Dataset Information

HAMP as a Prognostic Biomarker for Colorectal Cancer Based on Tumor Microenvironment Analysis.

ABSTRACT: Colorectal cancer (CRC) is the most common digestive tumor in the world and has a high mortality rate. The development and treatment of CRC are related to the immune microenvironment, but immune response-related prognostic biomarkers are lacking. In this study, we used The Cancer Genome Atlas (TCGA) to explore the tumor microenvironment (TME) and weighted gene coexpression network analysis (WGCNA) to identify significant prognostic genes. We also identified differentially expressed genes in the TCGA data and explored immune-related genes and transcription factors (TFs). Then, we built a TF regulatory network and performed a comprehensive prognostic analysis of an lncRNA-associated competitive endogenous RNA network (ceRNA network) to build a prognostic model. CCR8 and HAMP were identified both in the WGCNA key module and as immune-related genes. HAMP had good prognostic value for CRC and was highly expressed in CRC tissues and had a negative correlation with CD4⁺ T cells and M0 macrophages based on immunohistochemistry and immunofluorescence staining of clinical specimens.We found that HAMP had high prognostic and therapeutic target value for CRC and was associated with liver metastasis. These analysis results revealed that HAMP may be a candidate immune-related prognostic biomarker for CRC.

SUBMITTER: Wei FZ

PROVIDER: S-EPMC9386429 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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HAMP as a Prognostic Biomarker for Colorectal Cancer Based on Tumor Microenvironment Analysis.

Wei Fang-Ze FZ Mei Shi-Wen SW Wang Zhi-Jie ZJ Chen Jia-Nan JN Zhao Fu-Qiang FQ Li Juan- J Xiao Ti-Xian TX Zhao Wei W Ma Yun-Bin YB Yuan Wei W Liu Qian Q

Frontiers in oncology 20220805

Colorectal cancer (CRC) is the most common digestive tumor in the world and has a high mortality rate. The development and treatment of CRC are related to the immune microenvironment, but immune response-related prognostic biomarkers are lacking. In this study, we used The Cancer Genome Atlas (TCGA) to explore the tumor microenvironment (TME) and weighted gene coexpression network analysis (WGCNA) to identify significant prognostic genes. We also identified differentially expressed genes in the ...[more]

PMID: 35992796

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Project description:The tumor microenvironment (TME) plays an important role in the pathogenesis of many cancers. We aimed to screen the TME-related hub genes of colorectal adenoma (CRAD) and identify possible prognostic biomarkers. The gene expression profiles and clinical data of 464 CRAD patients in The Cancer Genome Atlas (TCGA) database were downloaded. The Estimation of STromal and Immune cells in MAlignant Tumours using Expression data (ESTIMATE) algorithm was performed to calculate the ImmuneScore, StromalScore, and EstimateScore. Thereafter, differentially expressed genes (DEGs) were screened. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein-protein interaction (PPI) analysis were performed to explore the roles of DEGs. Furthermore, univariate and multivariate Cox analyses were accomplished to identify independent prognostic factors of CRAD. CX3CR1 was selected as a hub gene, and the expression was confirmed in colorectal cancer (CRC) patients and cell lines. The correlations between CX3CR1 and tumor-infiltrating immune cells were estimated by Tumor IMmune Estimation Resource database (TIMER) and CIBERSORT analysis. Besides, we investigated the effects of coculture with THP-1-derived macrophages with HCT8 cells with low CX3CR1 expression on immune marker expression, cell viability, and migration. There were significant differences in the ImmuneScore and EstimateScore among different stages. Patients with low scores presented significantly lower lifetimes than those in the high-score group. Moreover, we recognized 1,578 intersection genes in ImmuneScore and StromalScore, and these genes were mainly enriched in numerous immune-related biological processes. CX3CR1 was found to be associated with immune cell infiltration levels, immune marker expression, and macrophage polarization. Simultaneous silencing of CX3CR1 and coculture with THP-1 cells further regulated macrophage polarization and promoted the cell proliferation and migration of CRC cells. CX3CR1 was decreased in CRAD tissues and cell lines and was related to T and N stages, tumor differentiation, and prognosis. Our results suggest that CX3CR1 contributes to the recruitment and regulation of immune-infiltrating cells and macrophage polarization in CRC and TAM-induced CRC progression. CX3CR1 may act as a prognostic biomarker in CRC.

