Uncovering the potential functions of lymph node metastasis-associated aberrant methylation differentially expressed genes and their association with the immune infiltration and prognosis in bladder urothelial carcinoma

Background Bladder urothelial carcinoma (BLCA) is a malignant tumor of the urinary system. This study aimed to explore the potential role of lymph node metastasis-associated aberrant methylation differentially expressed genes (DEGs) in BLCA. Methods CHAMP and limma packages were used to identify lym...

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Main Authors: Wenzhi Gao, Jiafeng Zhang, Tai Tian, Zhixin Fu, Liangliang Bai, Yifei Yang, Qiangqiang Wu, Wei Wang, Yuexian Guo
Format: Article
Language:English
Published: PeerJ Inc. 2023-04-01
Series:PeerJ
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Online Access:https://peerj.com/articles/15284.pdf
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author Wenzhi Gao
Jiafeng Zhang
Tai Tian
Zhixin Fu
Liangliang Bai
Yifei Yang
Qiangqiang Wu
Wei Wang
Yuexian Guo
author_facet Wenzhi Gao
Jiafeng Zhang
Tai Tian
Zhixin Fu
Liangliang Bai
Yifei Yang
Qiangqiang Wu
Wei Wang
Yuexian Guo
author_sort Wenzhi Gao
collection DOAJ
description Background Bladder urothelial carcinoma (BLCA) is a malignant tumor of the urinary system. This study aimed to explore the potential role of lymph node metastasis-associated aberrant methylation differentially expressed genes (DEGs) in BLCA. Methods CHAMP and limma packages were used to identify lymph node metastasis-associated aberrant methylation DEGs. Univariate Cox analysis and Lasso analysis were performed to identify the signature genes, and multivariate Cox analysis was used to construct the risk score. Subsequently, the molecular characteristics of the signature genes and the relationship between risk score and prognosis, clinical characteristics and immune cell infiltration were analyzed. The signature gene AKAP7 was selected for functional verification. Results A novel risk score model was constructed based on 12 signature genes. The risk score had a good ability to predict overall survival (OS). The nomogram constructed based on age, N stage and risk score had a higher value in predicting the prognosis of patients. It was also found that stromal activation in TIME may inhibit the antitumor effects of immune cells. Functional enrichment analysis revealed that ECM receptor interaction and focal adhesion were two important pathways involved in the regulation of BLCA. Immunohistochemistry showed that AKAP7 may be associated with the occurrence, clinical stages and grades, and lymph node metastasis of BLCA. In vitro cell experiments showed that the migration and invasion ability of EJ cells was significantly inhibited after AKAP7 overexpression, while the migration and invasion ability of T24 cells was significantly promoted after AKAP7 knockdown. Conclusion The risk score model based on lymph node metastasis-associated aberrant methylation DEGs has a good ability to predict OS and is an independent prognostic factor for BLCA. It was also found that stromal activation in TIME may inhibit the antitumor effects of immune cells. This implicates aberrant methylation modifications as an important factor contributing to the heterogeneity and complexity of individual tumor microenvironments. Functional enrichment analysis revealed that ECM receptor interaction and focal adhesion were two important pathways involved in the regulation of BLCA, which contributed to the exploration of the pathological mechanism of BLCA. In addition, immunohistochemistry showed that AKAP7 may be associated with the occurrence, progression and lymph node metastasis of BLCA. In vitro cell experiments showed that AKAP7 could also inhibit the migration and invasion of cancer cells.
