S100A7 as a potential diagnostic and prognostic biomarker of esophageal squamous cell carcinoma promotes M2 macrophage infiltration and angiogenesis.
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ABSTRACT:
SUBMITTER: Lu Z
PROVIDER: S-EPMC8265170 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer and the seventh most prevalent cause of cancer-related death worldwide. Tumor microenvironment (TME) has been confirmed to play an crucial role in ESCC progression, prognosis, and the response to immunotherapy. There is a need for predictive biomarkers of TME-related processes to better prognosticate ESCC outcomes.AimTo identify a novel gene signature linked with the TME to predict the prognosis of ESCC.MethodsWe calculated the immune/stromal scores of 95 ESCC samples from The Cancer Genome Atlas (TCGA) using the ESTIMATE algorithm, and identified differentially expressed genes (DEGs) between high and low immune/stromal score patients. The key prognostic genes were further analyzed by the intersection of protein-protein interaction (PPI) networks and univariate Cox regression analysis. Finally, a risk score model was constructed using multivariate Cox regression analysis. We evaluated the associations between the risk score model and immune infiltration via the CIBERSORT algorithm. Moreover, we validated the signature using the Gene Expression Omnibus (GEO) database. Within the ten gene signature, five rarely reported genes were further validated with quantitative real time polymerase chain reaction (qRT-PCR) using an ESCC tissue cDNA microarray.ResultsA total of 133 up-regulated genes were identified as DEGs. Ten prognostic genes were selected based on intersection analysis of univariate COX regression analysis and PPI, and consisted of C1QA, C1QB, C1QC, CD86, C3AR1, CSF1R, ITGB2, LCP2, SPI1, and TYROBP (HR>1, p<0.05). The expression of 9 of these genes in the tumor samples were significantly higher compared to matched adjacent normal tissue based on the GEO database (p<0.05). Next, we assessed the ability of the ten-gene signature to predict the overall survival of ESCC patients, and found that the high-risk group had significantly poorer outcomes compared to the low-risk group using univariate and multivariate analyses in the TCGA and GEO cohorts (HR=2.104, 95% confidence interval:1.343-3.295, p=0.001; HR=1.6915, 95% confidence interval:1.053-2.717, p=0.0297). Additionally, receiver operating characteristic (ROC) curve analysis demonstrated a relatively sensitive and specific profile for the signature (1-, 2-, 3-year AUC=0.672, 0.854, 0.81). To identify the basis for these differences in the TME, we performed correlation analyses and found a significant positive correlation with M1 and M2 macrophages and CD8+ T cells, as well as a strong correlation to M2 macrophage surface markers. A nomogram based on the risk score and select clinicopathologic characteristics was constructed to predict overall survival of ESCC patients. For validation, qRT-PCR of an ESCC patient cDNA microarray was performed, and demonstrated that C1QA, C3AR1, LCP2, SPI1, and TYROBP were up-regulated in tumor samples and predict poor prognosis.ConclusionThis study established and validated a novel 10-gene signature linked with M2 macrophages and poor prognosis in ESCC patients. Importantly, we identified C1QA, C3AR1, LCP2, SPI1, and TYROBP as novel M2 macrophage-correlated survival biomarkers. These findings may identify potential targets for therapy in ESCC patients.
| S-EPMC8677679 | biostudies-literature
Project description:Objective: The transcription factor forkhead box protein O1 (FOXO1) is critical for regulating cytokine and chemokine secretion. However, its function in the tumor microenvironment (TME) remains largely unexplored. In this study, we characterized the prognostic value of FOXO1 and the interaction between tumor-derived FOXO1 and M2 macrophages in esophageal squamous cell carcinoma (ESCC). Methods: FOXO1 expression and macrophage infiltration in clinical samples and mouse models were quantified using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry staining. Western blotting, qRT-PCR, and enzyme-linked immunosorbent assay were used to evaluate chemokine ligand 20 (CCL20) and colony stimulating factor 1 (CSF-1) expression in FOXO1(+) and FOXO1(-) tumor cells. Macrophage phenotypes were determined using qRT-PCR, flow cytometry, and RNA sequencing. Transcriptional activity was measured using chromatin immunoprecipitation (ChIP)-qPCR. Tumor viability was investigated using XTT proliferation and foci formation assays. Results: FOXO1 upregulation in tumor tissues was found to drive the polarization of M0 macrophages and infiltration of M2 macrophages into the TME, resulting in worse prognosis in ESCC patients. CSF-1, a vital factor inducing M0-to-M2 polarization, was upregulated via a FOXO1-mediated mechanism. RNA sequencing results corroborated that the FOXO1-induced macrophages exhibited similar molecular signatures to the IL4-stimulated M2 macrophages. The transwell assays showed that FOXO1 promoted the migration of M2 macrophages via CCL20 secretion, which could be inhibited using an anti-CCL20 antibody. FOXO1(+) tumor-induced M2 macrophages promoted tumor proliferation via the FAK-PI3K-AKT pathway and the PI3K inhibitor could effectively impede the oncogenical process. Conclusions: FOXO1 facilitated M0-to-M2 polarization and the recruitment of M2 macrophages in the TME via the transcriptional modulation of CCL20 and CSF-1. Our data deciphered the FOXO1-dependent mechanism in M2 macrophage infiltration in the TME of ESCC, which has implications for the development of novel prognostic and therapeutic targets to optimize the current treatment against ESCC.
