Metastasis Of Esophageal Cancer Research Articles

Epidemiology, Risk Factors, Clinical-Imaging Features And Priorities For The Prevention Of Esophageal Cancer In The Fergana Valley Of Uzbekistan

Cancer of the digestive system is the most common cause of death among malignant neoplasms (Table 1). According to the International Agency for Research on Cancer (IARC) for 2008, the incidence of cancer of the digestive system was 49.2 people per 100 thousand people per year, the mortality rate was 34.3 people per 100 thousand. At a relatively low incidence rate, esophageal cancer is the seventh most common cause of death from malignant tumors, giving way to lung, breast, stomach, liver, prostate, and colon cancers. This is due to the extremely malignant nature of the course, early metastasis, and late diagnosis of esophageal cancer. The aggressiveness index, calculated as the ratio of deaths to new cases, is extremely high in esophageal cancer and is about 95%. The absolute number of deaths from esophageal cancer in 2008 in the world was 406 thousand people. In developing countries, morbidity and mortality from esophageal cancer are significantly higher than in developed countries (Table 2). The most common two histological types of esophageal cancer are squamous cell carcinoma and esophageal adenocarcinoma. Despite the similarity of the clinical picture, diagnostic and therapeutic tactics, an extremely unfavorable prognosis for both forms of esophageal cancer, these malignant neoplasms have different risk factors, socio-geographic and ethnic characteristics, knowledge of which is necessary for the timely establishment of the diagnosis and preventive measures. Squamous cell carcinoma of the esophagus (Fig. 1) is an extremely aggressive epithelial malignant tumor of stratified squamous epithelium, in most cases localized between the middle and lower third of the esophagus, the tumor is rare in the cervical esophagus

Performance of Indocyanine-Green Imaging for Sentinel Lymph Node Mapping and Lymph Node Metastasis in Esophageal Cancer: Systematic Review and Meta-Analysis.

Lymphatic mapping with indocyanine-green (ICG) and near-infrared light fluorescent imaging is widely used for sentinel lymph node staging in different types of cancer but is not fully accepted for all procedures because studies have reported heterogeneous results. This study aimed to assess the detection rate (DR) of ICG imaging for sentinel lymph node mapping (SLNM) and lymph node metastases (LNMs) in esophageal cancer. A systematic search was performed to identify relevant studies examining the use of ICG imaging for SLNM in patients with esophageal cancer. Extracted results were pooled in a single-proportion meta-analysis, with a random-effects model, presented as forest plots. Six studies were included in the analysis. The ICG DR for SLNM was 89% [95% confidence interval (CI) 71%-96%]. The pooled sensitivity and specificity values for the detection of LNMs were 84% (95% CI 64%-94%) and 15% (95% CI 3%-45%), respectively. A trend towards a lower DR was found with increasing mean latency time between ICG injection and SLNM. ICG imaging is a technique that potentially could improve lymph node yield excision and, as a consequence, improve the detection of lymph node metastases.

Expression of Twist, Slug and Snail in esophageal squamous cell carcinoma and their prognostic significance.

Esophageal cancer is one of the most common types of malignancy worldwide. At present, surgical resection is the main treatment for esophageal cancer, but recurrence and distant metastasis are the main causes of mortality. The transcription factors Twist, Slug and Snail regulate epithelial-mesenchymal transition and thereby participate in tumor invasion and metastasis. The aim of the present study was to investigate the expression of Twist, Slug and Snail in esophageal squamous cell carcinoma (ESCC) and their prognostic significance. The expression of Twist, Slug and Snail in 229 paraffin-embedded ESCC and matched normal mucosal tissues was detected by immunohistochemistry. The expression differences of Twist, Slug and Snail in the ESCC and normal tissues were compared by χ2 test, and the associations between the three proteins and the clinicopathological parameters of ESCC were analyzed. The expression levels of Twist, Slug and Snail in 29 fresh frozen ESCC and matched normal mucosal tissues were detected by reverse transcription-quantitative PCR. The correlations among Twist, Slug and Snail in ESCC were examined by Pearson's correlation analyses. In addition, single factor and multivariate Cox regression analyses were used to analyze the influence of Twist, Slug and Snail on the prognosis of ESCC. Twist was found to be highly expressed in ESCC. The difference of Slug expression in ESCC was associated with differentiation degree, TNM stage and vascular invasion, but no significant association was observed between Snail expression and any clinicopathological parameters. In ESCC, there were significant differences in protein expression between Twist and Snail, and Slug and Snail. The mRNA expression level of Twist in ESCC was significantly higher than that in normal esophageal mucosa. However, the mRNA expression of Slug in normal esophageal mucosa was higher than that in ESCC, and the mRNA expression levels of Twist and Snail were positively correlated in ESCC. Kaplan-Meier analysis of 229 patients with ESCC revealed that Snail influenced the overall survival, as did the co-expression of Twist and Snail. Nerve invasion was also identified as an independent factor affecting the progression-free survival of ESCC. The results indicate that Twist is highly expressed, Slug may be a tumor suppressor, and Snail is an independent prognostic factor in ESCC. Twist and Snail are positively correlated, and the simultaneous inhibition of Twist and Snail protein expression may be beneficial for prolonging the overall survival of patients with ESCC.

