Bioinformatic analysis of the LCN2–SLC22A17–MMP9 network in cancer: The role of DNA methylation in the modulation of tumor microenvironment
Several features of cancer cells such as proliferation, invasion, metastatic spreading, and drug resistance are affected by their interaction with several tumor microenvironment (TME) components, including neutrophil gelatinase-associated lipocalin (NGAL), solute carrier family 22 member 17 (SLC22A1...
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| Format: | Article |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2022.945586/full |
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| author | Saverio Candido Saverio Candido Barbara Tomasello Alessandro Lavoro Luca Falzone Giuseppe Gattuso Angela Russo Sabrina Paratore James A. McCubrey Massimo Libra Massimo Libra |
| author_facet | Saverio Candido Saverio Candido Barbara Tomasello Alessandro Lavoro Luca Falzone Giuseppe Gattuso Angela Russo Sabrina Paratore James A. McCubrey Massimo Libra Massimo Libra |
| author_sort | Saverio Candido |
| collection | DOAJ |
| description | Several features of cancer cells such as proliferation, invasion, metastatic spreading, and drug resistance are affected by their interaction with several tumor microenvironment (TME) components, including neutrophil gelatinase-associated lipocalin (NGAL), solute carrier family 22 member 17 (SLC22A17), and matrix metallopeptidase 9 (MMP9). These molecules play a key role in tumor growth, invasion, and iron-dependent metabolism of cancer cells. However, the precise epigenetic mechanisms underlying the gene regulation of Lipocalin 2 (LCN2), SLC22A17, and MMP9 in cancer still remain unclear. To this purpose, computational analysis was performed on TCGA and GTEx datasets to evaluate the expression and DNA methylation status of LCN2, SLC22A17, and MMP9 genes in different tumor types. Correlation analysis between gene/isoforms expression and DNA methylation levels of LCN2, SLC22A17, and MMP9 was performed to investigate the role of DNA methylation in the modulation of these genes. Protein network analysis was carried out using reverse phase protein arrays (RPPA) data to identify protein–protein interactions of the LCN2–SLC22A17–MMP9 network. Furthermore, survival analysis was performed according to gene expression and DNA methylation levels. Our results demonstrated that LCN2 and MMP9 were mainly upregulated in most tumor types, whereas SLC22A17 was largely downregulated, representing a specific hallmark signature for all gastrointestinal tumors. Notably, the expression of LCN2, SLC22A17, and MMP9 genes was negatively affected by promoter methylation. Conversely, intragenic hypermethylation was associated with the overexpression of SLC22A17 and MMP9 genes. Protein network analysis highlighted the role of the LCN2–SLC22A17–MMP9 network in TME by the interaction with fibronectin 1 and claudin 7, especially in rectal tumors. Moreover, the impact of expression and methylation status of LCN2, SLC22A17, and MMP9 on overall survival and progression free interval was tumor type–dependent. Overall, our analyses provide a detailed overview of the expression and methylation status of LCN2, SLC22A17, and MMP9 in all TCGA tumors, indicating that the LCN2–SLC22A17–MMP9 network was strictly regulated by DNA methylation within TME. Our findings pave the way for the identification of novel DNA methylation hotspots with diagnostic and prognostic values and suitable for epi-drug targeting. |
| first_indexed | 2024-04-11T20:02:53Z |
| format | Article |
| id | doaj.art-c7eeb430f6894e2f8650e5799ce87227 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-04-11T20:02:53Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-c7eeb430f6894e2f8650e5799ce872272022-12-22T04:05:32ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2022-09-011010.3389/fcell.2022.945586945586Bioinformatic analysis of the LCN2–SLC22A17–MMP9 network in cancer: The role of DNA methylation in the modulation of tumor microenvironmentSaverio Candido0Saverio Candido1Barbara Tomasello2Alessandro Lavoro3Luca Falzone4Giuseppe Gattuso5Angela Russo6Sabrina Paratore7James A. McCubrey8Massimo Libra9Massimo Libra10Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, ItalyResearch Center for Prevention, Diagnosis and Treatment of Cancer, University of Catania, Catania, ItalyDepartment of Drug and Health Sciences, University of Catania, Catania, ItalyDepartment of Biomedical and Biotechnological Sciences, University of Catania, Catania, ItalyEpidemiology Unit, IRCCS Istituto Nazionale Tumori “Fondazione G. Pascale”, Naples, ItalyDepartment