Systematic profiling of ferroptosis gene signatures predicts prognostic factors in esophageal squamous cell carcinoma.
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ABSTRACT:
SUBMITTER: Lu T
PROVIDER: S-EPMC8080401 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Understanding interactions between tumor and the host immune system holds great promise to uncover biomarkers for targeted therapies and clinical outcomes. However, systematical analysis of immune signatures in esophageal squamous cell carcinoma (ESCC) remains largely unstudied. In this study, immune signatures containing 708 immune related genes were curated from mRNA microarray data with tumor and paired normal tissues from 119 ESCC patients. Differential expression and survival analysis were performed with validations from Human Protein Atlas and an independent cohort of 110 ESCC patients by immunohistochemistry staining. We identified a total of 186 significantly dysregulated genes in ESCC, including downregulated genes SPINK5, IL1RN and upregulated genes SPP1 and PLAU, which were further confirmed in Human Protein Atlas data. Moreover, nine immune related genes (ABL1, ATF2, ATG5, C6, CD38, HMGB1, ICOSLG, IL12RB2 and PLAU) were significantly associated with patients' overall survival, among which, prognostic model was built including three independent factors ABL1, CD38 and ICOSLG. Validation by immunohistochemistry staining suggested that combination with tumor infiltrated CD4+ and CD8+ T lymphocytes would yield higher performance in distinguishing cases as high or low risk of unfavorable prognosis. In summary, we profiled the immune status in ESCC and established predictive and prognostic factors for ESCC, which could reflect immune disorders within tumor microenvironments and independently distinguish patients with a high risk of reduced survival, providing novel predictive and therapeutic targets for ESCC patients in the future.
| S-EPMC5674952 | biostudies-literature
Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) has the highest mortality rates in China. The 5-year survival rate of ESCC remains dismal despite improvements in treatments such as surgical resection and adjuvant chemoradiation, and current clinical staging approaches are limited in their ability to effectively stratify patients for treatment options. The aim of the present study, therefore, was to develop an immunohistochemistry-based prognostic model to improve clinical risk assessment for patients with ESCC.MethodsWe developed a molecular prognostic model based on the combined expression of axis of epidermal growth factor receptor (EGFR), phosphorylated Specificity protein 1 (p-Sp1), and Fascin proteins. The presence of this prognostic model and associated clinical outcomes were analyzed for 130 formalin-fixed, paraffin-embedded esophageal curative resection specimens (generation dataset) and validated using an independent cohort of 185 specimens (validation dataset).ResultsThe expression of these three genes at the protein level was used to build a molecular prognostic model that was highly predictive of ESCC survival in both generation and validation datasets (P = 0.001). Regression analysis showed that this molecular prognostic model was strongly and independently predictive of overall survival (hazard ratio = 2.358 [95% CI, 1.391-3.996], P = 0.001 in generation dataset; hazard ratio = 1.990 [95% CI, 1.256-3.154], P = 0.003 in validation dataset). Furthermore, the predictive ability of these 3 biomarkers in combination was more robust than that of each individual biomarker.ConclusionsThis technically simple immunohistochemistry-based molecular model accurately predicts ESCC patient survival and thus could serve as a complement to current clinical risk stratification approaches.
