RNA sequencing reveals the expression profiles of circRNA and identifies a four-circRNA signature acts as a prognostic marker in esophageal squamous cell carcinoma

Abstract Background CircRNAs with tissue-specific expression and stable structure may be good tumor prognostic markers. However, the expression of circRNAs in esophageal squamous cell carcinoma (ESCC) remain unknown. We aim to identify prognostic circRNAs and construct a circRNA-related signature in ESCC. Methods RNA sequencing was used to test the circRNA expression profiles of 73 paired ESCC tumor and normal tissues after RNase R enrichment. Bioinformatics methods, such as principal component analysis (PCA), t-distributed Stochastic Neighbor Embedding (t-SNE) algorithm, unsupervised clustering and hierarchical clustering were performed to analyze the circRNA expression characteristics. Univariate cox regression analysis, random survival forests-variable hunting (RSFVH), Kaplan–Meier analysis, multivariable Cox regression and ROC (receiver operating characteristic) curve analysis were used to screen the prognostic circRNA signature. Real-time quantitative PCR (qPCR) and fluorescence in situ hybridization(FISH) in 125 ESCC tissues were performed. Results Compared with normal tissues, there were 11651 differentially expressed circRNAs in cancer tissues. A total of 1202 circRNAs associated with ESCC prognosis (P < 0.05) were identified. Through bioinformatics analysis, we screened a circRNA signature including four circRNAs (hsa_circ_0000005, hsa_circ_0007541, hsa_circ_0008199, hsa_circ_0077536) which can classify the ESCC patients into two groups with significantly different survival (log rank P < 0.001), and found its predictive performance was better than that of the TNM stage(0.84 vs. 0.66; 0.65 vs. 0.62). Through qPCR and FISH experiment, we validated the existence of the screened circRNAs and the predictive power of the circRNA signature. Conclusion The prognostic four-circRNA signature could be a new prognostic biomarker for ESCC, which has high clinical application value.

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Identification of the Prognostic Value of Tumor Microenvironment-Related Genes in Esophageal Squamous Cell Carcinoma

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2020.599475 ◽

2020 ◽

Vol 7 ◽

Author(s):

Donglei Zhang ◽

Changlin Qian ◽

Huabing Wei ◽

Xiaozhe Qian

Keyword(s):

Squamous Cell Carcinoma ◽

Tumor Microenvironment ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Risk Score ◽

Squamous Cell ◽

Prognostic Value ◽

Cox Regression ◽

Expression Profiles ◽

Cox Regression Analysis

Background: Esophageal squamous cell carcinoma (ESCC) is the most prevalent histological type of esophageal cancer, but there is a lack of definite prognostic markers for this cancer.Methods: We used the ESTIMATE algorithm to access the tumor microenvironment (TME) of ESCC cases deposited in the TCGA database, and identified TME-related prognostic genes using Cox regression analysis. A least absolute shrinkage and selector operation or LASSO algorithm was used to identify key prognostic genes. Risk scores were calculated, and a clinical predictive model was constructed to evaluate the prognostic value of TME-related genes.Results: We found that high immune and stromal scores were significantly associated with poor overall survival (p < 0.05). We identified a total of 1,151 TME-related differently expression genes, among which 67 were prognosis-related genes. Through the LASSO method, 13 key prognostic genes were selected, namely, ADAMTS16, LOC51089, CH25H, CORO2B, DLGAP1, GYS2, HAL, MXRA8, NPTX1, OTX1, RET, SLC24A2, and SPI1, and a 13-gene risk score was constructed. A higher score was indicative of a poorer prognosis than a lower risk score (hazard ratio = 8.21, 95% confidence interval: 2.56–26.31; P < 0.001). The risk score was significantly correlated with immune/stromal scores and various types of infiltrating immune cells, including CD8 cells, regulatory T cells, and resting macrophages.Conclusion: We characterized the tumor microenvironment in ESCC, and identified the key prognosis genes. The risk score based on the expression profiles of these genes is proposed as an indicator of TME status and is instrumental in predicting patient prognosis.