| S-EPMC7546008 | biostudies-literature
Project description:PurposeThis study aimed to investigate the relevance of cerebral endothelial cell adhesion molecule (CERCAM) expression to head and neck squamous cell carcinoma (HNSCC) prognosis and immune infiltration by macrophage M2 polarization.MethodsTimer, UALCAN and HPA databases was used to analyze the differences in mRNA and protein levels of CERCAM expression in HNSCC. The Timer database was also applied to analyze the correlation between CERCAM in HNSCC and immune infiltration. TCGA-HNSCC database was applied to analyze the correlation between CERCAM expression levels and clinicopathological features, and its diagnostic and prognostic value in HNSCC was also assessed. The cBioPortal and MethSurv databases were then applied to analyze the genetic variation and methylation status of CERCAM. In vitro cellular assays were performed to provide evidence that CERCAM promotes malignant biological behavior of tumors and promotes macrophage M2 polarization in tumors. Finally, underlying pathophysiological mechanisms of CERCAM involvement in the development of HNSCC were predicted using a bioinformatics approach.ResultsCERCAM is significantly overexpressed in HNSCC and correlates with poor prognostic levels and has good performance in predicting survival status in HNSCC patients. Cox regression analysis indicates that CERCAM expression levels are independent risk factors for predicting OS, DSS, and PFI. CERCAM promotes tumor malignant biological behavior and promotes macrophage M2 polarization immune infiltration in HNSCC. In addition, CERCAM promotes tumor cell adhesion in head and neck squamous carcinoma and promotes tumor progression through several oncogenic signaling pathways.ConclusionCERCAM may serve as a new diagnostic and prognostic biomarker in HNSCC and is a promising therapeutic target for HNSCC.
| S-EPMC10559510 | biostudies-literature
Project description:BackgroundImmune infiltrates in the tumor microenvironment have established roles in tumor growth, invasion, and metastasis. However, the diagnostic and prognostic potential of immune cell signature in esophageal squamous cell carcinoma (ESCC) remains unclear.ResultsThe proportions of 22 subsets of immune cells from 331 samples including 205 ESCC and 126 normal esophageal mucosa retrieved from TCGA, GEO, and GTEx databases were deciphered by CIBERSORT. Nine overlapping subsets of immune cells were identified as important features for discrimination of ESCC from normal tissue in the training cohort by LASSO and Boruta algorithms. A diagnostic immune score (DIS) developed by XGBoost showed high specificities and sensitivities in the training cohort, the internal validation cohort, and the external validation cohort (AUC: 0.999, 0.813, and 0.966, respectively). Furthermore, the prognostic immune score (PIS) was developed based on naive B cells and plasma cells using Cox proportional hazards model. The PIS, an independent prognostic predictor, classified patients with ESCC into low- and high-risk subgroups in the internal validation cohort (P = 0.038) and the external validation cohort (P = 0.022). In addition, a nomogram model comprising age, N stage, TNM stage, and PIS was constructed and performed excellent (HR = 4.17, 95% CI: 2.22-7.69, P < 0.0001) in all ESCC patients, with a time-dependent 5-year AUC of 0.745 (95% CI: 0.644 to 0.845), compared with PIS or TNM stage as a prognostic model alone.ConclusionOur DIS, PIS, and nomogram models based on infiltrated immune features may aid diagnosis and survival prediction for patients with ESCC.
