Mechanism In Esophageal Cancer Research Articles

Progress on the molecular targeted therapy in esophageal cancer

Esophageal cancer is the eighth most common cancer worldwide and one of the most common malignant tumors in China. Despite the continuous improvement in the methods of comprehensive treatment such as surgery, radiotherapy and chemotherapy, the prognosis and five-year survival rate of patients with esophageal cancer remain poor. Targeted therapy for esophageal cancer inhibits the proliferation and migration of esophageal cancer cells and promotes apoptosis by regulating related signaling pathways. Up to now, a variety of molecular targets and related regulatory mechanisms of esophageal cancer have been discovered, and a variety of targeted therapeutic drugs have been designed, some of which have achieved certain effects in clinical trials. At present, targeted molecular therapeutic targets such as HER-2, VEGFR, EGFR and other targeted therapeutic drugs(monoclonal antibodies and tyrosinase inhibitors) have achieved clinical effects in esophageal cancer treatments. Preliminary progress have been made in the study of some key kinases, such as such as mTOR, AXL, C-MET, AURKA, etc, in various signaling pathways, and the development of the relevant targeted therapeutic agents for esophageal cancer. Meanwhile, esophageal cancer immunotherapy targeting PD-1 shows good prospects, and the immunotherapy drugs, such as Pembrolizumab, have achieved good therapeutic effects. Additionally, new targets for esophageal cancer, such as MMP-9 and COX-2, have been found to be potential targets for esophageal cancer treatments. Key words: Esophageal cancer; Molecular targets; Targeted therapy; Signaling pathways

Robust analysis of novel mRNA–lncRNA cross talk based on ceRNA hypothesis uncovers carcinogenic mechanism and promotes diagnostic accuracy in esophageal cancer

BackgroundceRNAs have emerged as pivotal players in the regulation of gene expression and play a crucial role in the physiology and development of various cancers. Nevertheless, the function and underlying mechanisms of ceRNAs in esophageal cancer (EC) are still largely unknown.MethodsIn this study, profiles of DEmRNAs, DElncRNAs, and DEmiRNAs between normal and EC tumor tissue samples were obtained from the Cancer Genome Atlas database using the DESeq package in R by setting the adjusted P<0.05 and |log2(fold change)|>2 as the cutoff. The ceRNA network (ceRNet) was initially constructed to reveal the interaction of these ceRNAs during carcinogenesis based on the bioinformatics of miRcode, miRDB, miRTarBase, and TargetScan. Then, independent microarray data of GSE6188, GSE89102, and GSE92396 and correlation analysis were used to validate molecular biomarkers in the initial ceRNet. Finally, a least absolute shrinkage and selection operator logistic regression model was built using an oncogenic ceRNet to diagnose EC more accurately.ResultsWe successfully constructed an oncogenic ceRNet of EC, crosstalk of hsa-miR372-centered CADM2-ADAMTS9-AS2 and hsa-miR145-centered SERPINE1-PVT1. In addition, the risk-score model −0.0053*log2(CADM2)+0.0168*log2(SERPINE1)-0.0073*log2(ADAMTS9-AS2)+0.0905*log2(PVT1)+0.0047*log2(hsa-miR372)–0.0193*log2(hsa-miR145), (log2[gene count]) could improve diagnosis of EC with an AUC of 0.988.ConclusionWe identified two novel pairs of ceRNAs in EC and its role of diagnosis. The pairs of hsa-miR372-centered CADM2-ADAMTS9-AS2 and hsa-miR145-centered SERPINE1-PVT1 were likely potential carcinogenic mechanisms of EC, and their joint detection could improve diagnostic accuracy.