Significance of serglycin and its binding partners in autocrine promotion of metastasis in esophageal cancer.

Rationale: Little is known about the roles of proteoglycans in esophageal cancer. This study aims to investigate the roles and mechanisms of serglycin (SRGN) proteoglycan in promoting metastasis of esophageal squamous cell carcinoma (ESCC).Methods: Reverse phase protein array analysis was used to identify activated signaling pathways in SRGN-overexpressing cells. Chemokine array was used to identify differentially secreted factors from SRGN-overexpressing cells. Binding between SRGN and potential interacting partners was evaluated using proximity ligation assay and co-immunoprecipitation. The glycosaminoglycan (GAG) chains of SRGN were characterized using fluorophore-assisted carbohydrate electrophoresis. Tissue microarray and serum samples were used to determine the correlation of SRGN expression with clinicopathological parameters and patient survival.Results: In vitro and in vivo experiments showed that SRGN promoted invasion and metastasis in ESCC via activating ERK pathway, stabilizing c-Myc and upregulating the secretion of matrix metalloproteinases. SRGN-knockdown suppressed tumorigenic hallmarks. These SRGN-elicited functions were carried out in an autocrine manner by inducing the secretion of midkine (MDK), which was further identified as a novel binding partner of SRGN for the formation of a SRGN/MDK/CD44 complex. In addition, SRGN interacted with MDK and matrix metalloproteinase 2 in ESCC via its GAG chains, which were mainly decorated with chondroitin sulfate comprising of ∆di-4S and ∆di-6S CS. Clinically, high expression of serum SRGN in serum of patients with ESCC was an independent prognostic marker for poor survival.Conclusions: This study provides the first evidence that elevated serum SRGN has prognostic significance in patients with ESCC, and sheds light on the molecular mechanism by which elevated circulating SRGN in cancer patients might promote cancer progression.

Traditional Chinese Medicine Therapy for Esophageal Cancer: A Literature Review.

Esophageal cancer (EC) is the sixth leading cause of cancer-related deaths worldwide. Western medicine has played a leading role in its treatment, but its prognosis remains unsatisfactory. Therefore, the development of effective therapies is important. Traditional Chinese medicine (TCM) has been practiced for thousands of years, and involves taking measures before diseases occur, deteriorate, and recur. Interestingly, there is growing evidence that TCM can improve the therapeutic effects in reversing precancerous lesions, inhibiting the recurrence and metastasis of EC. In this article, we review traditional Chinese herbs and formulas that have preventive and therapeutic effects on EC, summarize the application and research status of TCM in patients with EC, and discuss its shortcomings and prospects in the context of translational, evidence-based, and precision medicine.

Case report of a patient with recurrence after endoscopic submucosal dissection for superficial esophageal cancer, diagnosed with mediastinal lymph node endoscopic ultrasound-fine needle aspiration based on the symptom of hoarseness

The patient was an 81-year-old man who presented with a complaint of hoarseness. When he was 80 years old, he had developed superficial esophageal cancer and had undergone endoscopic submucosal dissection (ESD) at our hospital. Two months after the ESD, he developed hoarseness. Computed tomography (CT) scan showed no abnormal findings at that time;therefore, he was diagnosed with idiopathic vocal cord paralysis, and followed up with symptom treatment in the Gastroenterology and Otolaryngology Departments. Ten months after the ESD, a CT scan revealed mediastinal lymph node swelling. He was admitted to our hospital for histopathological examination of the lymph node using endoscopic ultrasound-fine needle aspiration (EUS-FNA). The histopathological examination revealed squamous cell carcinoma of the lymph node, similar to the primary esophageal tumor. This result suggests that laryngeal nerve paralysis involving hoarseness is caused by lymph node metastasis of superficial esophageal cancer. We report that histopathological examination with EUS-FNA helps in determining the cause of hoarseness that develops after ESD.

