Pathogenesis Of Esophageal Cancer Research Articles

MiR-493 by regulating of c-Jun targets Wnt5a/PD-L1-inducing esophageal cancer cell development.

BackgroundEsophageal cancer is one of the most common cancers across the globe; the 5‐year survival of esophageal cancer patients is still low. MicroRNA (miRNA) dysregulation has been implicated in cancer development, and the miRNAs play a pivotal role in esophageal cancer pathogenesis. It is urgently needed to find out how miRNA dysregulation was involved in esophageal cancer (EC) development.MethodsThrough experiments in vivo and in vitro, we explored potential signaling pathways, miR‐493/Wnt5A/c‐JUN loop, in EC. Their mechanistic roles in EC cell proliferation, migration, and invasion were investigated through multiple validation steps in EC9706 and TE13 cell lines and EC specimens.ResultsOverexpression of miR‐493 attenuates esophageal cancer cell proliferation, migration, and invasion in vivo and in vitro. Moreover, miR‐493 downregulation is an unfavorable factor in EC and negatively correlated with Wnt5A. The existence of miR‐493 is also an important attribute of metabolism. Based on mechanism analyses, we show that miR‐493 inhibits the activity of c‐JUN and p‐PI3K/p‐AKT with enhanced p21 and directly regulates Wnt5A expression and function, whereas c‐JUN binds the promoter region of miR‐493 and suppressed the expression of miR‐493, forming a negative feedback loop.ConclusionsThe miR‐493/Wnt5A/c‐JUN loop is a molecular feedback loop that refers to the development of esophageal cancer cells and a potential target for the treatment of esophageal cancer.

Involvement of long non-coding RNAs in the progression of esophageal cancer.

Esophageal cancer (EC) is one of the most common malignant tumors of the digestive system with high incidence and mortality rate worldwide. Therefore, exploring the pathogenesis of EC and searching for new targeted therapies are the current research hotspot for EC treatment. Long non‐coding RNAs (lncRNAs) are endogenous RNAs with more than 200 nucleotides, but without protein‐coding function. In recent years, lncRNAs have gradually become the focuses in the field of non‐coding RNA. Some lncRNAs have been proved to be closely related to the pathogenesis of EC. Many lncRNAs are abnormally expressed in EC and participate in many biological processes including cell proliferation, apoptosis, and metastasis by inhibiting or promoting target gene expression. LncRNAs can also regulate the progression of EC through epithelial‐mesenchymal transformation (EMT), which is closely related to the occurrence, development, and prognosis of EC. In this article, we review and discuss the involvement of lncRNAs in the progression of EC.

Multiomic Analysis of Methylation and Transcriptome Reveals a Novel Signature in Esophageal Cancer.

Background:Epigenetic alterations have been shown to lead to human carcinogenesis. The aim of this study was to perform an integrative analysis to develop an epigenetic signature to predict overall survival (OS) of esophageal cancer.Methods:DNA methylation and messenger RNA expression data of esophageal cancer samples were downloaded from The Cancer Genome Atlas database and were incorporated and analyzed using an R package MethylMix. Functional enrichment analysis of the methylation-related differentially expressed genes (DEGs) was performed. Epigenetic signature and nomogram associated with the OS of esophageal cancer were established by the multivariate Cox model.Results:A total of 71 methylation-related DEGs were identified. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that these genes were involved in the biological process related to the initiation and progression of esophageal cancer. Two-gene (FAM24B and FAM200A) risk signature for OS was developed by multivariate Cox analysis, of which had high accuracy. The signature is independent of clinicopathological variables and indicated better predictive power than other clinicopathological variables. Moreover, we developed a novel prognostic nomogram based on risk score and 3 clinicopathological factors.Conclusions:Our study indicated possible methylation-related DEGs and established an epigenetic signature, which may provide novel insights for understanding the pathogenesis of esophageal cancer.

Expression profile of lncRNAs and miRNAs in esophageal cancer: Implications in diagnosis, prognosis, and therapeutic response.