ESCC ATLAS: A population wide compendium of biomarkers for Esophageal Squamous Cell Carcinoma

Esophageal cancer (EC) is the eighth most aggressive malignancy and its treatment remains a challenge due to the lack of biomarkers that can facilitate early detection. EC is identified in two major histological forms namely - Adenocarcinoma (EAC) and Squamous cell carcinoma (ESCC), each showing differences in the incidence among populations that are geographically separated. Hence the detection of potential drug target and biomarkers demands a population-centric understanding of the molecular and cellular mechanisms of EC. To provide an adequate impetus to the biomarker discovery for ESCC, which is the most prevalent esophageal cancer worldwide, here we have developed ESCC ATLAS, a manually curated database that integrates genetic, epigenetic, transcriptomic, and proteomic ESCC-related genes from the published literature. It consists of 3475 genes associated to molecular signatures such as, altered transcription (2600), altered translation (560), contain copy number variation/structural variations (233), SNPs (102), altered DNA methylation (82), Histone modifications (16) and miRNA based regulation (261). We provide a user-friendly web interface (http://www.esccatlas.org, freely accessible for academic, non-profit users) that facilitates the exploration and the analysis of genes among different populations. We anticipate it to be a valuable resource for the population specific investigation and biomarker discovery for ESCC.

Gene function analysis and underlying mechanism of esophagus cancer based on microarray gene expression profiling.

Esophageal cancer (EC) is one of the most common digestive malignant tumors worldwide. Over the past decades, there have been minimal improvements in outcomes for patients with EC. New targets and novel therapies are needed to improve outcomes for these patients. This study aimed to explore the molecular mechanisms of EC by integrated bioinformatic analyses of the feature genes associated with EC and correlative gene functions which can distinguish cancerous tissues from non-cancerous tissues. Gene expression profile GSE20347 was downloaded from Gene Expression Omnibus (GEO) database, including 17 EC samples and their paired adjacent non-cancerous samples. The differentially expressed genes (DEGs) between EC and normal specimens were identified and then applied to analyze the GO enrichment on gene functions and KEGG pathways. Corresponding Pathway Relation Network (Pathway-net) and Gene Signal Network (signal-net) of DEGs were established based on the data collected from GCBI datasets. The results showed that DEGs mainly participated in the process of cell adhesion, cell proliferation, survival, invasion, metastasis and angiogenesis. Aberrant expression of PTK2, MAPK signaling pathway, PI3K-Akt signaling pathway, p53 signaling pathway and MET were closely associated with EC carcinogenesis. Importantly, Interleukin 8 (IL8) and C-X-C chemokine receptor type 7 (CXCR-7) were predicted to be significantly related to EC. These findings were further validated by analyzing both TCGA database and our clinical samples of EC. Our discovery provides a registry of genes and pathways that are disrupted in EC, which has the potential to be used in clinic for diagnosis and target therapy of EC in future.

Ubiquitin-specific protease 4 improves the prognosis of the patients in esophageal cancer.

Our study mainly investigated ubiquitin-specific protease 4 (USP4) expression in pathogenesis of esophageal cancer. The data showed significantly increased expression of USP4 in cancer tissues compared to that in para-carcinoma tissues (68.38% ± 25.60% vs 13.04% ± 9.95%, P= 0.000) and positive correlation between USP4 and pathology grade (r= 0.249, P= 0.014), although survival analysis revealed that USP4 expression was positively associated with the prognosis (32.4% vs 10.9%, P= 0.043). Grouped analysis revealed that the prognosis of patients with high USP4 expression were significantly better only in the small tumor subgroup (diameter ⩽ 5 cm) (52.6% VS 8.6%, P= 0.001) and the early stage subgroup (stages 1 and 2) (60.0% VS 16.7%, P= 0.006). Moreover, in the subgroup of clinical stages 1 and 2 with tumor diameter ⩽ 5 cm, high USP4 expression prolonged the survival time of esophageal cancer patients more significantly (75.5% VS 5.9%, P= 0.000). Based on these results, we speculated that it was possible to significantly improve the prognosis of patients with low USP4 expression by targeted therapy in early esophageal cancer. Taken together, our study uncovered a previously unknown function of USP4 in esophageal cancer and more investigations would be carried out to further study its regulation gene network and molecular biological mechanism in esophageal cancer.

Autophagy regulated by JWA influenced sensitivity of esophageal cancer to cisplatin

Objective: To explore the effect of JWA on cisplatin sensitivity and its potential molecular mechanism in esophageal cancer. Methods: The siRNA was used to inhibit the JWA expression, then cisplatin sensitivity and LC3 (autophagy related protein) expression levels were observed in TE1 cells.Further, the effect of autophagy inhibitor tamoxifen (3-MA) on above process was determined.Cisplatin sensitivity of 20 fresh esophageal cancer samples was evaluated by histoculture drug response assay (HDRA). Result: Silencing JWA gene increased the sensitivity of TE1 cells to cisplatin (P<0.05), and decreased the LC3-Ⅰ and LC3-Ⅱ proteins induced by cisplatin.Furthermore, combined with 3-MA increased the inhibition rate of cisplatin in JWA silencing group (P<0.05). Additionally, the inhibition rate of cisplatin on tissues with low JWA expression were higher than those with high expression (45.6% vs 25.6%, P=0.005). Conclusions: JWA could influence the cisplatin sensitivity by regulating autophagy in esophageal cancer.

