Poor Prognosis In Esophageal Cancer Patients Research Articles

Rhein suppresses esophageal cancer development by regulating cell cycle through DNMT3B gene.

The mechanism by which DNMT3B facilitates esophageal cancer (ESCA) progression is currently unknown, despite its association with adverse prognoses in several cancer types. To investigate the potential therapeutic effects of the Chinese herbal medicine rhubarb on esophageal cancer (ESCA), we adopted an integrated bioinformatics approach. Gene Set Enrichment Analysis (GSEA) was first utilized to screen active anti-ESCA components in rhubarb. We then employed Weighted Gene Co-expression Network Analysis (WGCNA) to identify key molecular modules and targets related to the active components and ESCA pathogenesis. This system-level strategy integrating multi-omics data provides a powerful means to unravel the molecular mechanisms underlying the anticancer activities of natural products, like rhubarb. To investigate module gene functional enrichment, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted. In addition, we evaluated the predictive impact of DNMT3B expression on ESCA patients utilizing the Kaplan-Meier method. Finally, we conducted experiments on cell proliferation and the cell cycle to explore the biological roles of DNMT3B. In this study, we identified Rhein as the main active ingredient of rhubarb that exhibited significant anti-ESCA activity. Rhein markedly suppressed ESCA cell proliferation. Utilizing Weighted Gene Co-expression Network Analysis (WGCNA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, we determined that the blue module was associated with Rhein target genes and the cell cycle. Additionally, DNMT3B was identified as a Rhein target gene. Analysis of The Cancer Genome Atlas (TCGA) database revealed that higher DNMT3B levels were associated with poor prognosis in ESCA patients. Furthermore, Rhein partially reversed the overexpression of DNMT3B to inhibit ESCA cell proliferation. In vitro studies demonstrated that Rhein and DNMT3B inhibition disrupted the S phase of the cell cycle and affected the production of cell cycle-related proteins. In this study, we found that Rhein exerts its anti-proliferative effects in ESCA cells by targeting DNMT3B and regulating the cell cycle.

MiR-1301-3p promotes invasion and migration and EMT progression in esophageal cancer by downregulating NBL1 expression.

Esophageal cancer (ESCA) is one of the most aggressive and lethal human malignant cancers. MicroRNA-1301-3p (miR-1301-3p) plays vital roles in a majority of malignancies. The aim of this study was to investigate the role of miR-1301-3p/NBL1 axis on ESCA cell invasion, migration, epithelial-mesenchymal transition (EMT) process, as well as its association with prognosis of ESCA patients. The expression levels of miR-1301-3p and NBL1 were predicted by bioinformatics and further verified by RT-qPCR assays. Kaplan-Meier (K-M) plotter analysis and univariate and multivariate Cox analyses were used to evaluate the relationship between miR-1301-3p and clinicopathological variables and prognosis. The role of miR-1301-3p on cell invasion, migration was detected by transwell invasion, and wound healing assays, respectively. The EMT-related proteins were detected by western blot. The target genes and the target binding sites were predicted by bioinformatics and further determined by RT-qPCR assay. MiR-1301-3p was remarkably upregulated in ESCA tissues and cells, and its high expression was associated with poor prognosis of ESCA. Overexpression of miR-1301-3p promoted ESCA cell invasion, migration and mediated EMT process in vitro, whereas knockdown of miR-1301-3p showed the opposite effects. Moreover, NBL1 was predicted as a target gene of miR-1301-3p. NBL1 was lowly expressed in ESCA cells and significantly decreased after upregulation of miR-1301-3p. Meanwhile, we found that low expression of NBL1 was significantly associated with poor prognosis of ESCA patients. MiR-1301-3p is a potential biomarker for predicting the prognosis of ESCA patients. It may promote ESCA invasion, migration and EMT progression by regulating NBL1 expression.

Nomogram for predicting survival after lymphatic metastasis in esophageal cancer: A SEER analysis.

Lymphatic metastasis (LM) is a significant mechanism for the spread of esophageal cancer (EC) and predicts the poor prognosis of EC patients. This research aimed to assess the survival of patients with LM from EC by developing a nomogram. In this retrospective study, EC patients with LM from 2004 to 2015 in the Surveillance, Epidemiology, and End Results (SEER) database were divided by year of diagnosis into a training cohort and a validation cohort. Univariate and multivariate Cox regression analyses were employed to determine the prognostic factors of LM, and a nomogram was constructed. The discrimination and calibration of the nomogram were compared by the C-index, area under the curve value, and calibration plots. The survival time difference was compared using Kaplan-Meier curves. A total of 11,695 patients with EC were included in this analysis. LM occurred in 56.5% (n = 6614) of EC patients. In the post-propensity score matching (PSM) cohort, patients with LM had significantly lower median overall survival (OS) than those without LM. Multivariate Cox regression was used to identify the eleven independent prognostic factors. The C-index was 0.709 in both the training and test sets, revealing the good predictive performance of the nomogram. Based on the results of calibration plots and the receiver operating characteristic (ROC) curve, we demonstrate the great performance of the prognostic model. The survival time of EC patients with LM was remarkably lower than that of EC patients without LM. The nomogram model established in this study can precisely predict the survival of EC patients with LM.