Esophageal cancer is the seventh most common cancer worldwide. Although a number of environmental and lifestyle-related risk factors have been identified for this kind of cancer, the exact molecular mechanisms of tumor evolution have not been clarified yet. Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) as important regulators of gene expression and chromatin configuration have essential roles in the pathogenesis of esophageal cancer. They have been shown to alter the function of cancer-related signaling pathways such as phosphoinositide 3-kinase/protein kinase B and Wnt pathway, thus they might modulate the response of patients to pathway-targeted therapies. Moreover, a number of lncRNAs, such as AFAP1-AS1, UCA1, HOTAIR, LOC285194, and TUSC7, are involved in conferring chemoresistant/radioresistant in esophageal cancer cells. A complex network of interaction exists between lncRNAs and miRNAs in the context of esophageal cancer. Finally, various panels of lncRNAs and miRNAs have been introduced that can predict the survival of esophageal cancer patients. In this review article, we summarize the recent findings regarding the role of miRNAs and lncRNAs in the pathogenesis of esophageal cancer with the special focus on their regulatory roles on signaling pathways, their potential as diagnostic/prognostic markers, and their relevance with therapeutic response.

Viruses and esophageal cancer.

Esophageal adenocarcinoma (EAC) has had the fastest increasing incidence of any solid tumor in the United States in the last 30 years. Long standing gastroesophageal reflux disease is a well-established risk factor with strong associations with obesity, alcohol and tobacco. However, there are likely additional contributing factors. Viruses such as human papillomavirus, ebstein-barr virus and herpes simplex virus have been implicated in the pathogenesis of esophageal cancer. This review will discuss the known literature linking viruses to esophageal adenocarcinoma and consider future relationships such as identifying prognostic and predictive molecular biomarkers to guide therapies.

MicroRNA-301b and its target gene synaptosome-associated protein 91 as important modulators in esophageal cancer: functional experiments.

The aim of this study was to probe the influence of microRNA-301b (miR-301b) in esophageal cancer pathogenesis. Based on the data acquired from The Cancer Genome Atlas database, we found that miR-301b was highly expressed in esophageal cancer tissues and high expression of miR-301b was related to worse prognosis in patients with esophageal cancer. Quantitative real-time PCR revealed that the expression of miR-301b was higher in all examined esophageal cancer cell lines (ECA109, KY-SE150, TE-1, and NEC) than that in a human esophageal epithelial cell line (HEEC). Upregulation/downregulation of miR-301b facilitated/suppressed the growth, migration, and invasion of ECA109/KY-SE150 cells. Synaptosome-associated protein 91 (SNAP91) was proved to be one of the target genes of miR-301b and was negatively modulated by miR-301b. Besides, SNAP91 was lowly expressed in human esophageal cancer tissues and cell lines. Meanwhile, low expression of SNAP91 was concerned with poor prognosis in patients with esophageal cancer. Furthermore, we discovered that overexpression/depletion of SNAP91 suppressed/facilitated the proliferation of KY-SE150/ECA109 cells. MiR-301b and SNAP91 had little impact on HEEC cell proliferation and this degree of influence was negligible compared with their impacts on esophageal cancer cell proliferation. By rescue assay, we showed that overexpression of SNAP91 restrained the growth, migration, and invasion of ECA109 cells with overexpressed miR-301b while knockdown of SNAP91 showed the contrary effects on KY-SE150 cells with downregulated miR-301b. These consequences indicated that miR-301b played an important effect on esophageal cancer cells through regulating SNAP91, insinuating that miR-301b/SNAP91 might be novel potential targets for esophageal cancer therapy and prognosis.

β-elemene suppresses the malignant behavior of esophageal cancer cells by regulating the phosphorylation of AKT

