Prognosis In Esophageal Squamous Carcinoma Research Articles

TESC acts as a prognostic factor and promotes epithelial-mesenchymal transition progression in esophageal squamous carcinoma

BackgroundTescalcin (TESC) is a critical regulator of cell differentiation and growth, promoting malignant progression in various tumors. However, the role of TESC in esophageal squamous carcinoma (ESCC) remains unclear. MethodsImmunohistochemistry (IHC), quantitative real-time PCR (qRT-PCR), and western blot were utilized to identify the difference in TESC expression between ESCC tissues and normal tissues adjacent to the carcinoma. The relationship between TESC and several clinicopathological features was shown by the chi-square test. Log-rank analysis and Cox regression were used to detect the relationship between TESC and the prognosis in ESCC. Clone formation and cell count kit-8 (CCK-8) were applied to detect the impact of TESC on ESCC proliferation. Wound healing assay and transwell assay were used to confirm the influence of TESC on the invasion and migration. Spearman correlation coefficient was used to describe the correlation between TESC and epithelial-mesenchymal transition (EMT)-related protein expression in ESCC. Western blot was used to detect the effect of TESC on the expression of E-cadherin, N-cadherin, and Vimentin as well as AKT signaling pathway. Xenograft tumors were developed to test the pro-tumorigenic impacts of TESC in vivo. ResultsTESC was upregulated expression in ESCC tissues and was linked to poorer prognosis and worse tumor infiltration, TNM stage, and lymph node metastasis. Meanwhile, TESC was able to act as an independent prognostic factor in ESCC. TESC promoted tumor cell proliferation, invasion, migration, EMT progression, and activated the phosphorylation of the AKT pathway. Furthermore, TESC knockdown inhibited the growth of carcinoma in vivo. ConclusionTESC is a predictive factor for poor prognosis in ESCC and may provide a new strategy for ESCC treatment.

Construction and Evaluation of a Risk Score Model for Lymph Node Metastasis-Associated Circadian Clock Genes in Esophageal Squamous Carcinoma.

Studies suggested that circadian clock genes (CCGs) in human esophageal squamous carcinoma (ESCC) samples are dysregulated. However, the relevance of CCGs to lymph node metastasis (LNM) and prognosis of ESCC remains unclear. The differentially expressed genes (DEGs) between normal and ESCC samples in The Cancer Genome Atlas database (TCGA) database were intersected with the genes associated with LNM (LNMGs) in ESCC samples and 300 CCGs to obtain the differentially expressed LNM-associated CCGs (DE-LNM-CCGs). The risk model was constructed by Cox regression analysis in the TCGA-ESCC training set, and the accuracy of the risk model was verified by risk profile and overall survival profile. Furthermore, differences of 23 immune cells, 13 immune functions, and immune checkpoint molecules between the high- and low-risk groups were assessed using the single-sample gene set enrichment analysis (ssGSEA) algorithm. Gene set enrichment analysis (GSEA) was conducted to investigate the functional differences between low- and high-risk groups. Finally, we validated the mRNA expression levels of prognostic model genes by quantitative real-time polymerase chain reaction (qRT-PCR). A total of six DE-LNM-CCGs were identified in TCGA-ESCC. TP53 and NAGLU were selected by Cox regression analysis to construct the risk model. Risk profile plots, overall survival plots, and validation results of the risk model in the validation set indicated that the constructed risk model was reliable. The result of ssGSEA showed that the percentages of activated B cells, activated dendritic cells, effector memory CD8 T cells, immune function in neutrophils, plasmacytoid dendritic cells, T cell co-inhibition, and Type 17 T helper cells were different between the high- and low-risk groups. In addition, the expression of CD274, PDCD1, TNFRSF18, and TNFRSF9 was dysregulated between the high- and low-risk groups. GSEA revealed that the high-risk group was associated with cell differentiation, oxidative phosphorylation, and steroid biosynthesis pathways, while the low-risk group was associated with chromosome, ECM-receptor interaction, and other pathways. Finally, qRT-PCR results showed that the mRNA expression levels of two prognostic genes were consistent with TCGA. In conclusion, the risk model constructed based on TP53 and NAGLU could accurately predict the prognosis.

