AUTHOR=Candido Saverio , Tomasello Barbara , Lavoro Alessandro , Falzone Luca , Gattuso Giuseppe , Russo Angela , Paratore Sabrina , McCubrey James A. , Libra Massimo 

TITLE=Bioinformatic analysis of the LCN2–SLC22A17–MMP9 network in cancer: The role of DNA methylation in the modulation of tumor microenvironment

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=10

YEAR=2022

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2022.945586

DOI=10.3389/fcell.2022.945586

ISSN=2296-634X

ABSTRACT=<p>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 <italic>Lipocalin 2</italic> (<italic>LCN2</italic>), <italic>SLC22A17</italic>, and <italic>MMP9</italic> 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 <italic>LCN2</italic>, <italic>SLC22A17</italic>, and <italic>MMP9</italic> genes in different tumor types. Correlation analysis between gene/isoforms expression and DNA methylation levels of <italic>LCN2</italic>, <italic>SLC22A17</italic>, and <italic>MMP9</italic> 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 <italic>LCN2</italic>–<italic>SLC22A17</italic>–<italic>MMP9</italic> network. Furthermore, survival analysis was performed according to gene expression and DNA methylation levels. Our results demonstrated that <italic>LCN2</italic> and <italic>MMP9</italic> were mainly upregulated in most tumor types, whereas <italic>SLC22A17</italic> was largely downregulated, representing a specific hallmark signature for all gastrointestinal tumors. Notably, the expression of <italic>LCN2</italic>, <italic>SLC22A17</italic>, and <italic>MMP9</italic> genes was negatively affected by promoter methylation. Conversely, intragenic hypermethylation was associated with the overexpression of <italic>SLC22A17</italic> and <italic>MMP9</italic> genes. Protein network analysis highlighted the role of the <italic>LCN2</italic>–<italic>SLC22A17</italic>–<italic>MMP9</italic> 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 <italic>LCN2</italic>, <italic>SLC22A17</italic>, and <italic>MMP9</italic> 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 <italic>LCN2</italic>, <italic>SLC22A17</italic>, and <italic>MMP9</italic> in all TCGA tumors, indicating that the <italic>LCN2–SLC22A17–MMP9</italic> 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.</p>