BackgroundEsophageal cancer is a digestive tract malignancy, ranking sixth among the world's deadliest tumor incidence. However, the pathogenesis of esophageal cancer is complex and the prognosis remains poor. Therefore, in-depth study of the pathogenesis and developing effective treatments are of great value for esophageal cancer. β-elemene is a natural monomeric compound derived from the Chinese herbal Curcuma wenyujin. β-elemene has been reported to have anti-tumor effects and used as an adjunct to clinical therapy for multiple cancers. This study aims to explore the effects of β-elemene on esophageal cancer and its related molecular mechanisms. MethodsTE-1 and KYSE-150 cells were used to evaluate the activity of β-elemene on esophageal cancerin vitro and in vivo. Western blot was performed for protein expression assessment. CCK8 assay and cell cycle analysis were used for proliferation testing. Flow cytometry was performed for apoptosis detection. Wound healing assay was subjected to assess the migration ability. Transwell chamber assay was applied to assess the invasion ability. HE staining, TUNEL staining and immunohistochemical staining were used to evaluate the changes in tumor tissues. ResultsWe found that β-elemene treatment suppressed proliferation, as well as induced apoptosis of esophageal cancer cells. In addition, β-elemene inhibited the migration and invasion ability of esophageal cancer cells. Furthermore, β-elemene exerted its effects against esophageal cancer by specifically regulating AKT signaling, thereby controlling the expression of PD-L1. Conclusionβ-elemene inhibits proliferation and metastasis of esophageal cancer cells by regulating the phosphorylation of AKT.

MicroRNA‑200a promotes esophageal squamous cell carcinoma cell proliferation, migration and invasion through extensive target genes.

Despite investigations into microRNA (miRNA) expression in esophageal cancer (EC) tissue, miRNAs that participate in EC pathogenesis and their subsequent mechanisms of action remain to be determined. The present study aimed to identify important miRNAs that contribute to EC development, and to assess miRNA biomarkers that could be used in EC diagnosis, prognosis and therapy. Bioinformatics analysis was performed to reanalyze EC tissue miRNA expression microarray dataset GSE113776, which was followed by in vitro verification of miRNA functions using reverse transcription-quantitative PCR, western blot analysis and a dual-luciferase reporter assay. Out of 93 miRNAs extracted, only miR-200a was significantly increased in EC tissues. Transfection of KYSE150 esophageal squamous cell carcinoma (ESCC) cells with miR-200a mimics significantly increased their proliferative, migratory and invasive ability, whereas the opposite cell behaviors were observed in ESCC cells transfected with a miR-200a inhibitor. A total of six miR-200a target genes [catenin β1 (CTNNB1), cadherin-1 (CDH1), PTEN, adenomatous polyposis coli (APC), catenin α1 (CTNNA1) and superoxide dismutase 2 (SOD2)] were selected for further analysis based on Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathway analysis, protein-protein interaction network map data and protein expression in esophageal tissue. These target genes were downregulated under miR-200a expression and upregulated in the presence of the miR-200a inhibitor. The association between miR-200a and the 3′-untranslated region of target genes in ESCC cells was confirmed using a dual-luciferase reporter assay. In conclusion, the present study demonstrated that miR-200a may participate in the promotion of ESCC cell proliferation, migration and invasion, and provided novel evidence for the direct interaction between miR-200a and CTNNB1, CDH1, PTEN, APC, CTNNA1 and SOD2, which may contribute to the observed altered cell behavior.

Etiological involvement of weak acid reflux in the development of esophageal carcinoma.

435 Background: Patients with gastroesophageal reflux disease (GERD) with mixed gastric acid–bile acid reflux are at a high risk of developing reflux-induced esophageal cancer. Increased local production of prostaglandin E2 (PGE2) is etiologically associated with reflux-induced esophageal cancer pathogenesis; however, the underlying mechanism remains unclear. Our aim was to investigate the relationship between PGE2 production in esophageal cells and reflux fluids, particularly gastric acid. The effect of the Kampo medicine Hangeshashinto (HST), which reduced the incidence of reflux-induced esophageal cancer in rats (Surgery 2018), on PGE2 production was also examined. Methods: Esophageal squamous cell carcinoma were treated for 2 h with acidic culture condition (pH 3.5 – 6.5) and chenodeoxycholic acid (CDCA; 200, 400 μmol/L), followed by measurement of PGE2 production in the culture medium for the additional 6 h by enzyme-linked immunosorbent assay. Results: CDCA induced PGE2 production and significantly increased cyclooxygenase-2 (cox-2) expression. However, in weak acidic conditions (pH 4–5), a pH-specific and significant increase in PGE2 production with no increase in cox-2 expression was observed. cPLA2 inhibitor decreased the effect of weak acid stimulation, indicating that the mechanism underlying PGE2 production differs between weak acid and CDCA. In addition, HST significantly inhibited both weak acid- and CDCA-induced PGE2 production. Conclusions: The synergistic effect of bile acid-induced cox-2 expression and weak acid-induced arachidonic acid production via cPLA2 can cause excessive PGE2 production. Therefore, mixed reflux showing pH 4–5 could contribute to the high incidence of esophageal cancer, which might be prevented by HST treatment. Weak acid reflux around pH 4–5 has been observed in PPI-treated patients, who could exhibit excessive PGE2 production as well as increased risk of reflux-induced esophageal cancer.

