Selenium May Be Involved in Esophageal Squamous Cancer Prevention by Affecting GPx3 and FABP1 Expression: A Case-Control Study Based on Bioinformatic Analysis.

The role of selenium in the developmental process of esophageal cancer (EC) requires further investigation. To explore the relationship between selenium-related factors and EC through bioinformatic analysis, a case-control study was conducted to verify the results. Utilizing the GEPIA and TCGA databases, we delineated the differential expression of glutathione peroxidase 3 (GPx3) in EC and normal tissues, identified differentially expressed genes (DEGs), and a performed visualization analysis. Additionally, 100 pairs of dietary and plasma samples from esophageal precancerous lesions (EPLs) of esophageal squamous cancer (ESCC) cases and healthy controls from Huai'an district, Jiangsu, were screened. The levels of dietary selenium, plasma selenium, and related enzymes were analyzed using inductively coupled plasma mass spectrometry (ICP-MS) or ELISA kits. The results showed lower GPx3 expression in tumor tissues compared to normal tissues. Further analysis revealed that DEGs were mainly involved in the fat digestion and absorption pathway, and the core protein fatty acid binding protein 1 (FABP1) was significantly upregulated and negatively correlated with GPx3 expression. Our case-control study found that selenium itself was not associated with EPLs risk. However, both the decreased concentration of GPx3 and the increase in FABP1 were positively correlated with the EPLs risk (p for trend = 0.035 and 0.046, respectively). The different expressions of GPx3 and FABP1 reflect the potential of selenium for preventing ESCC at the EPLs stage. GPx3 may affect myocardial infarction through FABP1, which remains to be further studied.

Exploring cell competition for the prevention and therapy of esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is characterized by the development of cancer in the esophageal squamous epithelium through a step-by-step accumulation of genetic, epigenetic, and histopathological alterations. Recent studies have demonstrated that cancer-associated gene mutations exist in histologically normal or precancerous clones of the human esophageal epithelium. However, only a small proportion of such mutant clones will develop ESCC, and most ESCC patients develop only one cancer. This suggests that most of these mutant clones are kept in a histologically normal state by neighboring cells with higher competitive fitness. When some of the mutant cells evade cell competition, they become "super-competitors" and develop into clinical cancer. It is known that human ESCC is composed of a heterogeneous population of cancer cells that interact with and influence their environment and neighbors. During cancer therapy, these cancer cells not only respond to therapeutic agents but also compete with each other. Therefore, competition between ESCC cells within the same ESCC tumor is a constantly dynamic process. However, it remains challenging to fine-tune the competitive fitness of various clones for therapeutic benefits. In this review, we will explore the role of cell competition in carcinogenesis, cancer prevention, and therapy, using NRF2, NOTCH pathway, and TP53 as examples. We believe that cell competition is a research area with promising targets for clinical translation. Manipulating cell competition may help improve the prevention and therapy of ESCC.

Dietary intake of monounsaturated and polyunsaturated fatty acids is related to the reduced risk of esophageal squamous cell carcinoma.

BACKGROUND: The relationship of consumption of dietary fat and fatty acids with esophageal squamous cell carcinoma (ESCC) risk remains unclear. This study aimed to explore the relationship of dietary fat and fatty acids intake with ESCC risk. METHODS: This case-control study included 879 incident cases and 892 community-based controls recruited from Southwest China. A food frequency questionnaire was adopted to collect information about dietary information, and intake of fat, saturated fatty acid (SFA), monounsaturated fatty acid (MUFA), polyunsaturated fatty acid (PUFA), and total fatty acid (TFA) was calculated. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were estimated using the logistic regression model. RESULTS: When comparing the highest with lowest intake quintiles, MUFA (OR: 0.33, 95% CI: 0.21-0.51), PUFA (OR: 0.32, 95% CI: 0.20-0.51), and TFA (OR: 0.44, 95% CI: 0.28-0.70) were related to a reduced risk of ESCC after adjusting for confounders; for non-drinkers rather than drinkers, the intake of SFA was significantly related to a 61% (OR: 0.39, 95% CI: 0.19-0.81) reduced risk of ESCC when comparing the highest with the lowest intake quintiles. Dietary fat was not related to the risk of ESCC. CONCLUSIONS: This study suggested that the more intake of MUFA and PUFA, the lower risk of ESCC, whereas the protective effect of TFA was only observed among non-drinkers. Strategic nutritional programs should consider food rich in unsaturated fatty acids to mitigate the occurrence of ESCC.