A CASE OF VAGUS NERVE SCHWANNOMA DIFFICULT TO DISTINGUISH FROM LYMPH NODAL METASTASIS OF ESOPHAGEAL CANCER

In this report, we describe a rare case of vagus nerve schwannoma associated with esophageal cancer. A 70-year-old man visited our hospital complaining of worsening dysphagia. His upper gastrointenstinal endoscopy revealed a mass in the esophagus. A contrast-enhanced chest computed tomography also detected a 15 mm nodule attached to the tracheal membrane. This nodule was diagnosed as a metastatic lymph node. Although the primary tumor reduced after neoadjuvant chemotherapy, the nodule remained intact ; it showed fluorodeoxyglucose accumulation on positron emission tomography. We had a clinical diagnosis of stage III after neoadjuvant chemotherapy and underwent surgery. Intraoperatively, the nodule could not be detached from the right vagus nerve ; therefore, we excised the nodule along with the adjacent vagus nerve. The nodule was pathologically diagnosed as a vagus schwannoma. The nodule was not a regional lymph node metastasis of esophageal cancer. His postoperative course was uneventful, and he is currently undergoing outpatient follow-up without recurrence. J. Med. Invest. 68 : 205-208, February, 2021.

Chimeric RNA ASTN2-PAPPAas aggravates tumor progression and metastasis in human esophageal cancer.

Transcription-induced chimeric RNAs are an emerging area of research into molecular signatures for disease biomarker and therapeutic target development. Despite their importance, little is known for chimeric RNAs-relevant roles and the underlying mechanisms for cancer pathogenesis and progression. Here we describe a unique ASTN2-PAPPAantisense chimeric RNA (A-PaschiRNA) that could be the first reported chimeric RNA derived from the splicing of exons and intron antisense of two neighboring genes, respectively. Aberrant A-PaschiRNA level in ESCC tissues was associated with tumor progression and patients' outcome. In vitro and in vivo studies demonstrated that A-PaschiRNA aggravated ESCC metastasis and enhanced stemness through modulating OCT4. Mechanistic studies demonstrated that ERK5-mediated non-canonical PAF1 activity was required for A-PaschiRNA-induced cancer malignancy. The study defined an undocumented function of chimeric RNAs in aggravating cancer stemness and metastasis.

Detecting lymph node metastasis of esophageal cancer on dual-energy computed tomography.

BackgroundUsing conventional computed tomography (CT), the accurate diagnosis of lymph node (LN) metastasis of esophageal cancer is difficult.PurposeTo examine dual-energy CT parameters to predict LN metastasis preoperatively in patients with esophageal cancer.Material and MethodsTwenty-six consecutive patients who underwent dual-energy CT before an esophageal cancer surgery (19 patients with LN metastases) were analyzed. The included LNs had a short-axis diameter of ≥4 mm and were confirmed to be resected on postoperative CT. Their short-axis diameter, CT value, iodine concentration (IC), and fat fraction were measured on early- and late-phase contrast-enhanced dual-energy CT images and compared between pathologically confirmed metastatic and non-metastatic LNs.ResultsIn total, 51 LNs (34 metastatic and 17 non-metastatic) were included. In the early phase, IC and fat fraction were significantly lower in the metastatic than in the non-metastatic LNs (IC = 1.6 mg/mL vs. 2.2 mg/mL; fat fraction = 20.3% vs. 32.5%; both P < 0.05). Furthermore, in the late phase, IC and fat fraction were significantly lower in the metastatic than in the non-metastatic LNs (IC = 2.0 mg/mL vs. 3.0 mg/mL; fat fraction = 20.4% vs. 33.0%; both P < 0.05). Fat fraction exhibited accuracies of 82.4% and 78.4% on early- and late-phase images, respectively. Conversely, short-axis diameter and CT value on both early- and late-phase images were not significantly different between the metastatic and non-metastatic LNs (P > 0.05).ConclusionUsing dual-energy CT images, IC and fat fraction are useful for diagnosing LN metastasis in patients with esophageal cancer.