Role of COL3A1 and POSTN on Pathologic Stages of Esophageal Cancer

Background:Esophageal cancer (EC) is a primary malignant tumor originating from the esophageal of the epithelium. Surgical resection is a potential treatment for EC, but this is only appropriate for patients who have locally resectable lesions suitable for surgery. However, most patients with EC are at a late stage when diagnosed. Therefore, there is an urgent need to further explore the pathogenesis of EC to enable early diagnosis and treatment.Methods:Our study downloaded 2 expression spectrum datasets (GSE92396 and GSE100942) in the Gene Expression Omnibus (GEO) database. GEO2 R was used to identify the Differentially expressed genes (DEGs) between the samples of EC and control. Using the DAVID tool to make the Functional enrichment analysis. Constructing A protein–protein interaction (PPI) network. Identifying the Hub genes. The impact of hub gene expression on overall survival and their expression based on immunohistochemistry were analyzed. Associated microRNAs were also predicted.Results:There were 36 common DEGs identified. The analysis of GO and KEGG results shown that the variations were predominantly concentrated in the extracellular matrix (ECM), ECM organization, DNA binding, platelet activation, and ECM-receptor interactions. COL3A1 and POSTN had high expression in EC tissues which was compared with their expression in healthy tissues. Analysis of pathologic stages showed that when COL3A1 and POSTN were highly expressed, the stage of the pathologic of EC patients was relatively high (P < 0.005).Conclusions:COL3A1 and POSTN may play an important role in the advancement and occurrence of EC. These genes could provide some novel ideas and basis for the diagnosis and targeted treatment of EC.

MicroRNA‑542‑3p represses OTUB1 expression to inhibit migration and invasion of esophageal cancer cells.

Dysregulation of microRNAs (miRNAs) is involved in the pathogenesis of esophageal cancer. miRNA (miR)-542-3p is a tumor suppressor in multiple types of cancer. However, whether and how miR-542-3p contributes to the progression of esophageal cancer remains unknown, and this is the aim of the present study. In the current study, decreased expression of miR-542-3p was detected in tumor tissues compared with normal tissues from patients with esophageal cancer, and miR-542-3p expression was negatively correlated with mRNA expression levels of ovarian tumor domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) in tumor tissues from patients with esophageal cancer. In KYSE150 human esophageal squamous cell carcinoma cells, overexpression of miR-542-3p significantly decreased OTUB1 at mRNA and protein levels, whereas downregulation of miR-542-3p significantly increased OTUB1 expression. Using a dual-luciferase assay, OTUB1 was validated to be a target gene of miR-542-3p in KYSE150 cells. Functionally, miR-542-3p significantly inhibited the migration and invasion of KYSE150 cells by repression of OTUB1 expression. These results demonstrated that miR-542-3p may promote the metastasis of esophageal cancer cells, and indicated that miR-542-3p may be a treatment target for esophageal cancer.