Chemoprevention of Oesophageal Squamous-Cell Carcinoma and Adenocarcinoma: A Multicentre Retrospective Cohort Study.

BACKGROUND: Oesophageal cancer comprises 2 different histological variants: oesophageal squamous-cell carcinoma (ESCC) and adenocarcinoma (EAC). While there are multiple therapeutic options for both types, patients with advanced or metastatic oesophageal cancer still suffer from poor prognosis. AIMS: The study aimed to examine the association between the risk of oesophageal cancer and medications and to estimate the chemopreventive effects of commonly used drugs. METHODS: A multicentre retrospective cohort study was conducted using data from 9 hospital databases of hospitalized patients between 2014 and 2019. The primary outcomes were ESCC and EAC. The association of oesophageal cancer with drug use and clinical factors was evaluated. Odds ratios (ORs) were adjusted for age, sex, Charlson comorbidity index scores, and smoking with/without gastro-oesophageal reflux disease. RESULTS: The use of proton pump inhibitors (PPIs) (adjusted OR [aOR] 0.48, p < 0.0001), aspirin (aOR 0.32, p < 0.0001), cyclooxygenase-2 inhibitor (COX2I) (aOR 0.70, p = 0.0005), steroid (aOR 0.19, p < 0.0001), statin (aOR 0.43, p < 0.0001), and metformin (aOR 0.42, p < 0.0001) was associated with a lower risk of ESCC than that in non-use. The use of aspirin (aOR 0.33, p = 0.0006) and steroids (aOR 0.54, p = 0.022) was associated with a lower risk of EAC than that in non-use. CONCLUSION: COX2Is, statins, metformin, and PPIs could help in prevention of ESCC, and aspirin and steroids may be chemopreventive for both types of oesophageal cancer.

Dual inhibition of cMET and EGFR by microRNA-338-5p suppresses metastasis of esophageal squamous cell carcinoma.

MicroRNAs, as a group of post-transcriptional regulators, regulate multiple pathological processes including metastasis during tumor development. Here, we demonstrated the metastasis-suppressive function of microRNA (miR)-338-5p in esophageal squamous cell carcinoma (ESCC). Overexpression of miR-338-5p had inhibitory effect on invasive ability of ESCC cells and extracellular matrix degradation, whereas silencing miR-338-5p had opposite effects. Mechanistically, miR-338-5p directly targeted the 3' untranslated regions of hepatocellular growth factor receptor cMet (cMET) and epidermal growth factor receptor (EGFR). As a result, miR-338-5p inhibited the downstream signaling cascades of cMET and EGFR and repressed cMET- and EGFR-mediated ESCC cell invasion. Re-expression of cMET or EGFR in miR-338-5p overexpressing ESCC cells was sufficient to derepress ESCC cell invasion both in vitro and in vivo. We further showed that such manipulation downregulated the expression and secretion of matrix metalloproteinases 2 and 9, which resulted in impaired extracellular matrix degradation and cell invasion. Most importantly, systemic delivery of miR-338-5p mimic significantly inhibited metastasis of ESCC cells in nude mice. Taken together, our results uncovered a previously unknown mechanism through which miR-338-5p suppresses ESCC invasion and metastasis by regulating cMET/EGFR-matrix metalloproteinase 2/9 axis and highlighted the potential significance of miR-338-5p-based therapy in treating patients with metastatic ESCC.