Identification of miR-515-3p and its targets, vimentin and MMP3, as a key regulatory mechanism in esophageal cancer metastasis: functional and clinical significance

Metastasis is the main factor of treatment failure in cancer patients, but the underlying mechanism remains to be elucidated and effective new treatment strategies are urgently needed. This study aims to explore novel key metastasis-related microRNAs (miRNAs) in esophageal squamous cell carcinoma (ESCC). By comparing miRNA profiles of the highly metastatic ESCC cell sublines, we established through serial in vivo selection with the parental cells, we found that the expression level of miR-515-3p was lower in ESCC tumor tissues than adjacent normal tissues, further decreased in metastatic tumors, and moreover, markedly associated with advanced stage, metastasis and patient survival. The in vitro and in vivo assays suggested that miR-515-3p could increase the expression of the epithelial markers as well as decrease the expression of the mesenchymal markers, and more importantly, suppress invasion and metastasis of ESCC cells. Mechanistically, we revealed that miR-515-3p directly regulated vimentin and matrix metalloproteinase-3 (MMP3) expression by binding to the coding sequence and 3′untranslated region, respectively. In addition, the data from whole-genome methylation sequencing and methylation-specific PCR indicated that the CpG island within miR-515-3p promoter was markedly hypermethylated in ESCC cell lines and ESCC tumor tissues, which may lead to deregulation of miR-515-3p expression in ESCC. Furthermore, our preclinical experiment provides solid evidence that systemic delivery of miR-515-3p oligonucleotide obviously suppressed the metastasis of ESCC cells in nude mice. Taken together, this study demonstrates that miR-515-3p suppresses tumor metastasis and thus represents a promising prognostic biomarker and therapeutic strategy in ESCC.

TRIM 16 gene expression regulates the growth and metastasis of human esophageal cancer

Purpose: To investigate the effect of tripartite membrane protein TRIM) 16 gene silencing on human esophageal cancer (KYSE-270) cell proliferation, invasion and metastasis.Methods: Short interfering RNA (siRNA) TRIM 16 silencing fragment was transfected into KYSE-270 cells. Transfection efficiency was determined using real-time quantitative polymerase chain reaction (qRT-PCR). Cell proliferation, invasiveness and migration were measured by 3-(4,5-dimethylthiazol2-yl)- 2,5-diphenyl tetrazolium bromide (MTT) assay, Transwell invasion assay, and scratch test, respectively. Protein expressions of bax and bcl-2 were assayed using Western blotting.Results: The gene expression of TRIM 16 was significantly upregulated in esophageal cancer cells, relative to normal human esophageal cells, but was downregulated after gene silencing. Moreover, the silencing of TRIM 16 gene led to significant reductions in KYSE-270 cell viability, migration and invasiveness, but significantly increased KYSE270 cell apoptosis (p &lt; 0.05). The silencing of TRIM 16 gene also significantly upregulated bax protein expression, while downregulating the expression of bcl-2 protein (p &lt; 0.05).Conclusion: These results suggest that TRIM 16 gene silencing inhibits KYSE-270 cell proliferation, invasion and metastasis, and thus provide a basis for its development as a therapeutic approach for the management of esophageal cancer.&#x0D; Keywords: Apoptosis, Cell invasion, Esophageal cancer, Gene silencing, Metastasis

CT and Pathological Control Study on Small Cluster Lymph Nodes Metastases of Esophageal Cancer and Construction of Nomogram Prediction Model