| S-EPMC9251101 | biostudies-literature
Project description:BACKGROUND Exocyst complex component 3-like 1 (EXOC3L1) is ubiquitously present in multiple organs. However, its role in esophageal squamous cell carcinoma (ESCC) remains unknown. The aim of this study was to explore the relationship between EXOC3L1 and ESCC. MATERIAL AND METHODS A total of 652 normal samples and 82 ESCC samples obtained from the University of California Santa Cruz (UCSC) Xena were applied to detect the expression difference of EXOC3L1. GSE53625 with 179 paired samples and GSE161533 with 28 paired samples were used for validation. The correlation between clinicopathological features and EXOC3L1 expression was calculated. Kaplan-Meier method was employed to assess the prognostic value of EXOC3L1 in ESCC. Univariate and multivariate Cox regression analyses were carried out to screen the factors contributing to the prognosis of ESCC. In addition, functional enrichment analysis, protein-protein interaction (PPI) network analysis, and immune infiltration analysis were conducted to identify the significantly involved functions of EXOC3L1. RESULTS EXOC3L1 was significantly overexpressed in ESCC compared to normal samples. High expression of EXOC3L1 was associated with worse prognosis, and univariate and multivariate Cox regression analysis demonstrated that EXOC3L1 was an independent prognostic predictor of ESCC. Functional enrichment analysis and immune infiltration analysis disclosed that the expression of EXOC3L1 was correlated with the abundance of several types of immune cells. CONCLUSIONS EXOC3L1 plays a crucial role in the prognosis of ESCC, and it may serve as a reliable biomarker for predicting the survival and a potential therapeutic target for ESCC.
| S-EPMC9942429 | biostudies-literature
Project description:BackgroundArylsulfatase D (ARSD) belongs to the sulfatase family and plays a crucial role in maintaining the proper structure of bone and cartilage matrix. Although several researches have revealed the functions of ARSD in tumor progression, the prognostic value of ARSD in glioma and the related mechanisms have not been fully investigated.MethodsWe performed a pan-cancer analysis of ARSD, and investigated the relationship between expression of ARSD and overall survival (OS) in multiple glioma datasets. ROC curves and nomograms were created to investigate the predictive capacity of ARSD. Immune and analysis were conducted to investigate the mechanisms underlying the roles of ARSD in glioma. Glioma tissue samples were collected to verify the expression of ARSD in glioma, while the functions of ARSD were explored using cell experiment. M2 macrophage infiltration assay was used to determine the relation between ARSD and tumor immune microenvironment.ResultsSurvival analysis indicated that individuals with high ARSD expression in glioma had a shorter survival time. Cox analysis showed that ARSD had a good ability for predicting prognosis in glioma. Immune analysis suggested that ARSD could regulate immune cell infiltration and affect the Cancer-Immunity Cycle to create an immunosuppressive environment. Combined with cell experiment and bioinformatic analysis, we found that ARSD can promote glioma progression through regulation of JAK2/STAT3 pathway and M2 macrophage infiltration.ConclusionOur study found that ARSD can promote glioma development by regulating immune microenvironment and JAK2/STAT3 signaling pathway, which provided a potential therapy target for glioma treatment.
| S-EPMC10521731 | biostudies-literature
Project description:Gastric cancer is a common cancer afflicting people worldwide. Although incremental progress has been achieved in gastric cancer research, the molecular mechanisms underlying remain unclear. In this study, we conducted bioinformatics methods to identify prognostic marker genes associated with gastric cancer progression. Three hundred and twenty-seven overlapping DEGs were identified from three GEO microarray datasets. Functional enrichment analysis revealed that these DEGs are involved in extracellular matrix organization, tissue development, extracellular matrix-receptor interaction, ECM-receptor interaction, PI3K-Akt signaling pathway, focal adhesion, and protein digestion and absorption. A protein-protein interaction network (PPI) was constructed for the DEGs in which 25 hub genes were obtained. Furthermore, the turquoise module was identified to be significantly positively coexpressed with macrophage M2 infiltration by weighted gene coexpression network analysis (WGCNA). Hub genes of COL1A1, COL4A1, COL12A1, and PDGFRB were overlapped in both PPI hub gene list and the turquoise module with significant association with the prognosis in gastric cancer. Moreover, functional analysis demonstrated that these hub genes play pivotal roles in cancer cell proliferation and invasion. The investigation of the gene markers can help deepen our understanding of the molecular mechanisms of gastric cancer. In addition, these genes may serve as potential prognostic biomarkers for gastric cancer diagnosis.