PLCD1 Suppressed Cellular Proliferation, Invasion, and Migration via Inhibition of Wnt/ß-Catenin Signaling Pathway in Esophageal Squamous Cell Carcinoma.

BACKGROUND: Phospholipase C delta 1 (PLCD1) has been found to be abnormally expressed in various cancers. However, the potential roles of PLCD1 in esophageal squamous cell carcinoma (ESCC) are still unknown. METHODS: Western blot and qPCR were used to explore PLCD1 expression in various ESCC cells. MTT, colony formation assays, wound-healing assay, and transwell cell invasion assay were used to examine the cell viability in vitro. Western blot, qPCR, and luciferase assays were used to investigate the effects of PLCD1 on Wnt/ß-catenin signaling pathway. The xenograft models in nude mice were established to explore the roles of PLCD1 in vivo. RESULTS: We found that the expression of PLCD1 in ESCC cells was significantly downregulated than that in normal esophageal epithelial cells. In addition, upregulation of PLCD1 decreased the capacity of TE-1 and EC18 cells in proliferation, invasion, and migration. Then, the expression of ß-catenin/p-ß-catenin, C-myc, cyclin D1, MMP9, and MMP7 was investigated. PLCD1 activity was found to be negatively associated with the expression of ß-catenin, C-myc, cyclin D1, MMP9, and MMP7. Finally, the activity of PLCD1 in inhibiting ESCC proliferation in vivo was validated. CONCLUSION: The inhibitory effects of PLCD1 on the proliferation, invasion, and migration of TE-1 and EC18 cells might be associated with inhibition of Wnt/ß-catenin signaling pathway. PLCD1 played a key role in inhibiting ESCC carcinogenesis and progression in patients with ESCC.

Research on esophageal cancer: With personal perspectives from studies in China and Kenya.

The most common form of esophageal cancer (EC), esophageal squamous cell carcinoma (ESCC), is prevalent in many unindustrialized societies, among people with lower socioeconomic status and those who frequently use tobacco and alcohol. In some areas, ESCC mortality ranked top among all cancer. In this review, we begin with discussions of the extensive research on EC in Linxian in northern China that started 60 years ago and the recent studies in Kenya from our personal perspectives. Based on the results obtained from these studies and information from the literature, we summarize our current understanding about the risk factors for ESCC including lifestyle factors (smoking, alcohol, consumption of food and beverages at high temperature and other unhealthy habits), poor diet and nutritional insufficiencies and genetic susceptibility. Elimination or minimization of these environmental risk factors, as well as early detection and treatment of precancerous lesions, would be effective means for the prevention of ESCC. Current knowledge of molecular alterations in ESCC (gene mutations, hypermethylation and amplification or overexpression), as well as treatment of ESCC and the potential of targeted therapy, are also discussed. Finally, we propose effective approaches for the prevention of ESCC by adapting a healthy lifestyle, including a healthy diet that would also prevent other diseases. Community outreach, public education and international collaboration are important for achieving this public health goal.

MicroRNA­216a­5p suppresses esophageal squamous cell carcinoma progression by targeting KIAA0101.