Aim of this study was to explorer the predictor of small cluster lymph nodes metastasis of esophageal cancer and construction of nomogram prediction model. We retrospectively analyzed the 202 patients with pathologically confirmed esophageal cancer from Fujian Provincial Tumor Hospital between January 2008 and December 2009. The clinical and imaging features of preoperative enhanced CT of small clustered lymph nodes in the mediastinal and supraclavicular region were recorded in detail, and compared with postoperative pathological data. We have identified using single factor χ2 test or Fisher's exact test to explorer the predictors of small cluster lymph nodes metastasis of esophageal cancer, and using Logistic multivariate analysis. Based on binary Logistic regression analysis results, a nomogram model was established by using R software. The predicting accuracy of the nomogram was evaluated by C-index and calibration curve. The total of 961 small lymph node stations of 202 patients met with inclusion criteria were observed. The pathological positive rates of small cluster lymph nodes group and small non-clustered lymph nodes group were 55.3%(187/338) and 16.7%(104/623),The difference was statistically significant (P<0.05).Univariate χ2 test or Fisher's exact test showed that histological grading, vascular invasion and the short-axis diameter of lymph nodes were significantly associated with small cluster lymph node metastasis of esophageal cancer in supraclavicular area and mediastinal (all P < 0.05). Logistic multivariate analysis showed that histological grading, vascular invasion and the short-axis diameter of lymph nodes (≥0.545cm) were independent predictor factors for small cluster lymph node metastasis (P < 0.05).After the predictor factors were include into the nomogram, and its AUC was 0.5931 (95%CI 0.5363-0.6498).The calibration curve show that the predicted and actual lymph node metastasis were consistent. Histological grading, vascular invasion and the short-axis diameter of lymph nodes (≥0.545cm) were independent predictor factors for small cluster lymph node (≥ 3 lymph nodes clustered and nonfusion) metastasis of esophageal cancer patients in the supraclavicular and mediastinal and construction of nomogram prediction model.

MiR-15b, a diagnostic biomarker and therapeutic target, inhibits oesophageal cancer progression by regulating the PI3K/AKT signalling pathway.

MicroRNA (miR)-15b is an important regulator in several types of cancer, such as gastric cancer, colorectal cancer and oesophageal squamous cell carcinoma. The PI3K/AKT signalling pathway has been implicated in the growth and metastasis of oesophageal cancer (EC). The aim of the present study was to investigate the biological effects of miR-15b in EC, as well as the underlying mechanism involving the PI3K/AKT signalling pathway. The present study included 74 patients with EC and 74 healthy volunteers. The expression of miR-15b in peripheral blood mononuclear cells (PBMCs) and EC cell lines was evaluated via reverse transcription-quantitative PCR. The receiver operating characteristic curve was plotted to determine the diagnostic significance of miR-15b. EC cell viability, apoptosis, migration and invasion were analysed by conducting MTT, flow cytometry and transwell assays, respectively. Protein expression levels were analysed via western blotting. The results indicated that PBMCs isolated from patients with EC had lower miR-15b expression levels compared with PBMCs isolated from healthy volunteers. In patients with EC, miR-15b expression was strongly associated with tumour size, lymph node metastasis, TNM stage, fibrous membrane invasion and histologic grade. The results of the gain/loss-of-function in vitro experiments indicated that miR-15b inhibited EC cell viability, migration and invasion, facilitated EC cell apoptosis and attenuated the PI3K/AKT signalling pathway in EC109 and TE10 cells. Treatment of EC cells with the PI3K/AKT pathway agonist recilisib displayed the opposite effects, blocking the inhibitory function of miR-15b mimic on EC cell viability, migration and invasion. In summary, the results indicated that miR-15b suppressed EC cell viability, migration and invasion, and promoted EC cell apoptosis by inhibiting the PI3K/AKT signalling pathway.

SCAP Mediated GDF15-Induced Invasion and EMT of Esophageal Cancer.

Background: GDF15 is a potential biomarker for patients with esophageal cancer (EC). However, the mechanistic role of GDF15 in the invasion and metastasis of EC remains poorly understood.Methods: We determined the expression and function of GDF15 in esophageal cancer cells (ESCCs) and in patient tissue samples using western blotting, migration, and invasion assays, immunohistochemistry, Co-IP assays, and quantitative real-time-PCR. In addition, a pulmonary metastatic nude mouse model was used to determine the function of GDF15. We then supplemented our experimental results with database analysis to validate our findings.Results: GDF15 was upregulated in EC, and was associated with poor differentiation, high metastasis rates, and worse prognosis. GDF15 knock-down reduced the migration and invasion of ESCCs. Co-IP assays demonstrated its association with SCAP, while GDF15 knock-down decreased SCAP levels. SCAP overexpression reversed the migration, invasion and EMT in GDF15-siRNA ESCCs. However, after incubation with β-cyclodextrin (β-CD), the ability of migration and invasion was weakened, EMT was reversed again. Migration, invasion, and EMT were enhanced in GDF15-siRNA ESCCs cultured in the presence of cholesterol and were similar to GDF15-siRNA ESCCs overexpressing SCAP. In vivo, knockdown of GDF15 inhibited lung metastasis of ESCCs and was reversed by SCAP overexpression or high cholesterol diet. Increased lung metastasis after SCAP overexpression was partially suppressed by intraperitoneal injection of β-CD. In addition, we determined that GDF15 was a direct target of miR-1324, miR-1324 was down-regulated in EC tissues. MiR-1324 upregulation resulted in decreased GDF15 expression and metastasis in ESCCs.Conclusions: We demonstrated that SCAP mediated GDF15-induced the invasion and metastasis of EC by regulating cholesterol metabolism. In addition, GDF15 was shown to be a direct target of miR-1324.