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MicroRNA Expression Profiles in Superficial Esophageal Squamous Cell Carcinoma before Endoscopic Submucosal Dissection: A Pilot Study

International Journal of Molecular Sciences ◽

10.3390/ijms22094789 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4789

Author(s):

Shintaro Fujihara ◽

Hideki Kobara ◽

Noriko Nishiyama ◽

Kayo Hirose ◽

Hisakazu Iwama ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Endoscopic Submucosal Dissection ◽

Cell Carcinoma ◽

Squamous Cell ◽

Mirna Expression ◽

Expression Profiles ◽

Normal Tissues ◽

Mirna Expression Profiles

Esophageal squamous cell carcinoma (ESCC) has a poor prognosis when diagnosed at an advanced stage, and early detection and treatment are essential to improve survival. However, intraobserver and interobserver variation make the diagnosis of superficial ESCC difficult, and suitable biomarkers are urgently needed. Here, we compared the microRNA (miRNA) expression profiles of superficial ESCC tissues and adjacent normal tissues obtained immediately before esophageal endoscopic submucosal dissection. We found that ESCC and normal tissues differed in their miRNA expression profiles. In particular, miR-21-5p and miR-146b-5p were significantly upregulated and miR-210-3p was significantly downregulated in tumor tissues compared with normal tissues. We also detected significant associations between miRNA expression and ESCC invasion depth and lymphovascular invasion. The same differential expression of miR-21-5p, miR-146b-5p, and miR-210-3p was detected in ESCC cell lines compared with normal esophageal epithelial cells in vitro. However, transfection of ESCC cells with miR-210-3p and miR-21-5p mimics or inhibitors had partial effects on cell proliferation and invasion in vitro. These results indicate that miRNA expression is significantly deregulated in superficial ESCC, and suggest that the potential contribution of differentially expressed miRNAs to the malignant phenotype should be further investigated.

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Development and Validation of a Ferroptosis-Related Gene Signature and Nomogram for Predicting the Prognosis of Esophageal Squamous Cell Carcinoma

Frontiers in Genetics ◽

10.3389/fgene.2021.697524 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jiecheng Ye ◽

Yining Wu ◽

Heyuan Cai ◽

Li Sun ◽

Wanying Deng ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Risk Score ◽

Squamous Cell ◽

Prognostic Value ◽

Cox Regression ◽

Risk Group ◽

Clinical Variable ◽

Cox Regression Analysis

Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor with high mortality and poor prognosis. Ferroptosis is a newly discovered form of cell death induced by iron-catalyzed excessive peroxidation of polyunsaturated fatty acids (PUFAs). However, the prognostic value of ferroptosis-related genes (FRGs) for ESCC remains unclear. Based on the ESCC dataset from the Gene Expression Omnibus (GEO) database, we identified 39 prognostic FRGs through univariate Cox regression analysis. After LASSO regression and multivariate Cox regression analyses, a multigene signature based on 10 prognostic FRGs was constructed and successfully divided ESCC patients into two risk groups. Patients in the low-risk group showed a significantly better prognosis than patients in the high-risk group. In addition, we combined the risk score with clinical predictors to construct a nomogram for ESCC. The predictive ability of the nomogram was further verified by ROC curves and calibration plots in both the training and validation sets. The predictive power of the nomogram was demonstrated to be better than that of either the risk score or clinical variable alone. Furthermore, functional analysis revealed that the 10-FRG signature was mainly associated with ferroptosis, differentiation and immune response. Connectivity map analysis identified potential compounds capable of targeting FRGs in ESCC. Finally, we demonstrated the prognostic value of SRC gene in ESCC using the clinical samples and found that SRC inhibition sensitized ESCC cells to ferroptosis inducers by in vitro experiments. In conclusion, we identified and verified a 10-FRG prognostic signature and a nomogram, which provide individualized prognosis prediction and provide insight into potential therapeutic targets for ESCC.

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Autophagy-Related Three-Gene Prognostic Signature for Predicting Survival in Esophageal Squamous Cell Carcinoma

Frontiers in Oncology ◽

10.3389/fonc.2021.650891 ◽

2021 ◽

Vol 11 ◽

Author(s):

Heyang Cui ◽

Yongjia Weng ◽

Ning Ding ◽

Chen Cheng ◽

Longlong Wang ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Prognostic Model ◽

