AUTHOR=Wang Dan , Peng Li , Hua Li , Li Jiaxiang , Liu Yifei , Zhou Yanhong 

TITLE=Mapk14 is a Prognostic Biomarker and Correlates with the Clinicopathological Features and Immune Infiltration of Colorectal Cancer

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.2022.817800

DOI=10.3389/fcell.2022.817800

ISSN=2296-634X

ABSTRACT=<p><bold>Background:</bold> Colorectal cancer (CRC) is one of the most common gastrointestinal tumors, ranking in the top 5 of all common tumors in terms of incidence and mortality. However, the mechanisms driving the evolution of colorectal cancer remain unclear. Therefore, we investigated the association between <italic>Mapk14</italic> expression and clinicopathological and tumor-infiltrating immune cells.</p><p><bold>Methods:</bold> In this study, we collected CRC patient data from The Cancer Genome Atlas (TCGA), compared the expression level in CRC and normal colorectal tissue using the Wilcoxon rank sum test and assessed the relationship between <italic>Mapk14</italic> and clinicopathological features using the Welch one-way ANOVA test. Kaplan-Meier and timeROC GSE17537 datasets were obtained from the Gene Expression Omnibus (GEO) dataset to assess the prognostic impact of the <italic>Mapk14</italic> gene on colorectal cancer. Second, we further explored the methylation level of <italic>Mapk14</italic> and its influencing factors. Single-cell sequencing of <italic>Mapk14</italic> in the tumor immune microenvironment (TIME) was analyzed using the GSE108989 dataset. Further analyses based on the TIMER method were performed to assess the correlation between <italic>Mapk14</italic> and tumor immune infiltration, immune checkpoints, tumor mutational load and microsatellite instability. Finally, the results of the bioinformatics analysis were verified by an immunohistochemical analysis.</p><p><bold>Results:</bold> The results showed that the expression of <italic>Mapk14</italic> was upregulated in CRC tumor tissues compared with normal colorectal tissues and the high expression of Mapk14 was associated with poor clinicopathological features and poor prognoses in the CRC array. In addition, cg05798012 and cg25375420 of <italic>Mapk14</italic> are the main DNA methylation sites affecting OS. Single-cell sequencing of the tumor immune microenvironment showed that the abundance and cell state of dysfunctional T cells changed greatly. Importantly, the abnormal overexpression of <italic>Mapk14</italic> in colorectal cancer is related to the level of immune infiltration of immune cells (including CD8<sup>+</sup> T cells, neutrophils, dendritic cells, B cells, CD4<sup>+</sup> T cells, and macrophages). The high expression of Mapk14 was significantly correlated with immune checkpoints (including <italic>SIGLEC15</italic>, <italic>TIGIT</italic>, <italic>LAG3</italic>, <italic>CTLA4</italic> and <italic>PDCDILG2</italic>), while the high expression of <italic>Mapk14</italic> was negatively correlated with TMB and MSI but mostly positively correlated with drug sensitivity. Finally, the immunohistochemical results confirmed that the clinical stage (Ⅰ, Ⅱ, Ⅲ and Ⅳ) and M stage (M0 and M1) affected the abnormally high expression of Mapk14.</p><p><bold>Conclusion:</bold> A comprehensive bioinformatics study and experimental validation revealed that Mapk14 could serve as a novel prognostic biomarker associated with immune infiltration and pharmacotherapy and may represent a potential therapeutic target for the treatment of CRC.</p>