The KIAA0101 protein (also referred to as NS5ATP9 or Paf15) is overexpressed in esophageal squamous cell carcinoma (ESCC) and is associated with disease progression and poor patient survival, but how KIAA0101 expression is regulated remains unknown. The relationship between tumor miR­216a­5p expression and prognosis in patients with ESCC was revealed by survival analyses. Quantitative reverse­transcriptase PCR and western blot analysis were used to evaluate miR­216a­5p and KIAA0101 expression in human ESCC tissues and cell lines. The targeting of KIAA0101 by miR­216a­5p was verified by dual­luciferase reporter assays. The EC9706 and TE1 cell lines were transfected with miR­216a­5p mimics and inhibitor, or KIAA0101­specific shRNA and KIAA0101­expressing plasmids, in order to evaluate the effect of manipulating miR­216a­5p and KIAA0101 expression on ESCC cell proliferation, cell cycle progression, migration, and invasion. miR­216a­5p was lowly expressed and inversely correlated with KIAA0101 protein expression in ESCC tissues and cell lines. Lower miR­216a­5p expression was associated with worse prognosis in patients with ESCC. miR­216a­5p negatively regulated KIAA0101 expression by directly targeting the 3'­untranslated region of the KIAA0101 mRNA. Overexpression of miR­216a­5p suppressed the proliferation, migration, and invasion of the ESCC cell lines, whereas inhibition of miR­216a­5p had the opposite effects. Meanwhile, KIAA0101 promoted ESCC migration and invasion, and its overexpression abolished the antitumor effects of miR­216a­5p mimics. As a tumor suppressor, miR­216a­5p targets KIAA0101 to inhibit the proliferation, migration, and invasion of ESCC. Therefore, the miR­216a­5p/KIAA0101 axis may be a potential target for ESCC treatment.

Risk factors for precancerous lesions of esophageal squamous cell carcinoma in high-risk areas of rural China: A population-based screening study.

Although many studies in China have found that environmental or lifestyle factors are major contributors to the etiology of esophageal cancer, most of the patients in the above studies are in the middle and late stages, the early-stage patients account for a small proportion. To clarify the risk/protective factors contributing to early lesions, we conducted the present cross-sectional study.A total of 2925 healthy controls and 402 patients with esophageal precancerous lesions were included in our study by endoscopic examination. Information on risk/protective factors was collected by personal interview, and unconditional logistic regression was used to determine adjusted odds ratios (AORs) by the maximum-likelihood method.Smoking >20 pack-years (AOR = 1.48), duration of drinking >30 years (AOR = 1.40), alcohol consumption >100 mL/d (AOR = 1.44), gastroesophageal reflux disease (AOR = 1.75), esophagitis (AOR = 1.25), a family history of esophageal cancer (AOR = 1.92), or stomach cancer (AOR = 1.92) were significant risk factors for esophageal precancerous lesions. There was a negative correlation between abdominal obesity and early esophageal cancer and precancerous lesions (AOR = 0.75). In addition, we found that there was a synergistic effect between a family history of esophageal cancer and drinking (AOR = 3.00) and smoking (AOR = 2.90).Lifestyle risk factors, genetic factors, and upper gastrointestinal diseases are associated with the development of esophageal precancerous lesions. These results highlight the need for primary prevention to reduce the future burden of cancer and other chronic diseases in high-risk areas of rural China.

Age at Initiation and Frequency of Screening to Prevent Esophageal Squamous Cell Carcinoma in High-risk Regions: an Economic Evaluation.

The aim of this study was to identify the economic screening strategies for esophageal squamous cell carcinoma (ESCC) in high-risk regions. We used a validated ESCC health policy model for comparing different screening strategies for ESCC. Strategies varied in terms of age at initiation and frequency of screening. Model inputs were derived from parameter calibration and published literature. We estimated the effects of each strategy on the incidence of ESCC, costs, quality-adjusted life-year (QALY), and incremental cost-effectiveness ratios (ICERs). Compared with no screening, all competing screening strategies decreased the incidence of ESCC from 0.35% to 72.8%, and augmented the number of QALYs (0.002-0.086 QALYs per person) over a lifetime horizon. The screening strategies initiating at 40 years of age and repeated every 1-3 years, which gained over 70% of probabilities that was preferred in probabilistic sensitivity analysis at a $1,151/QALY willingness-to-pay threshold. Results were sensitive to the parameters related to the risks of developing basal cell hyperplasia/mild dysplasia. Endoscopy screening initiating at 40 years of age and repeated every 1-3 years could substantially reduce the disease burden and is cost-effective for the general population in high-risk regions.