The high expression of MTH1 and NUDT5 predict a poor survival and are associated with malignancy of esophageal squamous cell carcinoma.

BackgroundMTH1 and NUDT5 effectively degrade nucleotides containing 8-oxoguanine. MTH1 and NUDT5 have been linked to the malignancy of multiple cancers. However, their functions in tumor growth and metastasis in esophageal squamous carcinoma (ESCC) remain obscure. Our present study aims to explore their prognostic value in ESCC and investigate their function in MTH1 or NUDT5-knockout tumor cells.MethodsMTH1 and NUDT5 protein expression in ESCC adjacent normal tissues and tumor tissues was examined by immunohistochemistry staining. Kaplan–Meier curves were used to assess the association between their expression and overall survival (OS) in ESCC patients. Univariate and Multivariate Cox regression analyses were generated to determine the correlation between these protein expression and OS of ESCC patients. Protein expression in ESCC cell lines were measured by Western blotting. To explore the potential effects of the MTH1 and NUDT5 protein in ESCC, cell models with MTH1 or NUDT5 depletion were established. CCK-8, cell cycle, Western blotting, migration and invasion assays were performed.ResultsOur present study demonstrated that the levels of MTH1 and NUDT5 were upregulated in ESCC cell lines and ESCC tissues, the expression of MTH1 and NUDT5 in ESCC tissues was significantly higher than in adjacent non-tumorous, and higher levels of MTH1 and NUDT5 predicted a worse prognosis in patients with ESCC. MTH1 and NUDT5 are novel biomarkers of the progression of ESCC and a poor prognosis. We also found for the first time that the high expression of NUDT5 independently predicted lower OS in patients with ESCC (hazard ratio (HR) 1.751; 95% confidence interval (CI) [1.056–2.903]; p = 0.030). In addition, the depletion of MTH1 and NUDT5 strongly suppressed the proliferation of ESCC cells and significantly delayed the G1 phase of the cell cycle. Furthermore, we found that MTH1 and NUDT5 silencing inhibited epithelial–mesenchymal transition mainly by the MAPK/MEK/ERK dependent pathway, which in turn significantly decreased the cell migration and invasion of ESCC cells. Our results suggested that the overexpression of MTH1 and NUDT5 is probably involved in the tumor development and poor prognosis of ESCC.

EP300 as an oncogene correlates with poor prognosis in esophageal squamous carcinoma.

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.

WITHDRAWN: EP300 promotes tumor development and correlates with poor prognosis in esophageal squamous carcinoma