| S-EPMC4143329 | biostudies-literature
Project description:Background: The prognosis of patients with hepatocellular carcinoma (HCC) is negatively affected by the lack of effective prognostic indicators. The change of tumor immune microenvironment promotes the development of HCC. This study explored new markers and predicted the prognosis of HCC patients by systematically analyzing immune characteristic genes. Methods: Immune-related genes were obtained, and the differentially expressed immune genes (DEIGs) between tumor and para-cancer samples were identified and analyzed using gene expression profiles from TCGA, HCCDB, and GEO databases. An immune prognosis model was also constructed to evaluate the predictive performance in different cohorts. The high and low groups were divided based on the risk score of the model, and different algorithms were used to evaluate the tumor immune infiltration cell (TIIC). The expression and prognosis of core genes in pan-cancer cohorts were analyzed, and gene enrichment analysis was performed using clusterProfiler. Finally, the expression of the hub genes of the model was validated by clinical samples. Results: Based on the analysis of 730 immune-related genes, we identified 64 common DEIGs. These genes were enriched in the tumor immunologic related signaling pathways. The first 15 genes were selected using RankAggreg analysis, and all the genes showed a consistent expression trend across multi-cohorts. Based on lasso cox regression analysis, a 5-gene signature risk model (ATG10, IL18RAP, PRKCD, SLC11A1, and SPP1) was constructed. The signature has strong robustness and can stabilize different cohorts (TCGA-LIHC, HCCDB18, and GSE14520). Compared with other existing models, our model has better performance. CIBERSORT was used to assess the landscape maps of 22 types of immune cells in TCGA, GSE14520, and HCCDB18 cohorts, and found a consistent trend in the distribution of TIIC. In the high-risk score group, scores of Macrophages M1, Mast cell resting, and T cells CD8 were significantly lower than those of the low-risk score group. Different immune expression characteristics, lead to the different prognosis. Western blot demonstrated that ATG10, PRKCD, and SPP1 were highly expressed in cancer tissues, while IL18RAP and SLC11A1 expression in cancer tissues was lower. In addition, IL18RAP has a highly positive correlation with B cell, macrophage, Neutrophil, Dendritic cell, CD8 cell, and CD4 cell. The SPP1, PRKCD, and SLC11A1 genes have the strongest correlation with macrophages. The expression of ATG10, IL18RAP, PRKCD, SLC11A1, and SPP1 genes varies among different immune subtypes and between different T stages. Conclusion: The 5-immu-gene signature constructed in this study could be utilized as a new prognostic marker for patients with HCC.
| S-EPMC8494981 | biostudies-literature
Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) is an aggressive malignancy, with a high incidence and poor prognosis. In the past several decades, hundreds of proteins have been reported to be associated with the prognosis of ESCC, but none has been widely accepted to guide clinical care. This study aimed to identify proteins with great potential for predicting prognosis of ESCC.MethodsWe conducted a systematic review on immunohistochemical (IHC) prognostic markers of ESCC according to the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. Literature related to IHC prognostic markers of ESCC were searched from PubMed, Embase, Web of Science, and Cochrane Library until January 30th, 2017. The risk of bias of these original studies was evaluated using the Quality in Prognosis Studies (QUIPS) tool.ResultsWe identified 11 emerging IHC markers with reproducible results, including eight markers [epidermal growth factor receptor (EGFR), Cyclin D1, vascular endothelial growth factor (VEGF), Survivin, Podoplanin, Fascin, phosphorylated mammalian target of rapamycin (p-mTOR), and pyruvate kinase M2 (PKM2)] indicating unfavorable prognosis and 3 markers (P27, P16, and E-cadherin) indicating favorable prognosis of ESCC.ConclusionStrong evidence supports that these 11 emerging IHC markers or their combinations may be useful in predicting prognosis and aiding personalized therapy decision-making for ESCC patients.
| S-EPMC5561640 | biostudies-literature
Project description:The aim of the present study was to investigate the survival and prognostic factors of patients who were with advanced esophageal squamous cell carcinoma (ESCC) and developed an esophageal fistula. The data from 221 patients with advanced ESCC developed esophageal fistula from January 2008 to December 2017 at the Harbin Medical University Cancer Hospital was retrospectively analyzed. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by the Cox proportional hazard models. The median survival time after a diagnosis of the esophageal fistula was calculated using the Kaplan-Meier method. We found that the pathogens infected by patients are common bacteria in nosocomial infection. Besides, the incidence rate of esophagomediastinal fistula was the highest (54.2%) in the lower third of the esophagus. Kaplan-Meier analysis revealed a median survival time of 11.00 months and a median post-fistula survival time of 3.63 months in patients who developed esophageal fistula in advanced esophageal cancer. In the univariate analysis, gender, therapies for ESCC before the development of fistula, type of esophageal fistula, treatment of esophageal fistula and hemoglobin (Hb) level were the factors with significant prognostic value. Gender, type of esophageal fistula and Hb level were identified as independent prognostic factors in further multivariate analysis. In summary, our study demonstrated that several factors are significantly related to patients with esophageal fistula and should be concerned about in clinical practice.