M2 Macrophage-Derived Exosomal lncRNA AFAP1-AS1 and MicroRNA-26a Affect Cell Migration and Metastasis in Esophageal Cancer

Exosomes from cancer cells or immune cells, carrying bio-macromolecules or long non-coding RNAs (lncRNAs), participate in tumor pathogenesis and progression by modulating the microenvironment. This study aims to explore the function of M2 macrophage-derived exosomes on the invasion and metastasis of esophageal cancer (EC) with the involvement of the lncRNA AFAP1-AS1/microRNA-26a (miR-26a)/activating transcription factor 2 (ATF2) axis. We found that lncRNA AFAP1-AS1 could specifically bind to miR-26a, thus affecting the expression of miR-26a, and ATF2 was the direct target of miR-26a. Compared with M1 macrophage-derived exosomes, M2 macrophage-derived exosomes exhibited higher AFAP1-AS1 and ATF2 expression and lower miR-26a expression. Moreover, extracellular AFAP1-AS1 could be moved to KYSE410 cells via being incorporated into M2 macrophage-derived exosomes. M2 macrophage-derived exosomes could downregulate miR-26a and promote the expression of ATF2 through high expression of AFAP1-AS1, thus promoting the migration, invasion, and lung metastasis of EC cells; M2-exosomes upregulating AFAP1-AS1 or downregulating miR-26a ameliorated this effect. In summary, M2 macrophage-derived exosomes transferred lncRNA AFAP1-AS1 to downregulate miR-26a and upregulate ATF2, thus promoting the invasion and metastasis of EC. Targeting M2 macrophages and the lncRNA AFAP1-AS1/miR-26a/ATF2 signaling axis represents a potential therapeutic strategy for EC.

Circ-PRMT5 stimulates migration in esophageal cancer by binding miR-203.

The study aimed to uncover the role of circ-PRMT5 in triggering the migratory ability of esophageal cancer by regulating microRNA-203 (miR-203) level. Circ-PRMT5 levels in 56 matched esophageal cancer tissues and paracancerous ones were detected. The relationship between circ-PRMT5 level and clinical data of esophageal cancer patients was analyzed. Migratory abilities in TE-1 and OE33 cells influenced by circ-PRMT5 were evaluated by transwell and wound healing assay. Regulatory effect of circ-PRMT5 on miR-203 level, and the involvement of miR-203 in the development of esophageal cancer were determined through Dual-Luciferase reporter assay and rescue experiments. Circ-PRMT5 was upregulated in esophageal cancer tissues and cell lines. The expression level of circ-PRMT5 was positively correlated to the rates of lymphatic metastasis and distant metastasis of esophageal cancer. Knockdown of circ-PRMT5 attenuated migratory abilities in TE-1 and OE33 cells. MiR-203 was verified to be the target gene binding circ-PRMT5, with a negative correlation between each other. Notably, miR-203 was responsible for the regulatory effect of circ-PRMT5 on migratory ability in esophageal cancer. Circ-PRMT5 is positively correlated to the rates of lymphatic metastasis and distant metastasis of esophageal cancer. It promotes migratory ability in esophageal cancer by targeting miR-203.

Circ_0072088 Promotes Proliferation, Migration, and Invasion of Esophageal Squamous Cell Cancer by Absorbing miR-377.

