CEP55 Positively Affects Tumorigenesis of Esophageal Squamous Cell Carcinoma and Is Correlated with Poor Prognosis.
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ABSTRACT:
SUBMITTER: Yan SM
PROVIDER: S-EPMC8159646 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The genetic mechanisms underlying the poor prognosis of esophageal squamous cell carcinoma (ESCC) are not well understood. Here, we report somatic mutations found in ESCC from sequencing 10 whole-genome and 57 whole-exome matched tumor-normal sample pairs. Among the identified genes, we characterized mutations in VANGL1 and showed that they accelerated cell growth in vitro. We also found that five other genes, including three coding genes (SHANK2, MYBL2, FADD) and two non-coding genes (miR-4707-5p, PCAT1), were involved in somatic copy-number alterations (SCNAs) or structural variants (SVs). A survival analysis based on the expression profiles of 321 individuals with ESCC indicated that these genes were significantly associated with poorer survival. Subsequently, we performed functional studies, which showed that miR-4707-5p and MYBL2 promoted proliferation and metastasis. Together, our results shed light on somatic mutations and genomic events that contribute to ESCC tumorigenesis and prognosis and might suggest therapeutic targets.
| S-EPMC4833434 | biostudies-literature
Project description:Esophageal squamous cell carcinoma (ESCC) is a deadly malignant tumor that threatens human health. Long noncoding RNA (lncRNA) is widely expressed in eukaryotes and is closely associated with human disease progression. However, its role in ESCC remains incompletely understood. In this study, we analyzed the results of three gene expression omnibus (GEO) databases containing lncRNA expression data of ESCC and normal tissues. The results showed that HCP5 was significantly overexpressed in ESCC tissues, which was further verified in our collected ESCC samples. The functional study suggested that HCP5 knockdown inhibited ESCC cell proliferation and invasion. Regarding the mechanism, HCP5 was able to directly interact with YTHDF1, a N6-methyladenosine (m6A) reader, enhancing the binding of YTHDF1 to m6A-modified HK2 mRNA, leading to increasing HK2 stability, thereby promoting the Warburg effect (aerobic glycolysis) of ESCC cells. The nude mice model showed that the knockdown of HCP5 in vivo remarkably reduced tumor size. Clinically, high HCP5 was positively correlated with larger tumor volume, higher TNM stage and lymph node metastasis. Moreover, ESCC patients with high HCP5 exerted shorter survival time than patients with low HCP5. These findings uncover the importance of HCP5 in human ESCC progression; the turbulence of HCP5/YTHDF1/HK2 axis may be responsible for ESCC carcinogenicity.
| S-EPMC9208456 | biostudies-literature
Project description:E1A Binding Protein P300 (EP300) is one of the mutations of genes involved in histone modifications in esophageal squamous cell carcinoma (ESCC). However, its clinical relevance, potential function and mechanisms have remained elusive. Methods: Genomic sequencing datas from 325 esophageal squamous cell carcinoma (ESCC) cases were integrated and screened a series of frequently mutated histone modifier genes. EP300 was selected to further analyze its clinical significance, function and RNA-sequencing was performed to explore its potential mechanism. Results: Of 35 histone modifier genes, EP300 was not only a significantly mutated gene but also a frequently mutated gene with a mutation frequency of more than 10% in ESCC. EP300 mutation was associated with tumor grade, pathological T stage and lymph node metastasis, predicting a shorter cumulative survival status. Immunohistochemical analysis showed that EP300 expression was significantly higher in ESCC tumor tissues, and the expression levels were associated with poor survival of ESCC patients. Moreover, we found that EP300 knockdown led to inhibition of cell proliferation, colony formation, migration and invasion. RNA-sequencing showed EP300 knockdown led to a significant change of genes expression associated with angiogenesis, hypoxia and epithelial-to-mesenchymal transition (EMT). Conclusions: Taken together, our study identified a novel role and mechanism of EP300 in ESCC and provided epigenetic therapeutic strategies for the treatment of ESCC.