Abrogation of esophageal carcinoma development in miR-31 knockout rats.

MicroRNA-31 (miR-31) is overexpressed in esophageal squamous cell carcinoma (ESCC), a deadly disease associated with dietary Zn deficiency and inflammation. In a Zn deficiency-promoted rat ESCC model with miR-31 up-regulation, cancer-associated inflammation, and a high ESCC burden following N-nitrosomethylbenzylamine (NMBA) exposure, systemic antimiR-31 delivery reduced ESCC incidence from 85 to 45% (P = 0.038) and miR-31 gene knockout abrogated development of ESCC (P = 1 × 10-6). Transcriptomics, genome sequencing, and metabolomics analyses in these Zn-deficient rats revealed the molecular basis of ESCC abrogation by miR-31 knockout. Our identification of EGLN3, a known negative regulator of nuclear factor κB (NF-κB), as a direct target of miR-31 establishes a functional link between oncomiR-31, tumor suppressor target EGLN3, and up-regulated NF-κB-controlled inflammation signaling. Interaction among oncogenic miR-31, EGLN3 down-regulation, and inflammation was also documented in human ESCCs. miR-31 deletion resulted in suppression of miR-31-associated EGLN3/NF-κB-controlled inflammatory pathways. ESCC-free, Zn-deficient miR-31-/- rat esophagus displayed no genome instability and limited metabolic activity changes vs. the pronounced mutational burden and ESCC-associated metabolic changes of Zn-deficient wild-type rats. These results provide conclusive evidence that miR-31 expression is necessary for ESCC development.

Dietary carbohydrate intake and the risk of esophageal cancer: a meta-analysis.

BACKGROUND: Previous studies had been published to explore the association about carbohydrate intake on esophageal cancer risk, with inconsistent results. This meta-analysis aimed to assess the association between dietary carbohydrate intake and the risk of esophageal cancer. METHODS: Suitable studies were carefully searched with the databases of PubMed, Embase, the Cochrane Library, and Wanfang Database. A random-effects model was used for combined odds ratio (OR) and 95% confidence interval (CI). Stata software 14.0 was adopted for the analysis. RESULTS: At the end, 13 publications were included in our study. Pooled results suggested that highest category versus lowest category of carbohydrate intake could reduce the risk of esophageal cancer (summarized OR = 0.627, 95% CI = 0.505-0.778, I2 = 59.9%, Pfor heterogeneity = 0.001). The results for carbohydrate intake on the risk of esophageal adenocarcinoma (summarized OR = 0.569, 95% CI = 0.417-0.777) and esophageal squamous cell carcinoma (summarized OR = 0.665, 95% CI = 0.453-0.975) were consistent with the overall result. A positive association was found in European, Asian, North American populations, instead of South American populations. CONCLUSIONS: In conclusions, dietary carbohydrate intake may have a protective effect against the risk of esophageal cancer.

Aspirin and Its Potential Preventive Role in Cancer: An Umbrella Review.

Background: Aspirin is one of the most commonly prescribed drugs worldwide and has been reported to possess anti-cancer properties in addition to antipyretic and analgesic effects. This umbrella review summarizes systematic reviews and meta-analyses that investigate the association between aspirin and cancer risk, aiming to help clinical and public health decision-makers interpret the results of these studies when re-positioning aspirin. Methods: An umbrella review of systematic reviews and meta-analyses. Results: The associations that reached statistical significance (17 in total) indicated potential preventive effects of aspirin on certain cancers or precancerous lesions. We found that no association was supported by strong evidence. Only one association (aspirin and overall cancer risk) was supported by highly suggestive evidence. The evidence supporting the association between aspirin and the risk of breast cancer, non-cardia gastric cancer, or prostate cancer was considered to be highly suggestive. The remaining 23 associations were supported by weak (13) or not suggestive evidence (10). Conclusions: The association between aspirin and a reduced risk of esophageal squamous cell carcinoma is supported by strong evidence, researchers and policy makers should pay more attention to the potential merit of repositioning aspirin to prevent esophageal squamous cell carcinoma.

