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. 2024 Jun 18;24(1):213.
doi: 10.1186/s12935-024-03403-4.

Integrated profiling identifies DXS253E as a potential prognostic marker in colorectal cancer

Pu Xing  1 , Hao Hao  1 , Jiangbo Chen  1 , Xiaowen Qiao  1 , Tongkun Song  1 , Xinying Yang  1 , Kai Weng  1 , Yifan Hou  1 , Jie Chen  2 , Zaozao Wang  1 , Jiabo Di  1 , Beihai Jiang  3 , Jiadi Xing  4 , Xiangqian Su  5
Affiliations

Integrated profiling identifies DXS253E as a potential prognostic marker in colorectal cancer

Pu Xing et al. Cancer Cell Int. .

Abstract

Background: Increasing evidence suggests that DXS253E is critical for cancer development and progression, but the function and potential mechanism of DXS253E in colorectal cancer (CRC) remain largely unknown. In this study, we evaluated the clinical significance and explored the underlying mechanism of DXS253E in CRC.

Methods: DXS253E expression in cancer tissues was investigated using the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The Kaplan-Meier plot was used to assess the prognosis of DXS253E. The cBioPortal, MethSurv, and Tumor Immune Estimation Resource (TIMER) databases were employed to analyze the mutation profile, methylation, and immune infiltration associated with DXS253E. The biological functions of DXS253E in CRC cells were determined by CCK-8 assay, plate cloning assay, Transwell assay, flow cytometry, lactate assay, western blot, and qRT-PCR.

Results: DXS253E was upregulated in CRC tissues and high DXS253E expression levels were correlated with poor survival in CRC patients. Our bioinformatics analyses showed that high DXS253E gene methylation levels were associated with the favorable prognosis of CRC patients. Furthermore, DXS253E levels were linked to the expression levels of several immunomodulatory genes and an abundance of immune cells. Mechanistically, the overexpression of DXS253E enhanced proliferation, migration, invasion, and the aerobic glycolysis of CRC cells through the AKT/mTOR pathway.

Conclusions: We demonstrated that DXS253E functions as a potential role in CRC progression and may serve as an indicator of outcomes and a therapeutic target for regulating the AKT/mTOR pathway in CRC.

Keywords: Bioinformatics; Colorectal cancer; DXS253E; Glycolysis; Prognosis.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
The analysis flowchart of this study
Fig. 2
Fig. 2
DXS253E expression is increased in different types of tumors including colorectal cancer (CRC). A Pan-cancer analysis of DXS253E expression levels in human tumors according to the Cancer Genome Atlas (TCGA) dataset. B Expression of DXS253E in cancer and para-cancer paired tissues based on TCGA dataset. C, D Comparison of the expression levels of DXS253E in colon adenocarcinoma (COAD) (C) or rectum adenocarcinoma (READ) (D) and normal tissues from TCGA’s database. E Gene Expression Omnibus database (GEO) analysis of DXS253E expression in CRC tissues. F qRT-PCR assay of DXS253E mRNA expression levels in eight pairs of CRC and adjacent tissues from our experimental cohort. G Representative images of DXS253E expression in CRC tissues and matched normal tissues. Original magnifications 100× and 200× (inset panels). *P < 0.05, **P < 0.01, ***P < 0.001, ns, no significance
Fig. 3
Fig. 3
High DXS253E expression indicates aggressive clinical features and poor prognosis for CRC patients. A Association between DXS253E expression and clinical characteristics. B, C Effects of DXS253E level on overall survival (OS) and disease-specific survival (DSS) in COAD and READ. D Forest plot of univariate Cox regression analysis of DXS253E mRNA expression with OS and DSS in CRC with different clinicopathological features. E Forest plot of multivariate Cox regression analysis of DXS253E mRNA expression with OS and DSS in CRC with different clinicopathological features. *P < 0.05, **P < 0.01, ***P < 0.001
Fig. 4
Fig. 4
Mutation and methylation analysis of DXS253E in CRC. A Alteration frequency of the DXS253E gene across various cancers analyzed using the cBioPortal web resource. B Differential somatic mutations identified in CRC between low and high DXS253E expression groups. C Correlation between DXS253E mRNA expression level and methylation level. D Kaplan-Meier survival curves showing six methylation sites in the DXS253E gene
Fig. 5
Fig. 5
Functional enrichment analysis of differentially expressed genes (DEGs) according to DXS253E expression level in CRC. A Volcano plot for DEGs between low DXS253E and high DXS253E expression groups. B Heatmap showing the top 10 DEGs between low and high DXS253E-expression groups. C GO enrichment analysis of DXS253E-associated DEGs. D KEGG enrichment analysis of DXS253E-associated DEGs. E GSEA of relevant signaling pathways in CRC tissues based on DXS253E-related DEGs. F Volcano plot of co-expressed genes correlated with DXS253E expression using the LinkedOmics web resource. G Heatmaps of the top 50 genes that are positively or negatively associated with DXS253E. H Venn diagram of the number of intersections between DXS253E DEGs and co‐expressed genes in CRC. I Enrichment analysis of overlapping genes analyzed by the Metascape web resource
Fig. 6
Fig. 6
DXS253E expression is associated with multiple immune-related genes, and immune cell infiltration occurs in CRC. A Correlation of DXS253E with immunomodulatory genes in pan-cancer. B Heatmap of DXS253E expression with various tumor microenvironment cells in five independent datasets from the Tumor Immune Single-cell Hub (TISCH) database. C DXS253E expression in immune cells according to the Gene Expression Omnibus (GEO) GSE108989 and GSE136394 datasets. D Correlation between DXS253E and immune cell infiltration. E, F Relationship of DXS253E expression with the infiltration level of NK, NK CD56bright, eosinophil, Tcm, T helper, and Th2 cells using scatter plots (E) and box plots (F). *P < 0.05, **P < 0.01, ***P < 0.001
Fig. 7
Fig. 7
DXS253E facilitates CRC cell malignant phenotype and aerobic glycolysis via the AKT/mTOR pathway. A Western blot assay of DXS253E protein expression levels in NCM460, LoVo, HCT116, RKO, SW480, and SW620 cell lines. B qRT-PCR assay of DXS253E mRNA expression levels in normal epithelial colon cell line NCM460 and CRC cell lines. C DXS253E overexpression accelerates the proliferation of RKO and HCT116 cells. D High levels of DXS253E expression enhance colony formation in CRC cells. E Overexpression of DXS253E enhances the malignant progression of RKO and HCT116 cells. Bar graphs show the number of migrated or invaded cells. F High levels of DXS253E decrease the generation of reactive oxygen species (ROS). G DXS253E overexpression elevates lactate production. H, I DXS253E regulates the level of glycolytic genes in CRC cells, including HK2, PKM2, GLUT1, and LDHA with qRT-PCR and western blot. J DXS253E overexpression in CRC cells mediates the activation of the AKT/mTOR pathway. *P < 0.05, **P < 0.01, ***P < 0.001
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