Cox Regression ◽

The Cancer Genome Atlas ◽

Differentially Expressed ◽

Discovery Cohort ◽

Cox Regression Analysis

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignant tumors in China, and its prognosis remains poor. Autophagy is an evolutionarily conserved catabolic process involved in the occurrence and development of ESCC. In this study, we described the expression profile of autophagy-related genes (ARGs) in ESCC and developed a prognostic prediction model for ESCC patients based on the expression pattern of ARGs. We used four ESCC cohorts, GSE53624 (119 samples) set as the discovery cohort, The Cancer Genome Atlas (TCGA) ESCC set (95 samples) as the validation cohort, 155 ESCC cohort, and Oncomine cohort were used to screen and verify differentially expressed ARGs. We identified 34 differentially expressed genes out of 222 ARGs. In the discovery cohort, we divided ESCC patients into three groups that showed significant differences in prognosis. Then, we analyzed the prognosis of 34 differentially expressed ARGs. Three genes [poly (ADP-ribose) polymerase 1 (PARP1), integrin alpha-6 (ITGA6), and Fas-associated death domain (FADD)] were ultimately obtained through random forest feature selection and were constructed as an ARG-related prognostic model. This model was further validated in TCGA ESCC set. Cox regression analysis confirmed that the three-gene signature was an independent prognostic factor for ESCC patients. This signature effectively stratified patients in both discovery and validation cohorts by overall survival (P = 5.162E-8 and P = 0.052, respectively). We also constructed a clinical nomogram with a concordance index of 0.713 to predict the survival possibility of ESCC patients by integrating clinical characteristics and the ARG signature. The calibration curves substantiated fine concordance between nomogram prediction and actual observation. In conclusion, we constructed a new ARG-related prognostic model, which shows the potential to improve the ability of individualized prognosis prediction in ESCC.

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The Value of Complete Blood Count For The Prognosis Analysis of Esophageal Squamous Cell Carcinoma

10.21203/rs.3.rs-580465/v1 ◽

2021 ◽

Author(s):

Xiang Lv ◽

Songtao Han ◽

Bin Xu ◽

Yuqin Deng ◽

Feng Yangchun

Keyword(s):

Squamous Cell Carcinoma ◽

Regression Analysis ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Blood Count ◽

Cox Regression ◽

Complete Blood Count ◽

Analysis Model ◽

Cox Regression Analysis

Abstract Objective To investigate the value of complete blood count in predicting the survival rate of patients with esophageal squamous cell carcinoma. Methods A total of 3587 patients with esophageal squamous cell carcinoma who were initially admitted to the Affiliated Cancer Hospital of Xinjiang Medical University from January 2010 to December 2017 were collected by retrospective study. The relevant clinical data were collected by the medical record system, and the patients were followed up by the hospital medical record follow-up system. The follow-up outcome was death. The survival time of all patients was obtained. The survival curve was established using the cut-off value of each index obtained by ROC curve. The Cox proportional hazards regression analysis model and nomogram were established to predict the survival prognosis of esophageal squamous cell carcinoma. The role of each index in the prognosis of patients with esophageal squamous cell carcinoma was studied Results The cut-off values of NLR, NMR, LMR, RDW and PDW in blood routine were 3.52, 10.22, 2.25, 13.85% and 12.05%, respectively. Survival curve analysis showed that patients aged < 60 years and NLR < 3.52 had survival. All indicators were divided into high and low groups according to ROC curve. Univariate Cox regression analysis model showed that RDW (≥ 13.85) and NLR (≥ 3.52) groups were risk factors for the prognosis of ESCC, with HR values of 1.099 (1.015–1.191; p = 0.020) and 1.340 (1.231–1.458; p < 0.001) compared with RDW (< 13.85) and NLR (< 3.52), respectively; multivariate Cox regression analysis model showed that NLR was significantly associated with the prognosis of ESCC, with HR of 1.342 (1.232–1.461; p < 0.001) for NLR (≥ 3.52) NLR (< 3.52). Conclusion NLR results in blood count can be used to predict the survival of patients with esophageal squamous cell carcinoma.

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Prognostic value of programmed death-ligand 1 expression in patients with esophageal squamous cell carcinoma

10.21203/rs.3.rs-22029/v1 ◽

2020 ◽

Author(s):

Qun Zhang ◽

Feng Li ◽

Peng Cai ◽

Hongwei Li ◽

Hongmei Yin ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Cox Regression ◽

Tumor Resection ◽

Programmed Death Ligand 1 ◽

Cox Regression Analysis ◽

Programmed Death ◽

L1 Protein

Abstract Background To investigate the expression of PD-L1(programmed death-ligand 1)in patients with esophageal squamous cell carcinoma (ESCC) and its clinical significance. Methods The tissue expression of PD-L1 protein in 139 cases of ESCC and 50 adjacent non-malignant epithelial tissues (> 5 cm from the tumor resection margins) were identified by immunohistochemical staining. Subsequently, the relationship between expression and the observed clinical characteristics was analyzed. Results The positive expression rate of PD-L1 protein was increased in tumor tissues compared to that of adjacent noncancerous mucosa tissues (40.3% vs. 22.0%, P < 0.05). The findings also indicated that PD-L1 protein expression had no significant correlation with age, gender, tumor location, differentiation and lymph node (N) status (P > 0.05). The 91 months follow-up Kaplan-Meier survival analysis showed that patients in positively expressed PD-L1 group experienced a lower survival rate compared to their negatively expressed PD-L1 counterparts (32.1% vs. 48.2%, P < 0.05). The COX regression analysis results suggested that PD-L1 represented an independent prognosis factor for ESCC. Conclusions The findings indicated that PD-L1 plays an important role in the progression of ESCC and might represent a potential therapeutic and prognostic target for ESCC patients.