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Project description:BackgroundThe role of the PRDM5 in esophageal squamous cell carcinoma (ESCC) has not been revealed. This study investigated the relationship between PRDM5 expression and survival outcome in esophageal squamous cell carcinoma and explored the mechanism in tumor development.MethodsIn present study, expression of PRDM5 mRNA in esophageal squamous cell carcinoma patients was conducted using the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. The expression of PRDM5 was assessed by immunohistochemical staining. Kaplan-Meier curve and Cox regression analysis was performed to analyze the survival outcome and independent predictive factors. qRT-PCR and Methylation-specific PCR were performed to identify the mRNA level of PRDM5 and Methylation rate. Cibersort algorithm to analyze the relationship between PRDM5 expression and immune cell invasion. Western-blot was performed to confirm the expression of esophageal tumor tissues and adjacent tissues.ResultsThe TCGA database and GEO database show that PRDM5 mRNA level in esophageal squamous cell carcinoma adjacent tissues was higher than that of cancer tissues, and ESCC patients with high expression of PRDM5 mRNA had better overall survival. Tissue microarray showed that the protein level of PRDM5 in the adjacent tissues of patients with ESCC was higher than that in cancer tissues, and the expression level of PRDM5 was significantly correlated with the grade of clinicopathological characteristics (P < 0.001). Patients with high expression of PRDM5 displayed a better OS and DFS. Cox regression analysis showed that PRDM5 was an independent risk factor and prognostic factor for ESCC patients (HR: 2.626, 95%CI: 1.824-3.781; P < 0.001). The protein level of PRDM5 matched with the transcriptional level, whereas the DNA methylation affected the transcriptional level. Cibersort showed that T cells CD4 memory resting, mast cells resting, eosinophils, M2 macrophages and mast cells activated were significantly positively correlated with PRDM5 expression (P < 0.05), while regulatory T cells, monocytes and dendritic cells negatively correlated with PRDM5 expression (P < 0.05).ConclusionPRDM5 can be used as a biomarker to predict the survival of ESCC patients. Furthermore, PRDM5 expression in ESCC cells may affect WNT/β-catenin signaling pathways, thus further affect the ESCC cell proliferation, migration, and invasion capacity.
| S-EPMC9264607 | biostudies-literature
Project description:AbstractPlatelet-derived growth factor A (PDGFA), the most known member of PDGF family, plays a crucial role in occurrence and progression of different tumors. However, PDGFA expression and its clinical significance in esophageal squamous cell carcinoma (ESCC) are not clear. The present study aimed to assess the expression and prognostic value of PDGFA in ESCC.The Gene Expression Omnibus databases (GSE53625, GSE23400, and GSE67269) and fresh clinical samples were employed for detecting PDGFA messenger RNA expression in ESCC. The associations of PDGFA expression with clinicopathological characteristics were evaluated by chi-square test. Kaplan-Meier analysis and Cox proportional hazard regression model were performed to determine the prognostic value of PDGFA in ESCC patients. PDGFA-related signaling pathways were defined by gene set enrichment analysis based on Gene Expression Omnibus databases.The PDGFA messenger RNA expression was upregulated in ESCC tissues compared with paired adjacent noncancerous tissues (P < .05) and was positively correlated with T stage (P < .05). Kaplan-Meier survival analysis suggested that ESCC patients with high PDGFA expression were associated with poorer overall survival compared to those with low PDGFA expression (P < .05), especially in advanced T stage (P < .05). Cox analyses showed that high expression of PDGFA was an independent predictor for poor prognosis in ESCC patients. Gene set enrichment analysis identified 3 signaling pathways (extracellular matrix receptor interaction, focal adhesion, and glycosaminoglycan biosynthesis chondroitin sulfate) that were enriched in PDGFA high expression phenotype (all P < .01).PDGFA may serve as an oncogene in ESCC and represent an independent molecular biomarker for prognosis of ESCC patients.