| S-EPMC8802722 | biostudies-literature
Project description:Tumor-associated Macrophages (TAMs) play a vital role in the progression of glioma. Macrophage M2 has been confirmed to promote immunosuppression and proliferation of low-grade glioma (LGG). Here, we searched for genes negatively correlated with Macrophages M2 by bioinformatical methods and investigated their protective ability for prognosis. LGG and adjacent normal samples were screened out in TCGA and three GEO datasets. 326 overlapped differentially expressed genes were calculated, and their biological functions were investigated by Go and KEGG analyses. Macrophage M2 accounted for the highest proportion among all 22 immune cells by CIBERSORT deconvolution algorithm. The proportion of Macrophage M2 in LGG was also higher than that in normal tissue according to several deconvolution algorithms. 43 genes in the blue module negatively correlated with Macrophage M2 infiltration were identified by weighted gene coexpression network analysis (WGCNA). Through immune infiltration and correlation analysis, FGFBP3, VAX2, and SHD were selected and they were enriched in G protein-coupled receptors' signaling regulation and cytokine receptor interaction. They could prolong the overall and disease-free survival time. Univariate and multivariate Cox regression analyses were applied to evaluate prognosis prediction ability. Interestingly, FGFBP3 and AHD were independent prognostic predictors. A nomogram was drawn, and its 1-year, 3-year, and 5-year survival prognostic value was verified by ROC curves and calibration plots. In conclusion, FGFBP3, VAX2, and SHD were protective prognostic biomarkers against Macrophage M2 infiltration in low-grade glioma. The FGFBP3 and SHD were independent factors to effectively predict long-term survival probability.
| S-EPMC9012619 | biostudies-literature
Project description:Although various chemokines have pro-tumorigenic actions in cancers, the effects of CXCL16 remain controversial. The aim of this study was to investigate the molecular characteristics of CXCL16-expressing papillary thyroid cancers (PTCs). CXCL16 expressions were significantly higher in PTCs than benign or normal thyroid tissues. In the TCGA dataset for PTCs, a higher CXCL16 expression was associated with M2 macrophage- and angiogenesis-related genes and poor prognostic factors including a higher TNM staging and the BRAFV600E mutation. PTCs with a higher expression of 3-gene panel including CXCL16, AHNAK2, and THBS2 showed poor recurrence-free survivals than that of the lower expression group. Next, shCXCL16 was introduced into BHP10-3SCp cells to deplete the endogenous CXCL16, and then, the cells were subcutaneously injected to athymic mice. Tumors from the BHP10-3SCpshCXCL16 exhibited a delayed tumor growth with decreased numbers of ERG+ endothelial cells and F4/80+ macrophages than those from the BHP10-3SCpcontrol. CXCL16-related genes including AHNAK2 and THBS2 were downregulated in the tumors from the BHP10-3SCpshCXCL16 compared with that from the BHP10-3SCpcontrol. In conclusion, a higher CXCL16 expression was associated with macrophage- and angiogenesis-related genes and aggressive phenotypes in PTC. Targeting CXCL16 may be a good therapeutic strategy for advanced thyroid cancer.
| S-EPMC6746802 | biostudies-literature
Project description:Background: Tumor-associated macrophages (TAMs) are an important component of the tumor microenvironment (TME). However, the crosstalk between esophageal squamous cell carcinoma (ESCC) cells and TAMs remains largely unexplored. Methods: Clinical samples and the TCGA database were used to evaluate the relevance of SPP1 and TAM infiltration in ESCC. Mouse models were constructed to investigate the roles of macrophages educated by SPP1 in ESCC. Macrophage phenotypes were determined using qRT‒PCR and immunohistochemical staining. RNA sequencing was performed to elucidate the mechanism. Results: Increasing expression of SPP1 correlated with M2-like TAM accumulation in ESCC, and they both predicted poor prognosis in the ESCC cohort. Knockdown of SPP1 significantly inhibited the infiltration of M2 TAMs in xenograft tumors. In vivo mouse model experiments showed that SPP1-mediated education of macrophages plays essential roles in the progression of ESCC. Mechanistically, SPP1 recruited macrophages and promoted M2 polarization via CD44/PI3K/AKT signaling activation and then induced VEGFA and IL6 secretion to sustain ESCC progression. Finally, blockade of SPP1 with RNA aptamer significantly inhibited tumor growth and M2 TAM infiltration in xenograft mouse models. Conclusions: This study highlights a SPP1-mediated crosstalk between ESCC cells and TAMs in ESCC. SPP1 could serve as a potential target in ESCC therapy.
2024-09-09 | GSE256360 | GEO