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Predictive Value of LINC01133 for Unfavorable Prognosis was Impacted by Alcohol in Esophageal Squamous Cell Carcinoma

Cellular Physiology and Biochemistry ◽

10.1159/000491724 ◽

2018 ◽

Vol 48 (1) ◽

pp. 251-262 ◽

Cited By ~ 10

Author(s):

Xian-Zi Yang ◽

Qing-Jun He ◽

Tian-Tian Cheng ◽

Jun Chi ◽

Zi-Ying Lei ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Protective Factor ◽

Cox Regression ◽

Tnm Stage ◽

Rank Test ◽

Cox Regression Analysis ◽

Drinking Status

Background/Aims: Considerable evidence indicates that long noncoding RNAs (lncRNAs) exert importantly regulatory functions during human cancer initiation and progression and are promising biotargets in the flight against cancer. Methods: In this study, we evaluated the role of the lncRNA LINC01133 in esophageal squamous cell carcinoma (ESCC). LINC01133 expression in ESCC was examined by quantitative real-time PCR. The correlations between LINC01133 expression and clinicopathological variables and survival were examined by the χ2 test, Kaplan–Meier method, log-rank test, and univariate Cox regression analysis. Results: LINC01133 expression levels were frequently lower in ESCC tissues and cell lines than in paired normal tissues and an immortalized esophageal epithelial cell line, respectively. The expression of LINC01133 decreased in a TNM stage- and lifestyle-independent manner. LINC01133 was an independent protective factor and had an anti-tumor effect in the early stage of ESCC development. More importantly, we discovered that drinking status in our cohort impaired the predictive accuracy of LINC01133 for patients with ESCC. Furthermore, a new risk model combining LINC01133 expression, drinking status, and TNM stage provided better survival discrimination compared with three other predictors. Conclusions: Our data indicate that a loss of LINC01133 expression is a potential poor prognostic biomarker and therapeutic target for ESCC and provide additional prognostic information to improve the outcomes of ESCC patients.

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Benefit of chemotherapy based on platinum with definitive radiotherapy in older patients with locally advanced esophageal squamous cell carcinoma

Radiation Oncology ◽

10.1186/s13014-021-01931-1 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Haishan Wu ◽

Yilin Yu ◽

Qunhao Zheng ◽

Tianxiu Liu ◽

Yahua Wu ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Regression Analysis ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Older Patients ◽

Cox Regression ◽

Locally Advanced ◽

Cox Regression Analysis ◽

Significant Difference

Abstract Objective There is still no definitely therapeutic evidence of a beneficial effect of chemotherapy with radiotherapy for older patients with esophageal squamous cell carcinoma (ESCC). We aim to determine the influence of chemoradiotherapy (CRT) and radiotherapy (RT) alone in patients aged 65 years or older with locally advanced ESCC. Methods We retrospectively analyzed 581 ESCC patients who underwent CRT and RT alone. Univariate and multivariate Cox regression analysis was used to analyze the impact of clinical factors on long‐term overall survival (OS) and progression-free survival (PFS). Finally, we compared the toxicity rates of these patients. Results The median OS and PFS of the overall population were 23.2 months (2.0–162.6 months) and 18.6 months (1.1–159.6 months). Multivariate Cox regression analysis showed that chemotherapy (p < 0.05), tumor thickness (p < 0.01), and N stage (p < 0.05) were independent prognostic factors associated with both OS and PFS. In the chemotherapy subgroup, patients who received 2–8 cycles of chemotherapy had better OS than those who received 1 cycle (p = 0.015). The results also revealed that the CRT group has better OS and PFS than RT alone group for patients aged 65–74 years (both p < 0.01). However, for patients aged 75 years or older, there was no statistically significant difference between CRT and RT alone (both p > 0.05). Besides, higher staged ESCC has the inferior OS and PFS than lower staged ESCC for patients received RT alone and aged 65–74 years (both p < 0.05). Finally, there were significantly more severe hematologic toxicities in the CRT group than in those treated with RT alone in this study (p < 0.001). Conclusions The present study suggested that CRT for locally advanced ESCC in patients aged 65 years or older had a significant benefit over RT alone in terms of OS and PFS. However, for patients aged 75 years or older, there was no statistically significant difference between CRT and RT alone. CRT should be performed with special attention in patients aged 75 years or older.