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spelling doaj.art-17dfe3c6348f492295d1123f902d95422023-12-03T12:43:51ZengPeerJ Inc.PeerJ2167-83592023-04-0111e1528410.7717/peerj.15284Uncovering the potential functions of lymph node metastasis-associated aberrant methylation differentially expressed genes and their association with the immune infiltration and prognosis in bladder urothelial carcinomaWenzhi GaoJiafeng ZhangTai TianZhixin FuLiangliang BaiYifei YangQiangqiang WuWei WangYuexian GuoBackground Bladder urothelial carcinoma (BLCA) is a malignant tumor of the urinary system. This study aimed to explore the potential role of lymph node metastasis-associated aberrant methylation differentially expressed genes (DEGs) in BLCA. Methods CHAMP and limma packages were used to identify lymph node metastasis-associated aberrant methylation DEGs. Univariate Cox analysis and Lasso analysis were performed to identify the signature genes, and multivariate Cox analysis was used to construct the risk score. Subsequently, the molecular characteristics of the signature genes and the relationship between risk score and prognosis, clinical characteristics and immune cell infiltration were analyzed. The signature gene AKAP7 was selected for functional verification. Results A novel risk score model was constructed based on 12 signature genes. The risk score had a good ability to predict overall survival (OS). The nomogram constructed based on age, N stage and risk score had a higher value in predicting the prognosis of patients. It was also found that stromal activation in TIME may inhibit the antitumor effects of immune cells. Functional enrichment analysis revealed that ECM receptor interaction and focal adhesion were two important pathways involved in the regulation of BLCA. Immunohistochemistry showed that AKAP7 may be associated with the occurrence, clinical stages and grades, and lymph node metastasis of BLCA. In vitro cell experiments showed that the migration and invasion ability of EJ cells was significantly inhibited after AKAP7 overexpression, while the migration and invasion ability of T24 cells was significantly promoted after AKAP7 knockdown. Conclusion The risk score model based on lymph node metastasis-associated aberrant methylation DEGs has a good ability to predict OS and is an independent prognostic factor for BLCA. It was also found that stromal activation in TIME may inhibit the antitumor effects of immune cells. This implicates aberrant methylation modifications as an important factor contributing to the heterogeneity and complexity of individual tumor microenvironments. Functional enrichment analysis revealed that ECM receptor interaction and focal adhesion were two important pathways involved in the regulation of BLCA, which contributed to the exploration of the pathological mechanism of BLCA. In addition, immunohistochemistry showed that AKAP7 may be associated with the occurrence, progression and lymph node metastasis of BLCA. In vitro cell experiments showed that AKAP7 could also inhibit the migration and invasion of cancer cells.https://peerj.com/articles/15284.pdfBladder urothelial carcinomaDifferentially expressed genesMethylationRisk scoreImmune cell infiltrationAKAP7
spellingShingle Wenzhi Gao
Jiafeng Zhang
Tai Tian
Zhixin Fu
Liangliang Bai
Yifei Yang
Qiangqiang Wu
Wei Wang
Yuexian Guo
Uncovering the potential functions of lymph node metastasis-associated aberrant methylation differentially expressed genes and their association with the immune infiltration and prognosis in bladder urothelial carcinoma
PeerJ
Bladder urothelial carcinoma
Differentially expressed genes
Methylation
Risk score
Immune cell infiltration
AKAP7
title Uncovering the potential functions of lymph node metastasis-associated aberrant methylation differentially expressed genes and their association with the immune infiltration and prognosis in bladder urothelial carcinoma
title_full Uncovering the potential functions of lymph node metastasis-associated aberrant methylation differentially expressed genes and their association with the immune infiltration and prognosis in bladder urothelial carcinoma
title_fullStr Uncovering the potential functions of lymph node metastasis-associated aberrant methylation differentially expressed genes and their association with the immune infiltration and prognosis in bladder urothelial carcinoma
title_full_unstemmed Uncovering the potential functions of lymph node metastasis-associated aberrant methylation differentially expressed genes and their association with the immune infiltration and prognosis in bladder urothelial carcinoma
title_short Uncovering the potential functions of lymph node metastasis-associated aberrant methylation differentially expressed genes and their association with the immune infiltration and prognosis in bladder urothelial carcinoma
title_sort uncovering the potential functions of lymph node metastasis associated aberrant methylation differentially expressed genes and their association with the immune infiltration and prognosis in bladder urothelial carcinoma
topic Bladder urothelial carcinoma
Differentially expressed genes
Methylation
Risk score
Immune cell infiltration
AKAP7
url https://peerj.com/articles/15284.pdf
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