// Yanghui Bi 1, 2, 3, * , Ling Zhang 1, 2, 3, 4, * , Heyang Cui 1, 2, 3, * , Pengzhou Kong 1, 2, 3, * , Ting Yan 1, 2, 3 , Jiayi Li 5 , Zianyi Wang 6 , Caixia Cheng 1, 2, 3, 7 , Bin Song 1, 2, 3, 8 , Bin Yang 1, 2, 3, 9 , Enwei Xu 1, 2, 3, 10 , Jie Yang 1, 2, 3 , Xiaoling Hu 1, 2, 3, 11 , Ruyi Shi 1, 2, 3, 12 , Yu Qian 1, 2, 3 , Fang Wang 1, 2, 3 , Hongyi Li 1, 2, 3 , Zhiwu Jia 1, 2, 3 , Yanchun Ma 1, 2, 3 , Jian Yang 1, 2, 3 , Yike Li 1, 2, 3 , Juan Wang 1, 2, 3 , Yiqian Liu 1, 2, 3 , Yuanfang Zhai 1, 2, 3 , Lu Chang 1, 2, 3 , Yi Wang 1, 2, 3 , Yingchun Zhang 1, 2, 3 , Feng Liu 13 , Haiyan Liu 1, 2, 3, 14 , Yanyan Zhang 1, 2, 3, 15 , Jing Liu 1, 2, 3, 15 , Xiaolong Cheng 1, 2, 3, 16 and Yongping Cui 1, 2, 3 1 Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China 2 Key Laboratory of Carcinogenesis and Translational Research of Esophageal Cancer, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China 3 Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China 4 Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China 5 Anglo-Chinese School (Independent), Singapore 6 Taiyuan Lingde Secondary School, Taiyuan, Shanxi 030001, PR China 7 Department of Pathology, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China 8 Department of Oncology, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China 9 Department of General Surgery, Shanxi Cancer Hospital, Taiyuan, Shanxi 030001, PR China 10 Department of Pathology, Shanxi Cancer Hospital, Taiyuan, Shanxi 030001, PR China 11 Department of Pharmacology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China 12 Department of Cell Biology and Genetics, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China 13 Department of Forensic, Shanxi Medical University, Taiyuan, Shanxi 030001, China 14 Department of Nuclear Medicine, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China 15 Department of General Surgery, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China 16 Department of Anatomy, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China * These authors contributed equally to this work Correspondence to: Yongping Cui, email: cuiyp@sxmu.edu.cn Keywords: EP300; ESCC; prognosis; angiogenesis; EMT Received: August 21, 2017 Accepted: October 29, 2017 Published: January 02, 2018 ABSTRACT Recently, genomic sequencing research identified a range of mutations in genes encoding proteins involved in histone modifications in human cancers. Here, we integrated genomic sequencing data from 325 esophageal squamous cell carcinoma (ESCC) cases and screened a series of frequently mutated histone modifier genes, including MLL2, EP300, RB1 and KDM6A. Of them, EP300 was not only a significantly mutated gene but also a highly frequently mutated gene with mutation frequency more than 10% in ESCC. We found that EP300 mutation was associated with tumor grade, pathological T stage and lymph node metastasis, predicting a shorter cumulative survival status. Further immunohistochemical analysis based on tissue microarray 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 and colony formation, as well as cell migration and invasion. Combined the results of RNA-sequencing with validation test, EP300 knockdown led to a significant change in expression of genes associated with angiogenesis, hypoxia and epithelial mesenchymal transition. In particular, angiogenesis network included up-regulation of SERPINF1 and down-regulation of FGF2, FLT1, CCL2. In hypoxia network, core genes included down-regulated LDHA, ADM, SLC2A1 and CA9. EMT network covered the up-regulation of E-cadherin and down-regulation of N-cadherin, Snail and Vimentin. Taken together, our study identified a novel role and mechanism of EP300 in ESCC and provided epigenetic therapeutic strategies for the treatment of ESCC.

Simultaneous targeting PI3K and PERK pathways promotes cell death and improves the clinical prognosis in esophageal squamous carcinoma

PI3K pathway is an important anti-tumor target, but its effect and mechanism is not clear in esophageal squamous cell carcinoma (ESCC). By analysis of the Cancer Genome Atlas (TCGA) datasets, we found that PI3Ks level were significantly upregulated in human esophageal cancer tissues compared with that in non-cancer tissues. The alteration of PI3K can significantly affect the overall patient survival in ESCC but not in esophageal adenocarcinoma (EAC). We found that the classic PI3K inhibitor LY294002 obviously inhibited the canonical mammalian target of rapamycin (mTOR) pathway and restrained the growth of ESCC with less toxicity to normal cells. Besides, LY294002 inhibited noncanonical PKR-like ER kinase (PERK)/elF2α/ATF4 pathway as well. Both siRNA and the small molecule inhibitor GSK2656157 against PERK/elF2α/ATF4 pathway can significantly inhibit the growth of ESCC. More importantly, GSK2656157 aggravated the inhibitory effect of LY294002 on cell growth, colony formation, and apoptosis induction of ESCC. In addition of dual high expression of PI3K and PERK pathways in the ESCC patients, the difference of overall survival (OS) was more significant than using PI3K alone. These results indicated that dual targeting of PI3K and PERK pathways might improve clinical prognosis and enhance the treatment of ESCC patients.

The detective, prognostic, and predictive value of DNA methylation in human esophageal squamous cell carcinoma.