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Pan-Cancer Analysis of the Prognostic and Immunological Role of HSF1: A Potential Target for Survival and Immunotherapy

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/5551036 ◽

2021 ◽

Vol 2021 ◽

pp. 1-21

Author(s):

Fei Chen ◽

Yumei Fan ◽

Pengxiu Cao ◽

Bing Liu ◽

Jiajie Hou ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Cox Regression ◽

Expression Profiles ◽

Prognostic Significance ◽

Deep Understanding ◽

Clinicopathological Parameters ◽

Cox Regression Analysis ◽

Pan Cancer

Emerging evidence revealed the significant roles of heat shock factor 1 (HSF1) in cancer initiation, development, and progression, but there is no pan-cancer analysis of HSF1. The present study first comprehensively investigated the expression profiles and prognostic significance of HSF1 and the relationship of HSF1 with clinicopathological parameters and immune cell infiltration using bioinformatic techniques. HSF1 is significantly upregulated in various common cancers, and it is associated with prognosis. Pan-cancer Cox regression analysis indicated that the high expression of HSF1 was associated with poor overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), head and neck squamous cell carcinoma (HNSC), and kidney renal papillary cell carcinoma (KIRP) patients. The methylation of HSF1 DNA was decreased in most cancers and negatively correlated with the HSF1 expression. Increased phosphorylation of S303, S307, and S363 in HSF1 was observed in some cancers. HSF1 remarkably correlated with the levels of infiltrating cells and immune checkpoint genes. Our pan-cancer analysis provides a deep understanding of the functions of HSF1 in oncogenesis and metastasis in different cancers.

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Identification of a prognostic immune signature for esophageal squamous cell carcinoma to predict survival and inflammatory landscapes

10.21203/rs.3.rs-29561/v1 ◽

2020 ◽

Author(s):

Jie He ◽

Chaoqi Zhang ◽

Yuejun Luo ◽

Zhen Zhang ◽

Zhihui Zhang ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Cox Regression ◽

Lung Squamous Cell Carcinoma ◽

Training Set ◽

Cox Regression Analysis ◽

Related Risk ◽

Public Data

Abstract BackgroundImmunotherapy has achieved surprising success in the treatment of esophageal squamous cell carcinoma (ESCC). However, studies concerning immune phenotypes within the ESCC microenvironment and their relationship with prognostic outcomes are limited. Therefore, we aim to construct and validate an individual immune-related risk signature for patients with ESCC.MethodsWe collected 196 ESCC cases, including 119 samples from our previous public data (GSE53624) to use as a training set. We additionally collected an independent validation cohort consisting of 77 frozen tumor tissues with qPCR data. Head and neck squamous cell carcinoma (HNSCC) and lung squamous cell carcinoma (LUSC) cohorts were also collected for validation. A least absolute shrinkage and selection operator (LASSO) model and a stepwise Cox proportional hazards regression model were used to construct the immune-specific signature. The potential mechanism and inflammatory landscapes of the signature were explored by using bioinformatics and immunofluorescence assay methods.ResultsImmune-related genes were significantly altered in ESCC tissues, and 16 differentially expressed immune-related genes with the most prognostic value were filtered out (P<0.01). Then a six-gene-based signature (TSPAN2, AMBP, ITLN1, C6, PRLR, and MADCAM1) was generated from the training set. This signature classified the patients into two groups with significantly different overall and relapse-free survival. Furthermore, the signature showed similar prognostic values in different clinical subgroups and in the independent cohort, as well as in patients with HNSCC and LUSC. Multivariable Cox regression analysis confirmed that the signature was an independent prognostic factor for patients with ESCC in different cohorts. Pathway analysis showed that genes related to the signature were mostly involved in cell adhesion, leukocyte transendothelial migration, and cancer progression. Further analysis revealed that the signature was closely associated with specific inflammatory activities (activation of macrophages and T cells signaling transduction). Additionally, high-risk patients were found characterized by distinctive immune checkpoints panel and higher filtration of Tregs and fibroblasts. ConclusionWe constructed the first comprehensive immune-related risk signature for ESCC and furnished new hints of immune profiling of ESCC. Future prospective studies are needed to test the clinical utility of this signature in the individualized management of patients with ESCC.

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