High TRAF6 Expression Is Associated With Esophageal Carcinoma Recurrence and Prompts Cancer Cell Invasion.

Esophageal cancer is one of the most common types of cancer, and it has a poor prognosis. The molecular mechanisms of esophageal cancer progression remain largely unknown. In this study, we aimed to investigate the clinical significance and biological function of tumor necrosis factor receptor-associated factor 6 (TRAF6) in esophageal cancer. Expression of TRAF6 in esophageal cancer was examined, and its correlation with clinicopathological factors and patient prognosis was analyzed. A series of functional and mechanism assays were performed to further investigate the function and underlying mechanisms in esophageal cancer. Expression of TRAF6 was highly elevated in esophageal cancer tissues, and patients with high TRAF6 expression have a significantly shorter survival time than those with low TRAF6 expression. Furthermore, loss-of-function experiments showed that knockdown of TRAF6 significantly reduced the migration and invasion abilities of esophageal cancer cells. Moreover, the pro-oncogenic effects of TRAF6 in esophageal cancer were mediated by the upregulation of AEP and MMP2. Altogether, our data suggest that high expression of TRAF6 is significant for esophageal cancer progression, and TRAF6 indicates poor prognosis in esophageal cancer patients, which might be a novel prognostic biomarker or potential therapeutic target in esophageal cancer.

The Synthetic β-Nitrostyrene Derivative CYT-Rx20 Inhibits Esophageal Tumor Growth and Metastasis via PI3K/AKT and STAT3 Pathways.

The β-nitrostyrene family have been implicated for anti-cancer property. However, the pharmacological role of β-nitrostyrene in esophageal cancer remain unclear. Here, a β-nitrostyrene derivative, CYT-Rx20, was synthesized and assessed for its anti-cancer activities and underlying mechanism in esophageal cancer. CYT-Rx20 induced cytotoxicity in esophageal cancer cells by promoting apoptosis through activation of caspase cascade and poly(ADP-ribose) polymerase (PARP) cleavage. Besides, CYT-Rx20 inhibited esophageal cancer cell migration and invasion by regulating the expression of epithelial to mesenchymal transition (EMT) markers. CYT-Rx20 decreased cell viability and migration through suppression of the PI3K/AKT and STAT3 pathways. Of note, the cytotoxicity and anti-migratory effect of CYT-Rx20 were enhanced by co-treatment with SC79 (AKT activator) or colivelin (STAT3 activator), suggesting the dependency of esophageal cancer cells on AKT and STAT3 for survival and migration, an oncogene addiction phenomenon. In xenograft tumor-bearing mice, CYT-Rx20 significantly reduced tumor growth of the implanted esophageal cancer cells accompanied by decreased Ki-67, phospho-AKT, and phospho-STAT3 expression. In orthotopic esophageal cancer mouse model, decreased tumor growth and lung metastasis with reduced Ki-67 and phospho-STAT3 expression were observed in mice treated with CYT-Rx20. Together, our results suggest that CYT-Rx20 is a potential β-nitrostyrene-based anticancer compound against the tumor growth and metastasis of esophageal cancer.

MiR-200a-3p promotes the proliferation of human esophageal cancer cells by post-transcriptionally regulating cytoplasmic collapsin response mediator protein-1.

