Prognostic and clinicopathological insights of phosphodiesterase 9A gene as novel biomarker in human colorectal cancer.
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ABSTRACT: Background
PDE9A (Phosphodiesterase 9A) plays an important role in proliferation of cells, their differentiation and apoptosis via intracellular cGMP (cyclic guanosine monophosphate) signaling. The expression pattern of PDE9A is associated with diverse tumors and carcinomas. Therefore, PDE9A could be a prospective candidate as a therapeutic target in different types of carcinoma. The study presented here was designed to carry out the prognostic value as a biomarker of PDE9A in Colorectal cancer (CRC). The present study integrated several cancer databases with in-silico techniques to evaluate the cancer prognosis of CRC.Results
The analyses suggested that the expression of PDE9A was significantly down-regulated in CRC tissues than in normal tissues. Moreover, methylation in the DNA promoter region might also manipulate PDE9A gene expression. The Kaplan-Meier curves indicated that high level of expression of PDE9A gene was associated to higher survival in OS, RFS, and DSS in CRC patients. PDE9A demonstrated the highest positive correlation for rectal cancer recurrence with a marker gene CEACAM7. Furtheremore, PDE9A shared consolidated pathways with MAPK14 to induce survival autophagy in CRC cells and showed interaction with GUCY1A2 to drive CRPC.Conclusions
Overall, the prognostic value of PDE9A gene could be used as a potential tumor biomarker for CRC.
SUBMITTER: Susmi TF
PROVIDER: S-EPMC8136133 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: 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 Mapk14 expression and clinicopathological and tumor-infiltrating immune cells. Methods: 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 Mapk14 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 Mapk14 gene on colorectal cancer. Second, we further explored the methylation level of Mapk14 and its influencing factors. Single-cell sequencing of Mapk14 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 Mapk14 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. Results: The results showed that the expression of Mapk14 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 Mapk14 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 Mapk14 in colorectal cancer is related to the level of immune infiltration of immune cells (including CD8+ T cells, neutrophils, dendritic cells, B cells, CD4+ T cells, and macrophages). The high expression of Mapk14 was significantly correlated with immune checkpoints (including SIGLEC15, TIGIT, LAG3, CTLA4 and PDCDILG2), while the high expression of Mapk14 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. Conclusion: 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.
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