Esophageal cancer is one of the most common malignancies in the world. Squamous cell carcinoma accounts for approximately 90 % of esophageal cancer cases. Genetic and epigenetic changes have been found to accumulate during the development of various cancers, including esophageal squamous carcinoma (ESCC). Tobacco smoking and alcohol consumption are two major risk factors for ESCC, and both tobacco and alcohol were found to induce methylation changes in ESCC. Growing evidence demonstrates that aberrant epigenetic changes play important roles in the multiple-step processes of carcinogenesis and tumor progression. DNA methylation may occur in the key components of cancer-related signaling pathways. Aberrant DNA methylation affects genes involved in cell cycle, DNA damage repair, Wnt, TGF-β, and NF-κB signaling pathways, including P16, MGMT, SFRP2, DACH1, and ZNF382. Certain genes methylated in precursor lesions of the esophagus demonstrate that DNA methylation may serve as esophageal cancer early detection marker, such as methylation of HIN1, TFPI-2, DACH1, and SOX17. CHFR methylation is a late stage event in ESCC and is a sensitive marker for taxanes in human ESCC. FHIT methylation is associated with poor prognosis in ESCC. Aberrant DNA methylation changes may serve as diagnostic, prognostic, and chemo-sensitive markers. Characterization of the DNA methylome in ESCC will help to better understand its mechanisms and develop improved therapies.

Upregulation of the long noncoding RNA PCAT-1 correlates with advanced clinical stage and poor prognosis in esophageal squamous carcinoma.

Recent studies reveal that long noncoding RNAs (lncRNAs) play critical regulatory roles in cancer biology. Prostate cancer-associated ncRNA transcript 1 (PCAT-1) is one of the lncRNAs involved in cell apoptosis and proliferation of prostate cancer. This study aimed to assess the potential role of PCAT-1 specifically in the pathogenesis of esophageal squamous cell carcinoma (ESCC). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression level of PCAT-1 in matched cancerous tissues and adjacent noncancerous tissues from 130 patients with ESCC, 34 patients with non-small cell lung cancer (NSCLC), and 30 patients with gastric carcinoma (GC). The correlation of PCAT-1 with clinicopathological features and prognosis were also analyzed. The expression of PCAT-1 was significantly higher in human ESCC compared with the adjacent noncancerous tissues (70.8%, p < 0.01), and the high level of PCAT-1 expression was significantly correlated with invasion of the tumor (p = 0.024), advanced clinical stage (p = 0.003), lymph node metastasis (p = 0.032), and poor prognosis. However, PCAT-1 mRNA expression had no significant difference between paired primary cancerous tissues and the adjacent noncancerous tissues in 34 cases of NSCLC (p = 0.293) and 30 cases of GC (p = 0.125). High expression of PCAT-1 was specifically correlated with invasion of cancer tissues, metastasis of lymph node, and advanced tumor stage of ESCC. High expression of PCAT-1 might reflect poor prognosis of ESCC and indicate a potential diagnostic target in ESCC patients. Adjuvant therapy targeting PCAT-1 molecule might be effective in treatment of ESCC.

Clinical significance of expression of Yes-associated protein in human esophageal squamous carcinoma and precancerous lesions

Objective To investigate the expression of Yes-associated protein (YAP) in human esophageal squamous carcinoma and precancerous lesions,and its clinical significance.Methods The expression of YAP protein was detected by PV9000 immunohistochemical method in 125 esophageal squamous carcinoma specimens,23 cases of dysplasia and 125 cases of normal esophageal mucosa.Results The positive rate of YAP protein in esophageal squamous carcinoma specimens (50.4％) and dysplasia (34.8％) was significantly higher than that in normal esophageal mucosa (12.8％,P ＜ 0.01).YAP protein expression was not significantly associated with tumor location,age,or gender,but significantly correlated with tumor differentiation and stage (both P ＜ 0.05).Conclusion YAP is related to the occurrence and progression of human esophageal squamous carcinoma and may be used as an accessory parameter for early diagnosis and predicting the prognosis of esophageal squamous carcinoma. Key words: Yes-associated protein; Esophageal squamous cell carcinoma; Precancerous lesions ; Immunohistochemistry

Concurrent expression of C4.4A and Tenascin-C in tumor cells relates to poor prognosis of esophageal squamous cell carcinoma