The dysregulation of cytoplasmic collapsin response mediator protein1 (CRMP1) has been reported in lung cancer, medulloblastoma and esophageal cancer. However, the role of CRMP1 and its regulatory mechanisms in esophageal cancer remain unclear. In this study, we demonstrated that CRMP1 expression was downregulated in esophageal cancer tissues and that there were differences in its expression levels in different esophageal cancer cell lines. We found that CRMP1 overexpression inhibited the proliferation of esophageal cancer cells, whereas the silencing of CRMP1 promoted cell proliferation. We performed an analysis of potential microRNA(miRNA or miR) target sites using a commonly used prediction algorithm(TargetScan). The algorithm predicted that miR‑200a-3p targets the 3'untranslated region(3'UTR) of CRMP1. Further experiments confirmed this prediction. In addition, we found that miR‑200a-3p promoted the proliferation of esophageal cancer cells. Thus, our findings indicate that miR‑200a-3p promotes the proliferation of human esophageal cancer cells by post-transcriptionally regulating CRMP1.

The crucial role of miR-126 on suppressing progression of esophageal cancer by targeting VEGF-A.

BackgroundmiR-126 is a key regulator of oncogenic processes. It is functionally linked to cellular proliferation, survival and migration. Vascular endothelial growth factor A (VEGF-A), which is regarded as a tumorgenesis activator, could directly target miR-126 in several tumors. However, the mechanism in esophageal cancer remains unclear.Methods and resultsIn this study, the expression of miR-126 and VEGF-A were assessed in esophageal cancer tissues and esophageal cancer cell lines. We found that miR-126 has significantly lower expression in esophageal cancer tissues and esophageal cancer cell lines than in healthy tissues, while the expression of VEGF-A is high. Luciferase reporter assays were performed to investigate the relationship between VEGF-A and miR-126. We confirmed that VEGF-A is a target for miR-126. Furthermore, the proliferation of esophageal cancer cells with miR-126 overexpression and miR-126 knockdown was monitored using the MTT assay. The results showed that miR-126 could inhibit esophageal cancer cell proliferation in vitro. The effect of miR-126 was also detected in BALB/c nude mice with transplanted esophageal cancer cells. In vivo study showed that tumor growth was significantly suppressed by miR-126 overexpression.ConclusionsWe believe that restoring miR-126 levels may be a promising therapeutic approach in cases of esophageal cancer.

Convergent evidence from systematic analysis of GWAS revealed genetic basis of esophageal cancer.

Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with risk of esophageal cancer (EC). However, investigation of genetic basis from the perspective of systematic biology and integrative genomics remains scarce.In this study, we explored genetic basis of EC based on GWAS data and implemented a series of bioinformatics methods including functional annotation, expression quantitative trait loci (eQTL) analysis, pathway enrichment analysis and pathway grouped network analysis.Two hundred and thirteen risk SNPs were identified, in which 44 SNPs were found to have significantly differential gene expression in esophageal tissues by eQTL analysis. By pathway enrichment analysis, 170 risk genes mapped by risk SNPs were enriched into 38 significant GO terms and 17 significant KEGG pathways, which were significantly grouped into 9 sub-networks by pathway grouped network analysis. The 9 groups of interconnected pathways were mainly involved with muscle cell proliferation, cellular response to interleukin-6, cell adhesion molecules, and ethanol oxidation, which might participate in the development of EC.Our findings provide genetic evidence and new insight for exploring the molecular mechanisms of EC.

PLCE1 Suppresses p53 Expression in Esophageal Cancer Cells

The apoptotic mechanism dysfunction plays a critical role in cancer cell growth and escaping from cancer therapies; the underlying mechanisms are to be further elucidated. This study aims to investigate the role of phospholipase C epsilon 1 (PLCE1) in modulating the apoptosis mechanism in esophageal cancer (Eca) cells. The results showed that Eca cell lines, OE33 and CP-C cells expressed high levels of PLCE1. Knockdown of PLCE1 markedly increased 9.26 folds of the expression of p53 and 13.8 folds of the frequency of apoptotic CP-C cells via modulating the p53 promoter methylation.

Role of Cancer-Related Inflammation in Esophageal Cancer

Esophageal cancer (EC) is the ninth most common malignancy with a poor prognosis. It is clear that improvements need to be made to reveal the exact molecular mechanisms of EC. Cancer-related inflammation (CRI) recently has been proposed as a major physiological hallmark of malignancy and has important value in diagnosis, treatment, and prognosis. But the role of CRI in EC has remained unclear. In this review, we focus primarily on the function of key mediators of CRI in EC, including transcription factors, chemokines, cytokines, reactive oxygen species, COX-2, and specific microRNAs. Through a comprehensive analysis, we try to reveal the interaction between CRI and EC, providing novel preventive, diagnostic, and therapeutic strategies to reduce the health burden of EC.