Project description:Background: Ecto-5'-nucleotidase (NT5E) encodes the cluster of differentiation 73 (CD73), whose overexpression contributes to the formation of immunosuppressive tumor microenvironment and is related to exacerbated prognosis, increased risk of metastasis and resistance to immunotherapy of various tumors. However, the prognostic significance of NT5E in pan-cancer is obscure so far. Methods: We explored the expression level of NT5E in cancers and adjacent tissues and revealed the relationship between the NT5E expression level and clinical outcomes in pan-cancer by utilizing the UCSC Xena database. Then, correlation analyses were performed to evaluate the relationship between NT5E expression and immune infiltration level via EPIC, MCP-counter and CIBERSORT methods, and the enrichment analysis were employed to identify NT5E-interacting molecules and functional pathways. Furthermore, we conducted single-cell analysis to explore the potential role of NT5E on single-cell level based on the CancerSEA database. Meanwhile, gene set enrichment analysis (GSEA) in single-cell level was also conducted in TISCH database and single-cell signature explorer was utilized to evaluate the epithelial-mesenchymal transition (EMT) level in each cell type. Results: The expression level of NT5E was aberrant in almost all cancer types, and was correlated with worse prognosis in several cancers. Notably, NT5E overexpression was related to worse overall survival (OS) in pancreatic adenocarcinoma (PAAD), head and neck squamous cell carcinoma (HNSC), mesothelioma (MESO), stomach adenocarcinoma (STAD), uveal melanoma (UVM) and cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) (p < 0.01). NT5E-related immune microenvironment analysis revealed that NT5E is associated positively with the degree of infiltration of cancer-associated fibroblasts (CAFs) and endothelial cells in most cancers. Enrichment analysis of cellular component (CC) demonstrated the critical part of NT5E played in cell-substrate junction, cell-substrate adherens junction, focal adhesion and external side of plasma membrane. Finally, single-cell analysis of NT5E illuminated that EMT function of CAFs was elevated in basal cell carcinoma (BCC), skin cutaneous melanoma (SKCM), HNSC and PAAD. Conclusion: NT5E could serve as a potential prognostic biomarker for cancers. The potential mechanism may be related to the upregulated EMT function of CAFs, which provides novel inspiration for immunotherapy by targeting CAFs with high NT5E expression.

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Project description:BackgroundThe tumor microenvironment (TME) plays a crucial role in tumorigenesis, progression, and therapeutic response in many cancers. This study aimed to comprehensively investigate the role of TME in colorectal cancer (CRC) by generating a TMEscore based on gene expression.MethodsThe TME patterns of CRC datasets were investigated, and the TMEscores were calculated. An unsupervised clustering method was used to divide samples into clusters. The associations between TMEscores and clinical features, prognosis, immune score, gene mutations, and immune checkpoint inhibitors were analyzed. A TME signature was constructed using the TMEscore-related genes. The results were validated using external and clinical cohorts.ResultsThe TME pattern landscape was for CRC was examined using 960 samples, and then the TMEscore pattern of CRC datasets was evaluated. Two TMEscore clusters were identified, and the high TMEscore cluster was associated with early-stage CRC and better prognosis in patients with CRC when compared with the low TMEscore clusters. The high TMEscore cluster indicated elevated tumor cell scores and tumor gene mutation burden, and decreased tumor purity, when compared with the low TMEscore cluster. Patients with high TMEscore were more likely to respond to immune checkpoint therapy than those with low TMEscore. A TME signature was constructed using the TMEscore-related genes superimposing the results of two machine learning methods (LASSO and XGBoost algorithms), and a TMEscore-related four-gene signature was established, which had a high predictive value for discriminating patients from different TMEscore clusters. The prognostic value of the TMEscore was validated in two independent cohorts, and the expression of TME signature genes was verified in four external cohorts and clinical samples.ConclusionOur study provides a comprehensive description of TME characteristics in CRC and demonstrates that the TMEscore is a reliable prognostic biomarker and predictive indicator for patients with CRC undergoing immunotherapy.

Dataset Information

HAMP as a Prognostic Biomarker for Colorectal Cancer Based on Tumor Microenvironment Analysis.

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HAMP as a Prognostic Biomarker for Colorectal Cancer Based on Tumor Microenvironment Analysis.

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