The Prevalence and Association of Human Papillomavirus with Esophageal Cancer in West Azerbaijan, Iran

Background: Esophageal cancer (EC) is a common cancer worldwide. Despite epidemiological studies, the etiology of EC is undetected. It was recommended that tobacco, alcohol, food carcinogens, and infectious agents may be involved in the pathogenesis of EC. Accumulating evidence suggests the role of human papillomavirus (HPV) on EC. Objectives: The aim of this study was to evaluate the prevalence and association of HPV with EC. Methods: In this case-control study, 86 samples of formalin-fixed and paraffin-embedded esophageal tissues were gathered from the pathology laboratory, Imam Khomeini Hospital, Urmia, West Azerbaijan, Iran. A total of 43 samples were esophageal cancers (cases) and 43 samples were esophageal non-cancerous tissues (controls). The tissues were sectioned and deparaffinized, and deoxyribonucleic acid was extracted. The polymerase chain reaction test was conducted to detect HPV, using general (GP5+/GP6+) and type-specific (E6/E7) primers. HPV types were confirmed by sequencing. The data were analyzed by the SPSS software. Results: Out of 86 samples, 23 (26.74%) were positive for HPV (15 cases, and 8 controls). By type-specific primers, high-risk HPVs were detected in the cases (3 HPV-16, 10 HPV-18, 1 HPV-31, and 1 HPV-33) and the controls (6 HPV-18, 1 HPV-31, and 1 HPV-33). No significant association was observed between HPV and EC (P = 0.078). Conclusions: Although no significant association was observed between HPV and EC, high-risk HPV genotypes were found in esophageal cancers more than non-cancerous esophageal tissues. To confirm this result, more studies should be carried out in other populations.

TRPM8 facilitates proliferation and immune evasion of esophageal cancer cells.

Esophageal cancer is seen with increasing incidence, but the underlying mechanism of esophageal cancer is still unknown. Transient receptor potential melastatin (TRPM) is non-selective cation channels. It has been verified that TRPM channels play crucial roles in development and progression of multiple tumors. Increasing studies have shown that TRPM8, a member of TRPM channels, promotes growth of tumors. However, it is still unclear whether TRPM8 has biological effect on esophageal cancer. In the current work, we found that TRPM8 was overexpressed in esophageal cancer samples and cell lines. Further investigation revealed that TRPM8 promoted proliferation of esophageal cancer cells. Next, the co-incubation assay including EC109 cells and CD8+ T cells revealed that TRPM8 overexpression and TRPM8 agonist reduced the cytotoxic effect of CD8+ T cell on esophageal cancer cells. Finally, we explored the mechanism and found that calcineurin-nuclear factor of activated T cells 3 (NFATc3) pathway contributed to the expression of programmed death ligand 1 (PD-L1) induced by TRPM8 overexpression and TRPM8 agonist, which might lead to immune evasion of esophageal cancer cells. These findings uncovered the crucial role of TRPM8 in the pathogenesis of esophageal cancer.

ALC1 knockdown enhances cisplatin cytotoxicity of esophageal squamous cell carcinoma cells by inhibition of glycolysis through PI3K/Akt pathway

AimsAmplified in liver cancer 1 gene (ALC1), a recently identified oncogene, was reported to be overexpressed in esophageal cancer cell lines and identified as a target oncogene in esophageal cancer pathogenesis. However, little literature is available to illustrate its significance in cisplatin resistance of esophageal squamous cell carcinoma (ESCC) cells. The aim of the current study was to investigate the effect of ALC1 on cisplatin cytotoxicity of ESCC cells and to study the potential mechanisms. Main methodsALC1 at mRNA and protein levels were detected by qRT-PCR and western blot, respectively. Cell viability was evaluated using CCK-8 assay. Apoptosis was assessed using caspase-3/7 activity assay and flow cytometry analysis. Glycolysis level was evaluated by measuring glucose consumption and lactate production. The protein levels of p-protein kinase B (Akt) and Akt were determined by western blot. Key findingsALC1 was highly expressed in ESCC cells compared with human normal esophageal epithelial Het-1A cells. ALC1 knockdown suppressed the viability, induced apoptosis and enhanced cisplatin cytotoxicity in ESCC cells. In addition, ALC1 knockdown inhibited glycolysis and inactivated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in ESCC cells. Mechanistically, activation of the PI3K/Akt pathway by 740Y-P blocked the effects of ALC1 knockdown on cisplatin cytotoxicity and glycolysis in ESCC cells. In contrast, inhibition of the PI3K/Akt pathway by LY294002 or glycolysis by 2-deoxyglucose resisted the effect of ALC1 overexpression on cisplatin cytotoxicity in ESCC cells. SignificanceALC1 knockdown enhanced cisplatin cytotoxicity of ESCC cells by inhibition of glycolysis through inactivation of the PI3K/Akt pathway.