| S-EPMC8137088 | biostudies-literature
Project description:Esophageal squamous cell carcinoma (SCC) is frequently diagnosed at advanced stage and associated with poor prognosis. This study aimed to identify differentially expressed genes for further evaluated as biomarkers for predicting survival of the patients. Five paired of cancerous and normal tissues from esophageal SCC patients were subjected to cDNA microarray analysis and one of these differentially expressed genes, NEK6, was further verified in esophageal SCC tissues. The data showed 444 up-regulated genes and 918 down-regulated genes in tumor tissues (2 folds as a cut-off value). qRT-PCR data showed that 20 of 30 (66.7%) increased levels of NEK6 mRNA in cancerous tissues compared to that of distant normal tissues, while immunohistochemical data showed that 49/94 (52.13%) of the archived esophageal SCC tissues expressed higher levels of NEK6 than that of normal tissues. NEK6 expression was associated with depth of tumor invasion (P=0.005), lymph node metastasis (P=0.018), and advanced clinical tumor stages (P=0.004) of these 94 patients. Kaplan Meier curve showed that the overall survival of NEK6-positive patients was much lower than those of NEK6-negative patients (P<0.001). The median survival of NEK6-positive patients was 23 months, whereas the median survival of NEK6-negative patients was 64 months. The cumulative 5-year survival rate of NEK6-positive patients was 14.3% (7/49), whereas the rate of NEK6-negative patients was 64.4% (29/45). Multivariate analysis showed that N classification (P=0.002) and NEK6 expression (P<0.001) were independent predictors for esophageal SCC patients. These data demonstrated that NEK6 expression may serve as an independent prognostic indicator for patients with esophageal SCC. Gene expression in five paired of cancerous and normal tissues from esophageal SCC patients were measured using Human Genome 4x44K v2 Microarray.
2013-09-30 | E-GEOD-45168 | biostudies-arrayexpress
Project description:Aquaporin 1 (AQP1) is a membrane protein whose main function is to transfer water across cellular membranes. Recent studies have described important roles for AQP1 in epithelial carcinogenesis and tumor behavior. The objectives of the present study were to investigate the role of AQP1 in the regulation of genes involved in tumor progression and the clinicopathological significance of its expression in esophageal squamous cell carcinoma (ESCC). An immunohistochemical analysis was performed on 50 primary tumor samples underwent esophagectomy. AQP1 was primarily located in the cytoplasm and/or the nuclear membrane of carcinoma cells. The 5-year survival rate of patients with the "cytoplasm dominant" expression of AQP1 (47.1%) was significantly lower than other patients (83.2%). The depletion of AQP1 using siRNA induced apoptosis in TE5 and TE15 cells. The results of microarray analysis revealed that Death receptor signaling pathway-related genes were changed in AQP1-depleted TE5 cells. In conclusion, the results of the present study suggested that the cytoplasm dominant expression of AQP1 is related to a poor prognosis in patients with ESCC, and that it activates tumor progression by affecting Death receptor signaling pathway. These results provide insights into the role of AQP1 as a mediator of and/or a biomarker for ESCC.
| S-EPMC6057448 | biostudies-literature
Project description:Esophageal squamous cell carcinoma (SCC) is frequently diagnosed at advanced stage and associated with poor prognosis. This study aimed to identify differentially expressed genes for further evaluated as biomarkers for predicting survival of the patients. Five paired of cancerous and normal tissues from esophageal SCC patients were subjected to cDNA microarray analysis and one of these differentially expressed genes, NEK6, was further verified in esophageal SCC tissues. The data showed 444 up-regulated genes and 918 down-regulated genes in tumor tissues (2 folds as a cut-off value). qRT-PCR data showed that 20 of 30 (66.7%) increased levels of NEK6 mRNA in cancerous tissues compared to that of distant normal tissues, while immunohistochemical data showed that 49/94 (52.13%) of the archived esophageal SCC tissues expressed higher levels of NEK6 than that of normal tissues. NEK6 expression was associated with depth of tumor invasion (P=0.005), lymph node metastasis (P=0.018), and advanced clinical tumor stages (P=0.004) of these 94 patients. Kaplan Meier curve showed that the overall survival of NEK6-positive patients was much lower than those of NEK6-negative patients (P<0.001). The median survival of NEK6-positive patients was 23 months, whereas the median survival of NEK6-negative patients was 64 months. The cumulative 5-year survival rate of NEK6-positive patients was 14.3% (7/49), whereas the rate of NEK6-negative patients was 64.4% (29/45). Multivariate analysis showed that N classification (P=0.002) and NEK6 expression (P<0.001) were independent predictors for esophageal SCC patients. These data demonstrated that NEK6 expression may serve as an independent prognostic indicator for patients with esophageal SCC.