C4.4A is a glycolipid-anchored membrane protein expressed in several human malignancies. We recently found that C4.4A expression was associated with poor prognosis of esophageal squamous carcinoma cells (ESCCs), but the underlying mechanism is unknown. To uncover this, we performed PCR array analysis using the HCT116 cell line, a positive control for C4.4A expression and we found that Tenascin-C (TNC) among the many adhesion molecules and extracellular matrix proteins was the best candidate for C4.4A molecule induction. Based on in vitro studies using the TE8 esophageal cancer cells, we examined by immunohistochemistry TNC expression in 111 ESCCs. We found that the TNC-positive group (24.3%) had significantly poorer prognosis than the TNC-negative group in 5-year overall survival. We also found there was a significant correlation between TNC and C4.4A in ESCC tissues (P=0.007). Finally, we found that only the double-positive group for C4.4A and TNC had a significantly worse prognosis (P=0.005). Our data suggest that TNC expression in ESCC may in part explain why C4.4A is associated with a poor prognosis of ESCC since TNC can promote invasion and metastasis.

Expression of Ras-GTPase-activating protein SH 3 domain binding protein and osteopontin in esophageal squamous carcinoma and their effects on prognosis

To investigate the expressions and significances of Ras-GTPase-activating protein SH 3 domain binding protein(G3BP) and osteopontin (OPN) proteins in esophageal squamous carcinoma (ESC). The expressions of G3BP and OPN proteins in 80 cases of ESC were detected by immunohistochemistry. The relationships between the 2 protein expression and tumor size, differentiation degree, TNM stage, lymph node metastasis and prognosis of ESC were also explored. (1) The positive expression rate of G3BP in ESC was 71.3%, and the rate in lymphoid metastatic group was significantly higher than that in non lymphoid metastatic group (Z=-2.283, P=0.022), but no relations were found between G3BP expression and diameter of tumor, differentiation and TNM grade (P>0.05). The G3BP positive expression group had shorter survival time than G3BP negative expression group (P=0.000). (2) The positive expression rate of OPN in ESC was 100%, and the degree of OPN expression was correlated with the differentiation (chi(2)=10.766, P=0.005) and lymphoid metastasis (Z=-2.289, P=0.022), but no relationship was found between the diameter of tumor and TNM grade (P>0.05). The expression of OPN were significantly related to survivals in a negative time-dependent manner in ESC patients (P=0.000). (3) The expression of G3BP protein correlated positively with the degree of OPN expression in ESC tissue (r(s)=0.376, P=0.001). The expressions of G3BP and OPN proteins have a close relationship with lymphoid metastasis and survival in ESC patients. G3BP and OPN proteins can be considered as predictors of prognosis in ESC patients.

The value of postoperative arterial infusion chemotherapy in patients with T3 esophageal squamous carcinoma after radical surgery

To studying the porgnostic factors after curative esophagetomy for the thoracic segment T3 esophageal after radical surgery. 190 patients suffering from T3 squamous carcinoma of lower thoracic esophagus who underwent radical surgery from January 1990 to January 1999, 158 males and 32 females, aged 62.98 (40 approximately 81), were divided into 2 groups: 108 patients (experimental group, T3N0M0 56 cases and T3N1M0 52 cases) underwent surgery and arterial infusion (cisplatin 80 mg/m(2) and fluorouracil (800 mg/m(2)) with or without epirubicin since 3 approximately 4 weeks postoperatively, the interval of each periods is 4 - 6 weeks. and the other 82 patients (T3N0M0 48 cases and T3N1M0 34 cases) underwent surgery only. Fifty-six out of the 108 cases in the experimental group (T3N0M0 26 cases and T3N1M0 30 cases) underwent 3 periods of chemotherapy for less than 3 periods of chemotherapy with an interval between 2 periods of 4 approximately 6 weeks, and the other 52 patients (T3N0M0 30 cases and T3N1M0 22 cases) underwent chemotherapy for 3 periods or over. All cases were followed up for more than 5 years. Kaplan-Meier survival curve was used to analyze the survival rate. Cox regression model was used to analyze the influencing factors of prognosis. There was no significant difference in the overall long-term survival rate between the experimental group and control group, however, the survival rate of those receiving 3 periods of chemotherapy and over was significantly higher than those receiving less than 3 periods of chemotherapy Lymph node metastatic status was an important factor in prognosis of esophageal squamous carcinoma. Without severe side effects, postoperative chemotherapy by transcatheter arterial infusion prolongs the survival rate of the patients with esophageal squamous carcinoma who have been previously treated by radical surgery.