| S-EPMC6960064 | biostudies-literature
Project description:The tumor microenvironment (TME) of esophageal squamous cell carcinoma (ESCC) impacts tumor progression but is poorly understood. We obtained tumor tissues from 279 patients after esophagectomy and characterized the TME in intraepithelial and stromal regions using multiplex fluorescent immunohistochemistry (mfIHC). A heterogeneous immune population infiltrating tumor and the uninvolved esophageal tissue were observed. The infiltration of intraepithelial programmed death ligand 1 (PD-L1)-positive tumor-associated macrophages (TAMs) and stromal granzyme B+ activated cytotoxic T cells (aCTLs) correlated with both prolonged overall survival (OS) and disease-free survival (DFS). The intraepithelial memory T cell infiltration predicted longer OS, while intraepithelial and stromal regulatory T cell (Treg) infiltration was associated with shortened OS and DFS, respectively. Multivariate models combining immune infiltrates and clinicopathological factors outperformed tumor-node-metastasis (TNM) stage in predicting OS and DFS at 3 and 5 years. The infiltration of Treg inversely correlated with that of the antitumor effectors including CTLs, aCTLs, and natural killer (NK) cells. Intraepithelial memory T cell infiltration also negatively correlated with PD-L1 expression. In spatial analysis, intraepithelial dendritic cell (DC)-memory T cell engagement increased in high PD-L1+ TAM infiltration group. The characterization of the TME revealed a complex interplay between immune populations and may be employed to stratify patient for prognosis prediction and immunotherapy.
| S-EPMC7889084 | biostudies-literature
Project description:We aimed to report patients' survival after surgical resection of eSCC and to ascertain the clinical, imaging, and pathological factors related to patient prognosis. This retrospective study included 435 patients with eSCC of <stage T2 (median follow-up period, 49.3 months). A total of 103 (23.7%) patients died, and 89 (20.5%) experienced recurrence during follow-up. The maximum standardized uptake value (SUVmax) on positron emission tomography (PET)/computed tomography (CT) of the primary tumor was significantly correlated with tumor length, nodal metastasis, and pathologic T stage in a positive linear fashion. In the multivariate analysis, higher SUVmax on PET/CT was a negative prognostic factor for both disease-free survival (DFS) and overall survival (OS). Contrarily, the presence of nodal metastasis was a prognostic factor only for DFS, and pathologic T stage only for OS. By applying SUVmax cut-off, both DFS and OS were significantly different among three groups when divided by cut-off values (A: SUVmax ≤ 3.05, B: SUVmax 3.06 - 5.64, C: SUVmax ≥ 5.65). In patients with a surgically resectable eSCC, measuring the SUVmax of the primary tumor during PET/CT can help predict patient survival. Additionally, PET/CT renders triage criterion for endoscopic submucosal dissection (ESD; T1a cancer and SUVmax, ≤3.05).
| S-EPMC7081270 | biostudies-literature
Project description:Background: The role of ferroptosis in esophageal squamous cell carcinoma (ESCC) is still unclear. Methods: The association of iron metabolism and ferroptosis-related genes with the prognosis, copy number variation (CNV), TMB, and immune cell infiltration of ESCC was explored using data from the GEO and TCGA database and validated by immunofluorescence in 112 ESCC patients from our center. The potential anti-cancer drugs and compounds from the GDSC and the Connectivity Map database were also screened. Results: A total of 117 iron metabolism and ferroptosis-related genes were identified. We found the expressions of PRNP, SLC3A2, SLC39A8, and SLC39A14 negatively related to the prognosis of ESCC patients, while ATP6V0A1 and LCN2 were opposite, which was validated in 112 ESCC samples from our center. And a prognostic signature was constructed based on their expressions and Cox regression coefficient (β). The low-score group exhibited a significantly worse OS. Besides, analysis of 179 ESCC samples from GSE53625 revealed that patients of poorly differentiation, more than 60 years, T4 stage, advanced N stage, advanced stage, and adjuvant therapy also exhibited a significantly shorter OS, based on which a nomogram to predict the OS was established. Moreover, the low-score group exhibited significantly higher CNV and TMB and more frequent mutations of TP53, MUC16, and NOTCH1. Higher proportion of Macrophages M2, and lower proportion of T cells follicular helper were observed in the low-score group. We discovered that AZD7762, Sunitinib, Cytarabine, Docetaxel, Vinblastine, and Elesclomol exhibited lower IC50 in the low-score group. And 20 potential compounds were identified from the CMap database. Conclusions: Six iron metabolism and ferroptosis-related genes were associated with the prognosis, CNV, TMB, and immune cell infiltration of ESCC. Some potential anti-cancer drugs and compounds may be helpful for OS.