M6A demethylase FTO promotes tumor progression via regulation of lipid metabolism in esophageal cancer

BackgroundEpitranscriptomics studies have contributed greatly to the development of research on human cancers. In recent years, N6-methyladenosine (m6A), an RNA modification on the N-6 position of adenosine, has been found to play a potential role in epigenetic regulation. Therefore, we aimed to evaluate the regulation of cancer progression properties by m6A.ResultsWe found that m6A demethylase fat mass and obesity-associated protein (FTO) was highly expressed in esophageal cancer (EC) stem-like cells, and that its level was also substantially increased in EC tissues, which was closely correlated with a poor prognosis in EC patients. FTO knockdown significantly inhibited the proliferation, invasion, stemness, and tumorigenicity of EC cells, whereas FTO overexpression promoted these characteristics. Furthermore, integrated transcriptome and meRIP-seq analyses revealed that HSD17B11 may be a target gene regulated by FTO. Moreover, FTO promoted the formation of lipid droplets in EC cells by enhancing HSD17B11 expression. Furthermore, depleting YTHDF1 increased the protein level of HSD17B11.ConclusionsThese data indicate that FTO may rely on the reading protein YTHDF1 to affect the translation pathway of the HSD17B11 gene to regulate the formation of lipid droplets in EC cells, thereby promoting the development of EC. The understanding of the role of epitranscriptomics in the development of EC will lay a theoretical foundation for seeking new anticancer therapies.

Long Noncoding RNA WDFY3-AS2 Represses the Progression of Esophageal Cancer through miR-18a/PTEN Axis.

Background Understanding the role of lncRNAs in the development of human malignancies is necessary for the targeted therapy of malignant tumors, including esophageal cancer (EC). Nevertheless, the specific role and regulatory mechanism of lncRNA WDFY3-AS2 in EC are still unclear. Here, we examined the functional role and regulatory mechanism of WDFY3-AS2 in EC. Materials and Methods RT-qPCR assay was applied to measure the expression of WDFY3-AS2 and miR-18a in EC samples and cells. The luciferase reporter and RIP assays were used to check the relationship between WDFY3-AS2, miR-18a, and PTEN. Counting Clock Kit-8 (CCK-8) assay was carried out to detect cell viability, and transwell assays were used for measuring cell migration and invasion. Results Underexpression of WDFY3-AS2 was found in EC specimens and cells, which predicted a poor prognosis of EC patients. Reexpression of WDFY3-AS2 repressed the progression of EC via inhibiting cell proliferation, migration, and invasion. Additionally, WDFY3-AS2 was negatively correlated with miR-18a and positively with PTEN. Furthermore, we discovered that the expression of PTEN decreased by miR-18a mimic was rescued by WDFY3-AS2 overexpression. Conclusions WDFY3-AS2 modulates the expressional level of PTEN as a competitive endogenous RNA via sponging miR-18a in EC, which suggests that the WDFY3-AS2/miR-18a/PTEN pathway might be involved in the progression of EC.

MFI2-AS1 enhances the survival of esophageal cancer cell via regulation of miR-331-3p/SOX4

Purpose: To investigate the specific role of melanotransferrin antisense RNA (MFI2-AS1) in esophageal cancer (EC) progression. Methods: The differential expression of MFI2-AS1 in EC tissues and cells was determined using quantitative reverse transcription–polymerase chain reaction (qRT-PCR). Silencing MFI2-AS1 was performed by transfection with specific short hairpin RNAs targeting MFI2-AS1. The 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (MTT) and flow cytometry (FC) were used to assess cell viability and apoptosis of EC cells, respectively. The sponging microRNA (miRNA) of MFI2-AS1 was validated using luciferase activity and RNA immunoprecipitation assays while the downstream target gene of the sponging miRNA was evaluated by luciferase activity assay. Results: MFI2-AS1 was significantly enhanced in EC tissues (p < 0.01) and indicated a poor prognosis in EC patients. Knockdown of MFI2-AS1 in EC cells decreased cell viability and promoted cell apoptosis of EC cells. Functionally, MFI2-AS1 targeted miR-331-3p, and sex-determining region on Ychromosome-related high-mobility-group box4 (SOX4) was identified as a target gene of miR-331-3p. Ectopic expression of SOX4 counteracted the suppressive effect of MFI2-AS1 knockdown on EC cell viability and stimulative effect on EC cell apoptosis. Conclusion: The pro-oncogenic effect of MFI2-AS1 on EC progression occurs via the regulation of the miR-331-3p/SOX4 axis, providing a new potential therapeutic target for EC.

Role of MLH1 methylation in esophageal cancer carcinogenesis and its clinical significance.