CircRAD23B facilitates proliferation and invasion of esophageal cancer cells by sponging miR-5095

Esophageal cancer is one of the most malignant tumors in digestive system, but the pathogenesis of esophageal cancer is still unclear. It has been verified that circular RNAs (circRNAs) play critical roles in development and progression of tumors. However, little research concentrates on the role of circRNAs in the pathogenesis of esophageal cancer. In the present study, we found that circular RNA-RAD23B (circRAD23B) was upregulated in specimens of patients with esophageal cancer. Further investigation revealed that circRAD23B promoted proliferation and invasion of esophageal cancer cells. Next, we identified microRNA-5095 (miR-5095) as a target of circRAD23B, and found that miR-5095 was negatively correlated to the expression of circRAD23B in esophageal cancer. In addition, circRAD23B facilitated expression of PARP2 and AKT2 by sponging miR-5095, which might underlie the growth of esophageal cancer. In summary, these data displayed the crucial role of circRAD23B/miR-5095 regulating PARP2 and AKT2 in esophageal cancer, and provided a novel mechanism in the pathogenesis of esophageal cancer.

High expression of DNA methyltransferase 1 in Kazakh esophageal epithelial cells may promote malignant transformation induced by N-methyl-N'-nitro-N-nitrosoguanidine.

We examined the role of DNA methyltransferase 1 (DNMT1) in N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced malignant transformation of Kazakh esophageal epithelial (EE) cells to better understand the pathogenesis of esophageal cancer (EC). The 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide method and colony formation assays were performed to determine the MNNG dose for malignant transformation. Colony formation assays showed the effects of different frequencies of MNNG exposure and different cell passages on malignant transformation. A nude mouse tumor experiment indicated the malignancy of Kazakh EE cells expressing high DNMT1 levels and of transformed cells. The result shows that when the dose, frequency, and time of MNNG exposure increased, cell morphology became irregular, cell-contact suppression disappeared, and cell tolerance and growth rate increased. Colony formation occurred in the Kazakh-DNMT1 group after 14 transfections and 27 passages. Significant differences in DNMT1 mRNA and protein levels were observed in different types of cells and tumor tissues (F = 140.644, p < 0.001; F = 105.545, p < 0.001). Our study demonstrated that DNMT1 could promote MNNG to induce malignant transformation of EE cells, and this study will help understand EC better in order to develop appropriate treatment strategies.

Geographic distribution and time trends of esophageal cancer in Brazil from 2005 to 2015.

The purpose of the present study was to investigate the geographical distribution and time trends of the incidence and lethality of esophageal cancer (EC) in Brazil. The present study conducted an ecological study of EC using records from January 2005 to December 2015 in the Health Informatics Department of the Brazilian Ministry of Health (DATASUS) registry. In addition to demographical data on the population, EC incidence and lethality rates were estimated from hospitalizations and in-hospital mortalities and were adjusted by total available hospital beds. The adjusted EC rates per 100,000 increased from 9.1 in 2005 to 12.1 in 2015. The prevalence among males increased from 69 to 78%, while the female rates remained stable over the same period. Although EC was the most common in South and Southeast Brazil, the rates increased proportionately more in the other regions of the country, especially among males. Geographical analysis revealed higher rates of EC in more urbanized areas, with a coast-to-inland gradient. While rates increased in people older than 50 years, they decreased among people below this age. However, the lethality rates remained stable and high during the study period, overlapping with hospital admission rates. The recent increasing trend in the EC incidence, with shifts from the south towards the north and from more urbanized towards rural areas, suggests that environmental factors are crucial in EC pathogenesis. The concentration of EC in South Brazil may reflect the presence of major environmental factors in association with a possible genetic predisposition. The unchanging high mortality associated with EC in the rapidly aging population suggests that EC will continue to impose a significant social and economic burden in the future.

A novel tumor suppressor SPINK5 targets Wnt/β-catenin signaling pathway in esophageal cancer.