2013-09-30 | GSE45168 | GEO
Project description:Esophageal squamous cell carcinoma (ESCC) is associated with the accumulation of genetic and epigenetic changes in the background mucosa. Dysregulated DNA methylation is known to lead to the inactivation of tumor suppressor genes and the activation of oncogenes. To identify the genes whose expression is perturbed by abnormal DNA methylation in ESCC, integrative transcriptomics by serial analysis of gene expression (SAGE) and methylome sequencing by methyl-DNA immunoprecipitation (MeDIP) analysis were performed. We found 159 genes with significantly decreased expression in ESCC compared to that in noncancerous esophageal mucosa. MeDIP-seq analysis identified hypermethylation in the promoter region of 56 of these genes. Using surgically resected tissues of 40 cases, we confirmed that the paired-like homeodomain 1 (PITX1) gene was hypermethylated in ESCC compared to that in normal tissues (P < 0.0001) by pyrosequencing. PITX1 overexpression in ESCC cell lines inhibited cell growth and colony formation, whereas PITX1 knockdown accelerated cell growth. A PITX1-transfected ESCC cell line, KYSE30, formed smaller tumors in nude mice than in mock-transfected cells. Hypermethylation of PITX1 was associated with tumor depth (P = 0.0011) and advanced tumor stage (P = 0.0052) and predicted poor survival in ESCC (hazard ratio, 0.1538; 95% confidence interval, 0.03159-0.7488; P = 0.0169). In this study, we found a novel tumor suppressor gene of ESCC, PITX1, which is silenced by DNA hypermethylation. Downregulation of PITX1 contributes to the growth and progression of ESCC. Hypermethylation of the PITX1 in ESCC correlated with tumor progression and advanced stage cancer, and may predict a poor prognosis.
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Project description:Oral squamous cell carcinoma (OSCC) is a cancerous disease with poor prognosis. According to the statistics, the 5-year survival rate has not improved significantly over the past 20 years. The platelet-derived growth factor (PDGF) and its signaling pathway is a key regulator of angiogenesis and tumorigenesis. High level of PDGF and its receptor (PDGFR) have been reported in several types of malignancies. In this study, we investigated the relationship of the molecular expression levels of PDGF and PDGFR with clinicopathological parameters in OSCC. To this end, we measured the mRNA and protein levels of PDGF and PDGFR by real-time quantitative PCR (qRT-PCR), immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA), respectively. We found positive correlations of the mRNA levels of PDGFA, PDGFB, and PDGFRB with lymph node metastasis and poor overall survival (OS). High expression of PDGF, PDGFRA, and PDGFRB were remarkably associated with lymph node metastasis and poor OS, as determined by immunohistochemistry. Preoperative serum levels of PDGF-AA and PDGF-BB had a positive correlation with preoperative platelet count. Elevated serum levels of PDGF-AA. PDGF-BB, and platelet count correlated with lymph node metastasis and an unfavorable outcome. In multivariate Cox regression analysis, PDGFA mRNA, PDGFB mRNA, PDGFRB mRNA, PDGF immunoexpression, PDGFRB immunoexpression, serum PDGF-AA, serum PDGF-BB, and platelet count emerged as significant independent prognostic factors for OS. In vitro, we found that elevated PDGF promotes colony formation, migration, and invasiveness of SAS and OECM-1 cancer cell lines. Our results suggest that the expression level of serum PDGF has the potential to become a useful diagnostic marker for the prognosis of OSCC. In addition, PDGFR should be considered as a potential therapeutic target for OSCC. Furthermore, research should be undertaken to elucidate the role of PDGF and PDGFR regarding the behavior of tumor cells in OSCC.
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