability to influence tumor progression. Besides, the immune microenvironment showed significant differences between the GS-like group and the GU-like group, which was specifically manifested as high expression of CTLA4, GITR, TNFSF14, and regulatory T cells (Tregs) as well as low expression of endothelial cells (ECs) in the GU-like group. Finally, the prognostic value and clinical relevance of GILncSig were verified in GEO datasets and other urinary tumors in TCGA dataset. Conclusion: In conclusion, our study provided a new perspective for the role of lncRNAs in genomic instability and revealed that genomic instability may mediate tumor progression by affecting immunity. Besides, MNX1-AS1 played critical roles in promoting the progression of ccRCC, which may be a potential therapeutic target. What is more, the immune atlas of genomic instability was characterized by high expression of CTLA4, GITR, TNFSF14, and Tregs, and low expression of ECs. |
format | Online Article Text |
id | pubmed-8546190 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-85461902021-10-27 Genomic Instability Promotes the Progression of Clear Cell Renal Cell Carcinoma Through Influencing the Immune Microenvironment Wei, Xiyi Wang, Yichun Ji, Chengjian Luan, Jiaocheng Yao, Liangyu Zhang, Xi Wang, Shuai Yao, Bing Qin, Chao Song, Ninghong Front Genet Genetics Background: Long non-coding RNAs (lncRNAs) are now under discussion as novel promising biomarkers for clear cell renal cell carcinoma (ccRCC). However, the role of genomic instability-associated lncRNA signatures in tumors has not been thoroughly uncovered. The purpose of our study is to probe the role of genomic instability-derived lncRNA signature (GILncSig) and to further investigate the mechanism of genomic instability-mediated ccRCC progression. Methods: The transcriptome data and somatic mutation profiles of ccRCC as well as clinical characteristics used in this study were obtained from The Cancer Genome Atlas database and Gene Expression Omnibus database. Lasso regression analysis was performed to construct the GILncSig. Gene set enrichment analysis (GSEA) was performed to elucidate the biological functions and relative pathways. CIBERSORT and EPIC algorithm were applied to calculate the proportion of immune cells in ccRCC. ESTIMATE algorithm was utilized to compute the immune microenvironment scores. Results: In total, 148 novel genomic instability-derived lncRNAs in ccRCC were identified. Immediately, on the basis of univariate cox analysis and lasso analysis, a GILncSig was appraised, through which the patients were allocated into High-Risk and Low-Risk groups with significantly different characteristics and prognoses. In addition, we confirmed that the somatic mutation count, tumor mutation burden, and the expression of UBQLN4, which were ascertainably associated with genomic instability, were significantly correlated with the GILncSig, indicating its reliability as a measurement of the genomic instability. Furthermore, the efficiency of GILncSig in prognostic aspects was better than the single mutation gene in ccRCC. In addition, MNX1-AS1 was defined to be a potential biomarker characterized by strong correlation with clinical features. Moreover, GSEA results indicated that the IL6/JAK/STAT3/SIGNALING pathway could be considered as a potential mechanism of genomic instability to influence tumor progression. Besides, the immune microenvironment showed significant differences between the GS-like group and the GU-like group, which was specifically manifested as high expression of CTLA4, GITR, TNFSF14, and regulatory T cells (Tregs) as well as low expression of endothelial cells (ECs) in the GU-like group. Finally, the prognostic value and clinical relevance of GILncSig were verified in GEO datasets and other urinary tumors in TCGA dataset. Conclusion: In conclusion, our study provided a new perspective for the role of lncRNAs in genomic instability and revealed that genomic instability may mediate tumor progression by affecting immunity. Besides, MNX1-AS1 played critical roles in promoting the progression of ccRCC, which may be a potential therapeutic target. What is more, the immune atlas of genomic instability was characterized by high expression of CTLA4, GITR, TNFSF14, and Tregs, and low expression of ECs. Frontiers Media S.A. 2021-10-12 /pmc/articles/PMC8546190/ /pubmed/34712264 http://dx.doi.org/10.3389/fgene.2021.706661 Text en Copyright © 2021 Wei, Wang, Ji, Luan, Yao, Zhang, Wang, Yao, Qin and Song. 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 | Genetics Wei, Xiyi Wang, Yichun Ji, Chengjian Luan, Jiaocheng Yao, Liangyu Zhang, Xi Wang, Shuai Yao, Bing Qin, Chao Song, Ninghong Genomic Instability Promotes the Progression of Clear Cell Renal Cell Carcinoma Through Influencing the Immune Microenvironment |
title | Genomic Instability Promotes the Progression of Clear Cell Renal Cell Carcinoma Through Influencing the Immune Microenvironment |
title_full | Genomic Instability Promotes the Progression of Clear Cell Renal Cell Carcinoma Through Influencing the Immune Microenvironment |
title_fullStr | Genomic Instability Promotes the Progression of Clear Cell Renal Cell Carcinoma Through Influencing the Immune Microenvironment |
title_full_unstemmed | Genomic Instability Promotes the Progression of Clear Cell Renal Cell Carcinoma Through Influencing the Immune Microenvironment |
title_short | Genomic Instability Promotes the Progression of Clear Cell Renal Cell Carcinoma Through Influencing the Immune Microenvironment |
title_sort | genomic instability promotes the progression of clear cell renal cell carcinoma through influencing the immune microenvironment |
topic | Genetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8546190/ https://www.ncbi.nlm.nih.gov/pubmed/34712264 http://dx.doi.org/10.3389/fgene.2021.706661 |
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