Esophageal cancer is one of the most common tumor in the world, and the morbidity rate is as high as 100/100 000 in some parts of China. Therefore, it is important and urgent to explore the pathogenesis of esophageal cancer and find new therapeutic targets for esophageal cancer. In this study, we found that a novel tumor suppressor SPINK5 is significantly reduced in the development of esophageal cancer, and is closely related to the pathological differentiation and lymph node metastasis of esophageal cancer via bioinformatics analysis and esophageal cancer tissue array. Further studies have found that SPINK5 is closely related to Wnt/β‐catenin signaling pathway by bioinformatics analysis and western blot. In esophageal cancer cells, SPINK5 overexpression can inhibit Wnt/β‐catenin signaling pathway. Combined with LiCl or MG‐132 treatment, SPINK5 can inhibit GSK3β phosphorylation and promote β‐catenin protein degradation, thus inhibit Wnt/β‐catenin signaling pathway. In vivo study, SPINK5 overexpression can significantly inhibit the growth of esophageal cancer cells. Our study shows that SPINK5 can inhibit the proliferation, migration, and invasion of esophageal cancer cells by inhibiting Wnt/β‐catenin signaling pathway, and thus plays an important role in the development of esophageal cancer, and may serve as a treatment target of esophageal cancer.

Analysis of Significant Genes and Pathways in Esophageal Cancer Based on Gene Expression Omnibus Database

ObjectiveTo screen antigen targets for immunotherapy by analyzing over-expressed genes, and to identify significant pathways and molecular mechanisms in esophageal cancer by using bioinformatic methods such as enrichment analysis, protein-protein interaction (PPI) network, and survival analysis based on the Gene Expression Omnibus (GEO) database. MethodsBy screening with highly expressed genes, we mainly analyzed proteins MUC13 and EPCAM with transmembrane domain and antigen epitope from TMHMM and IEDB websites. Significant genes and pathways associated with the pathogenesis of esophageal cancer were identified using enrichment analysis, PPI network, and survival analysis. Several software and platforms including Prism 8, R language, Cytoscape, DAVID, STRING, and GEPIA platform were used in the search and/or figure creation. ResultsGenes MUC13 and EPCAM were over-expressed with several antigen epitopes in esophageal squamous cell carcinoma (ESCC) tissue. Enrichment analysis revealed that the process of keratinization was focused and a series of genes were related with the development of esophageal cancer. Four genes including ALDH3A1, C2, SLC6A1, and ZBTB7C were screened with significant P value of survival curve. ConclusionsGenes MUC13 and EPCAM may be promising antigen targets or biomarkers for esophageal cancer. Keratinization may greatly impact the pathogenesis of esophageal cancer. Genes ALDH3A1, C2, SLC6A1, and ZBTB7C may play important roles in the development of esophageal cancer.

The Methylenetetrahydrofolate Reductase C677T Polymorphism in Patients with Esophageal Cancer

Background: Esophageal cancer is the eighth most common cancer worldwide and the 6th cause of cancer related death. Genetic factors are also responsible in pathogenesis of esophageal cancer. This study aimed to investigate the association between methylenetetrahydrofolate reductase C677T polymorphism and esophageal cancer in Iranian population. Methods and Materials: A cross-sectional study was conducted among patients diagnosed with esophageal cancer in Imam Reza hospital between June 2007 and June 2014, Tehran, Iran. Genotyping was performed using restriction fragment length polymorphism (RFLP)-PCR method using Hinf-1 restriction endonuclease enzyme. Results: The frequencies of various genotypes of MTHFR gene were not statistically significant in cases and controls (P=0.348). There were no statistically significant difference in frequency of C and T alleles in patients with esophageal cancer and controls (P=0.084). Mean survival of patients with esophageal cancer was 31.25 ± 4.25 months in patients with CC genotype, 38.2 ± 4.11 months in CT genotype and 37.2 ± 6.44 months in patients with TT genotype (P=0.459). Allele frequency was not also associated with mean survival in patients and controls (P=0.168). Conclusion: Methylenetetrahydrofolate reductase C677T polymorphism was not associated with esophageal cancer and did not impact on survival in this subset of Iranian patients.