Circular RNA (circRNA) is an endogenous noncoding RNA. Accumulative investigations have confirmed that circRNAs play a vital role in carcinogenesis and tumor progression. Herein, we examined the expression and mechanism of circ_0072088 in esophageal squamous cell carcinoma (ESCC). As a result, circ_0072088 was significantly overexpressed in ESCC tissues and cells, which was closely associated with tumor size, invasion depth, clinical stage, and lymph node metastasis of esophageal cancer. Nuclear and cytoplasmic separation as well as FISH assays showed that circ_0072088 was mainly localized in the cytoplasm of ESCC cells. RNase R treatment assay revealed that circ_0072088 was steadier than linear ZFR mRNA. circ_0072088 promoted ESCC cell proliferation, migration and invasion in vitro, and cell proliferation in vivo. Mechanistically, circ_0072088 upregulated VEGF gene expression by acting as the sponge of miRNA-377. In conclusion, circ_0072088 might be used as a diagnostic biomarker and therapeutic target for ESCC.

Identification of hub genes associated with esophageal cancer progression using bioinformatics analysis.

The underlying causes of esophageal cancer (EC) are unknown. To explore the molecular mechanisms that lead to EC, gene expression profiles of large cohorts of patients with EC were obtained from The Cancer Genome Atlas and the Gene Expression Omnibus (GEO) databases (GSE5364, GSE20347 and GSE23400). The present study identified 83 upregulated and 22 downregulated genes between EC and normal tissue using R statistical software and the GEO2R web tool. The Database for Annotation, Visualization and Integrated Discovery was used to identify the associated pathways, and for functional annotation of the differentially expressed genes (DEGs). Protein-protein interactions of these DEGs were analyzed based on the Search Tool for the Retrieval of Interacting Genes database, and hub genes were visualized using Cytoscape software. An online Kaplan-Meier plotter survival analysis tool was utilized to evaluate the prognostic value of hub gene expression in patients with EC. Further analysis of an additional dataset from GEO (GSE21293) revealed that these genes were associated with infiltration and metastasis in EC. In addition, the Gene Expression Profiling Interactive Analysis tool was used to evaluate expression levels of hub genes in patients with EC for different pathological stages. The Ualcan analysis tool was used to evaluate the expression levels of hub genes for different histological types. Overall, ubiquitin conjugating enzyme E2 C, cyclin dependent kinase inhibitor 3, CDC28 protein kinase regulatory subunit 2, kinesin family member 20A (KIF20A) and RAD51 associated protein 1 (RAD51AP1) were upregulated in EC tissues compared with normal tissues, and upregulation of these genes was a poor prognostic factor for patients with EC, indicating that these genes may mediate EC cell infiltration and metastasis. Among the hub genes, KIF-20A had potential value for predicting the pathological stage of EC. KIF20A and RAD51AP1 were more informative biomarkers of esophageal squamous cell carcinoma. Further studies are required to explore the value of these genes in the treatment of EC.

ASO Author Reflections: Lymph Node Metastasis of Esophageal Cancer After Trimodal Therapy.

ASO Author Reflections: Lymph Node Metastasis of Esophageal Cancer After Trimodal Therapy.

Thymine DNA glycosylase‐regulated TAZ promotes radioresistance by targeting nonhomologous end joining and tumor progression in esophageal cancer

Radiation resistance is a major cause of esophageal cancer relapse or metastasis. Transcriptional coactivator with PDZ binding domain (TAZ) is a final effector of the Hippo signaling pathway and plays critical roles in several types of cancer, but how it participates in the progression and radiation resistance of esophageal cancer remains unclear. Here, we revealed that TAZ was the strongest prognostic factor among Hippo pathway members. Overexpression of TAZ predicted poor outcome and adverse pathological features. In cell and animal models, TAZ facilitated cell proliferation, motility, and radiation resistance. Additionally, TAZ promoted expression of nonhomologous end joining (NHEJ)‐related genes, which are the main contributors to repair irradiation‐induced DNA breaks and result in radiation resistance. Amplification of the TAZ gene occurred in 2.5%‐3.2% of esophageal cancers. In addition, the CpG islands of the TAZ gene were demethylated in esophageal cancer under thymine DNA glycosylase (TDG) regulation. Knockdown of TDG inhibited cell growth, motility, and radiation resistance, which were overridden by TAZ overexpression. Collectively, these findings suggest that the TDG/TAZ/NHEJ axis is a critical player in esophageal cancer progression and radiation resistance, as well as a potential target for radiotherapy.