The mutL homolog-1 (MLH1) is a DNA mismatch repair gene and has been reported to be frequently methylated in numerous cancers. However, the association between MLH1 methylation and esophageal cancer (EC), as well as its clinical significance, remains unclear. Hence, we conducted a systematic meta-analysis based on 19 articles (including 1384 ECs, 345 premalignant lesions, and 1244 healthy controls). Our analysis revealed that the frequency of MLH1 methylation was significantly elevated during EC carcinogenesis. In addition, we observed that MLH1 promoter methylation was associated with age (odds ratio [OR]=1.79; 95% CI =1.20–2.66), advanced tumor grade (OR=3.7; 95% CI =2.37–5.77), lymph node metastasis (OR=2.65; 95% CI =1.81–3.88), distant metastasis (OR=7.60; 95% CI =1.23–47.19), advanced clinical stage (OR=4.46; 95% CI =2.88–6.91), and poor prognosis in EC patients (hazard ratio =1.64, 95% CI =1.00–2.69). The pooled sensitivity, specificity, and area under the curve of MLH1 methylation in EC patients versus healthy individuals were 0.15, 0.99, and 0.77, respectively. Our findings indicate that MLH1 methylation is involved in the carcinogenesis, progression, and metastasis of EC. Moreover, methylated MLH1 could be a potential diagnostic and prognostic biomarker for EC.

FOXK1 plays an oncogenic role in the development of esophageal cancer

Forkhead box k1 (FOXK1) is a member of the FOX class of transcription factors and it is dysregulated in many solid tumors including hepatocellular carcinoma, gastric cancer, colorectal cancer and prostate cancer. However, the expression status of FOXK1 and its clinical significance in esophageal cancer (EC) is still uncertain. Our study aimed at investigating the significance of FOXK1 expression in human EC and its biological function in the development of EC. We found that FOXK1 was overexpressed in EC tissues compared with corresponding non-tumor tissues using immunohistochemistry. And high FOXK1 expression was related to poor differentiation of EC. The Kaplan-Meier curve indicated that high FOXK1 expression may result in poor prognosis of EC patients. Furthermore, overexpression of FOXK1 in EC9706 cell inhibited cell apoptosis and promoted cell proliferation and migration, and suppression of FOXK1 in EC109 cell obtained reverse results. Our data suggest that FOXK1 plays an oncogenic role in EC pathogenesis and can serve as a therapeutic target for patients with EC.

Survivin over-expression is correlated with a poor prognosis in esophageal cancer patients

BackgroundThe prognostic role of survivin in esophageal cancer (EC) remains controversial. This meta-analysis aimed to clarify the association of survivin with survival in EC patients. MethodsRelevant studies published up to November 2014 were identified using PubMed and Embase. Only studies in which survivin was detected through immunohistochemical staining were included. STATA 12.0 was used in this meta-analysis. ResultsA total of 9 studies, which comprised 610 patients, were included in the meta-analysis. The combined hazard ratio (HR) of 1.76 (95% CI, 1.40–2.21; P<0.001) suggests that survivin overexpression in EC patients was significantly associated with poor overall survival. Moreover, the results showed a significant relationship between overall survival and survivin expression was also displayed in studies with a non-Asian country (HR, 1.75; 95% CI, 1.30–2.35), patient number ≥50 (HR, 1.86; 95% CI, 1.57–2.20), the cut-off level ≥5% (HR, 1.43; 95% CI, 0.94–2.17) and the esophageal squamous cell carcinoma (HR, 1.82; 95% CI, 1.43–2.30). However, combined odds ratio of survivin indicated that survivin overexpression has no correlation with stage, grade of differentiation, lymph node status, depth of invasion and distant metastasis of EC (P>0.05). ConclusionSurvivin overexpression is associated with poor prognosis in EC patients.

687P - Synuclein-Gamma (Sncg) Predicts Poor Clinical Outcome in Esophageal Cancer Patients

ABSTRACT Aim: Esophageal cancer (EC) is a rare tumor with poor prognosis due to diagnosis at advanced stage and lack in high sensitive and specific markers which can detect the disease at earlier stages. The aim of our study was to evaluate the immunohistochemical (IHC) expression of synuclein-gamma (SNCG) in correlation with its association with clinicopathological parameters and prognostic value in EC patients. Methods: SNCG levels were assessed with IHC methods in cancer tissues from 73 patients with EC. The intensity and area of the IHC reactions were evaluated using the semi-quantitative scoring system. Results: Median age was 57 (range, 29-78) years old. Forty-seven percent of the patients were male. Thirty-seven percent of the patients had upper or middle localized tumor whereas 59% had epidermoid carcinoma. More than half of the patients (61%) had undergone operation where 57% received adjuvant treatment (chemotherapy or chemoradiotherapy). Median overall survival was 11.3 ± 1.8 months (95%CI: 7.7-14.9 months). SNCG positivity was significantly associated with the histological type of EC and inoperability (for SNCG positive vs. negative group; epidermoid 80% vs. 53%; p = 0.05 and inoperable 59% vs.32%; p = 0.04, respectively). Lymph node metastasis, inoperability and receiving no adjuvant treatment had significantly adverse effect on survival in the univariate analysis (p = 0.01, p Conclusions: Our results are the first to suggest that SNCG is a new independent predictor for poor prognosis in EC patients in the literature. Disclosure: All authors have declared no conflicts of interest.