| S-EPMC8965120 | biostudies-literature
Project description:BackgroundCuproptosis, a form of copper-dependent programmed cell death recently presented by Tsvetkov et al., have been identified as a potential therapeutic target for refractory cancers and ferroptosis, a well-known form describing iron-dependent cell death. However, whether the crossing of cuproptosis-related genes and ferroptosis-related genes can introduce some new idea, thus being used as a novel clinical and therapeutic predictor in esophageal squamous cell carcinoma (ESCC) remains unknown.MethodsWe collected ESCC patient data from the Gene Expression Omnibus and the Cancer Genome Atlas databases and used Gene Set Variation Analysis to score each sample based on cuproptosis and ferroptosis. We then performed weighted gene co-expression network analysis to identify cuproptosis and ferroptosis-related genes (CFRGs) and construct a ferroptosis and cuproptosis-related risk prognostic model, which we validated using a test group. We also investigated the relationship between the risk score and other molecular features, such as signaling pathways, immune infiltration, and mutation status.ResultsFour CFRGs (MIDN, C15orf65, COMTD1 and RAP2B) were identified to construct our risk prognostic model. Patients were classified into low- and high-risk groups based on our risk prognostic model and the low-risk group showed significantly higher survival possibilities (P < 0.001). We used the "GO", "cibersort" and "ESTIMATE" methods to the above-mentioned genes to estimate the relationship among the risk score, correlated pathways, immune infiltration, and tumor purity.ConclusionWe constructed a prognostic model using four CFRGs and demonstrated its potential clinical and therapeutic guidance value for ESCC patients.
| S-EPMC10465684 | biostudies-literature
Project description:Aurora kinase A, as a pro-carcinogenic in gastric cancer and glioma kinase, is enhanced in several human tumors. However, it's regulatory mechanism in esophageal squamous cell carcinoma (ESCC) remains unclear. Thus, this study aimed to investigate the expression status, functional roles, and molecular mechanisms of AURKA in ESCC development. AURKA expression was analyzed by the screening of the GEO database and detected using an immunohistochemical method. The biological function of AURKA on ESCC was evaluated in vitro and in vivo. Western blot assay, malondialdehyde (MDA), iron, and glutathione (GSH) kits were utilized to assess changes in ferroptosis. Database analysis results showed that AURKA was a differential gene in ESCC and was highly expressed in human ESCC tissues. Functionally, AURKA knockdown decreased ESCC cell proliferation, invasion, and metastasis both in vitro and in vivo. Moreover, when AURKA was knockdown, cells were more correctly blocked in the G2/M phase, and the ferroptosis-related MDA and Fe increased, whereas the GSH reduced. Consistently, Glutathione peroxidase 4 (GPX4) and solute carrier family 7a member 11 (SLC7A11) expression were downregulated by AURKA knockdown. However, ferroptosis inhibitor partially restore ESCC cell proliferation, invasion, and metastasis caused by AURKA knockdown. AURKA knockdown enhances ferroptosis and acts against cancer progression in ESCC. AURKA acts as a tumor-promoting gene and may serve as potential target for ESCC treatment.
| S-EPMC10987997 | biostudies-literature