MDM2 is Overexpressed and Regulated by the Eukaryotic Translation Initiation Factor 4E (eIF4E) in Human Squamous Cell Carcinoma of Esophagus

We investigated the association between the increased eukaryotic translation initiation factor 4E (eIF4E) level and MDM2 overexpression in the esophageal cancer tissue and cells. This was a retrospective study of specimens from esophageal cancer patients treated over a 5-year period in a Taiwan university hospital. The predictor variable was eIF4E level in esophageal tumors and CE48T/VGH and TE6 esophageal carcinoma cell lines. The main outcome variable was MDM2 overexpression. Appropriate descriptive and univariate statistics were computed, and a P value of <0.05 was considered statistically significant. There were two study sample groups. Immunohistochemistry analyses of the first sample group (51 esophageal tumors) revealed that 19 specimens demonstrated MDM2 elevation and 20 specimens had eIF4E overexpression. eIF4E elevation was evidenced by accumulation of the protein in the cytoplasm. There was a significant association between the eIF4E and MDM2 expression (P < 0.001). Western blot analysis and semiquantitative reverse transcriptase-polymerase chain reaction of the second specimen group (20 pairs of tumors and normal tissues) revealed the co-elevation of MDM2 and eIF4E (P = 0.008). There was no increased mdm2 transcript in most of the specimens. Without significant alterations in the mdm2 mRNA level and subcellular distribution, MDM2 protein was upregulated in CE48T/VGH cultured cells expressing ectopic eIF4E. Conversely, reduction of eIF4E by specific siRNA enabled TE6 cells synthesizing reduced amounts of MDM2. Our findings indicate that MDM2 protein levels are strongly associated with and regulated by eIF4E in a posttranscriptional mechanism in esophageal cancer.

MicroRNA-373 (miR-373) post-transcriptionally regulates large tumor suppressor, homolog 2 (LATS2) and stimulates proliferation in human esophageal cancer

LATS2 is a member of the LATS tumor suppressor family. It has been implicated in regulation of the cell cycle and apoptosis. Frequent loss of heterozygosity (LOH) of LATS2 has been reported in human esophageal cancer. But, the LATS2 gene expression and its regulatory mechanism in esophageal cancer remain unclear. The present study has shown that LATS2 protein expression was mediated by miR-373 at the post-transcriptional level and inversely correlated with miR-373 amounts in esophageal cancer cell lines. Furthermore, we demonstrated that the direct inhibition of LATS2 protein was mediated by miR-373 and manipulated the expression of miR-373 to affect esophageal cancer cells growth. Moreover, this correlation was supported by data collected ex vivo, in which esophageal cancer tissues from esophageal squamous cell carcinoma (ESCC) patients were analyzed. Finally, by miRNA microarray analysis, four miRNAs including miR-373 were over-expressed in ESCC samples. Our findings reveal that miR-373 would be a potential oncogene and it participates in the carcinogenesis of human esophageal cancer by suppressing LATS2 expression.

Molecular profiling to identify molecular mechanism in esophageal cancer with familial clustering

To identify the genes and molecular functional pathways involved in esophageal cancer, we analyzed the gene expression profile of esophageal tumor tissue from patients having family history of esophageal cancer by cDNA microarray. Three hundred and fifty differentially expressed genes (26 up-regulated and 324 down-regulated) were identified. Genes involved in humoral immune response (PF4), extracellular matrix organization (COL4A4), metabolism of xenobiotics (EPHX1), TGF-beta signaling (SMAD1) and calcium signaling pathways (VDAC1) were down-regulated and genes involved in regulation of actin cytoskeleton (WASL), neuroactive ligand receptor interaction (GRM3), Toll-like receptor (CD14), B-cell receptor (IFITM1) and insulin signaling pathways (FOXO1A) were up-regulated. Validation of differential expression of subset of genes by QRT-PCR and tissue microarray in familial and non-familial cases showed no significant difference in expression of these genes in two groups suggesting familial clustering occurs as result of sharing of common environmental factors. Gene expression profiling of clinical specimens from well characterized populations that have familial clustering of cancer identified molecular mechanism associated with progression of esophageal cancer.