of Biomedical and Biotechnological Sciences, University of Catania, Catania, ItalyPathological Anatomy Unit, ARNAS Garibaldi Hospital, Catania, ItalyPathological Anatomy Unit, ARNAS Garibaldi Hospital, Catania, ItalyDepartment of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, United StatesDepartment of Biomedical and Biotechnological Sciences, University of Catania, Catania, ItalyResearch Center for Prevention, Diagnosis and Treatment of Cancer, University of Catania, Catania, ItalySeveral features of cancer cells such as proliferation, invasion, metastatic spreading, and drug resistance are affected by their interaction with several tumor microenvironment (TME) components, including neutrophil gelatinase-associated lipocalin (NGAL), solute carrier family 22 member 17 (SLC22A17), and matrix metallopeptidase 9 (MMP9). These molecules play a key role in tumor growth, invasion, and iron-dependent metabolism of cancer cells. However, the precise epigenetic mechanisms underlying the gene regulation of Lipocalin 2 (LCN2), SLC22A17, and MMP9 in cancer still remain unclear. To this purpose, computational analysis was performed on TCGA and GTEx datasets to evaluate the expression and DNA methylation status of LCN2, SLC22A17, and MMP9 genes in different tumor types. Correlation analysis between gene/isoforms expression and DNA methylation levels of LCN2, SLC22A17, and MMP9 was performed to investigate the role of DNA methylation in the modulation of these genes. Protein network analysis was carried out using reverse phase protein arrays (RPPA) data to identify protein–protein interactions of the LCN2–SLC22A17–MMP9 network. Furthermore, survival analysis was performed according to gene expression and DNA methylation levels. Our results demonstrated that LCN2 and MMP9 were mainly upregulated in most tumor types, whereas SLC22A17 was largely downregulated, representing a specific hallmark signature for all gastrointestinal tumors. Notably, the expression of LCN2, SLC22A17, and MMP9 genes was negatively affected by promoter methylation. Conversely, intragenic hypermethylation was associated with the overexpression of SLC22A17 and MMP9 genes. Protein network analysis highlighted the role of the LCN2–SLC22A17–MMP9 network in TME by the interaction with fibronectin 1 and claudin 7, especially in rectal tumors. Moreover, the impact of expression and methylation status of LCN2, SLC22A17, and MMP9 on overall survival and progression free interval was tumor type–dependent. Overall, our analyses provide a detailed overview of the expression and methylation status of LCN2, SLC22A17, and MMP9 in all TCGA tumors, indicating that the LCN2–SLC22A17–MMP9 network was strictly regulated by DNA methylation within TME. Our findings pave the way for the identification of novel DNA methylation hotspots with diagnostic and prognostic values and suitable for epi-drug targeting.https://www.frontiersin.org/articles/10.3389/fcell.2022.945586/fullLCN2SLC22A17MMP9cancerDNA methylationgene expression |
| spellingShingle | Saverio Candido Saverio Candido Barbara Tomasello Alessandro Lavoro Luca Falzone Giuseppe Gattuso Angela Russo Sabrina Paratore James A. McCubrey Massimo Libra Massimo Libra Bioinformatic analysis of the LCN2–SLC22A17–MMP9 network in cancer: The role of DNA methylation in the modulation of tumor microenvironment Frontiers in Cell and Developmental Biology LCN2 SLC22A17 MMP9 cancer DNA methylation gene expression |
| title | Bioinformatic analysis of the LCN2–SLC22A17–MMP9 network in cancer: The role of DNA methylation in the modulation of tumor microenvironment |
| title_full | Bioinformatic analysis of the LCN2–SLC22A17–MMP9 network in cancer: The role of DNA methylation in the modulation of tumor microenvironment |
| title_fullStr | Bioinformatic analysis of the LCN2–SLC22A17–MMP9 network in cancer: The role of DNA methylation in the modulation of tumor microenvironment |
| title_full_unstemmed | Bioinformatic analysis of the LCN2–SLC22A17–MMP9 network in cancer: The role of DNA methylation in the modulation of tumor microenvironment |
| title_short | Bioinformatic analysis of the LCN2–SLC22A17–MMP9 network in cancer: The role of DNA methylation in the modulation of tumor microenvironment |
| title_sort | bioinformatic analysis of the lcn2 slc22a17 mmp9 network in cancer the role of dna methylation in the modulation of tumor microenvironment |
| topic | LCN2 SLC22A17 MMP9 cancer DNA methylation gene expression |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2022.945586/full |
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