Protective effects of Alda-1, an ALDH2 activator, on alcohol-derived DNA damage in the esophagus of human ALDH2*2 (Glu504Lys) knock-in mice.

Alcohol consumption is the key risk factor for the development of esophageal squamous cell carcinoma (ESCC), and acetaldehyde, a metabolite of alcohol, is an alcohol-derived major carcinogen that causes DNA damage. Aldehyde dehydrogenase2 (ALDH2) is an enzyme that detoxifies acetaldehyde, and its activity is reduced by ALDH2 gene polymorphism. Reduction in ALDH2 activity increases blood, salivary and breath acetaldehyde levels after alcohol intake, and it is deeply associated with the development of ESCC. Heavy alcohol consumption in individuals with ALDH2 gene polymorphism significantly elevates the risk of ESCC; however, effective prevention has not been established yet. In this study, we investigated the protective effects of Alda-1, a small molecule ALDH2 activator, on alcohol-mediated esophageal DNA damage. Here, we generated novel genetically engineered knock-in mice that express the human ALDH2*1 (wild-type allele) or ALDH2*2 gene (mutant allele). Those mice were crossed, and human ALDH2*1/*1, ALDH2*1/*2 and ALDH2*2/*2 knock-in mice were established. They were given 10% ethanol for 7 days in the presence or absence of Alda-1, and we measured the levels of esophageal DNA damage, represented by DNA adduct (N2-ethylidene-2'-deoxyguanosine). Alda-1 significantly increased hepatic ALDH2 activity both in human ALDH2*1/*2 and/or ALDH2*2/*2 knock-in mice and reduced esophageal DNA damage levels after alcohol drinking. Conversely, cyanamide, an ALDH2-inhibitor, significantly exacerbated esophageal DNA adduct level in C57BL/6N mice induced by alcohol drinking. These results indicate the protective effects of ALDH2 activation by Alda-1 on esophageal DNA damage levels in individuals with ALDH2 gene polymorphism, providing a new insight into acetaldehyde-mediated esophageal carcinogenesis and prevention.

Association Between Metformin Use and Risk of Esophageal Squamous Cell Carcinoma in a Population-Based Cohort Study.

OBJECTIVES: Esophageal cancer is a highly fatal malignant neoplasm, with 2 etiologically different histological types. A large prospective study is expected to elucidate the specific risk of the 90% subtype of esophageal cancer, esophageal squamous cell carcinoma (ESCC), with metformin therapy. This study aims to determine the association between metformin use and incident ESCC risk. METHODS: This was a nationwide population-based prospective cohort study conducted in Sweden in 2005-2015. Among 8.4 million participants identified in the cohort, 411,603 (5%) were metformin users. The users were compared with 10 times as many frequency-matched nonusers of metformin (n = 4,116,030) by age and sex. Metformin use was treated as a time-varying variate, and multivariable cause-specific proportional hazards model was used to calculate hazard ratios (HR) with 95% confidence intervals (CI) for ESCC, adjusted for age, sex, calendar year, residence area, tobacco smoking, alcohol overconsumption, and use of nonsteroidal anti-inflammatory drugs or statins. RESULTS: The incidence rates of ESCC were 3.5 per 100,000 person-years among the metformin users and 5.3 per 100,000 person-years in the nonusers. Metformin users overall were at a decreased risk of ESCC compared with nonusers (HR 0.68, 95% CI 0.54-0.85). The decrease in risk was more pronounced in new metformin users (HR 0.44, 95% CI 0.28-0.64) and participants aged 60-69 years (HR 0.45, 95% CI 0.31-0.66). DISCUSSION: Metformin use decreases the risk of developing ESCC.

Development of an Empirically Calibrated Model of Esophageal Squamous Cell Carcinoma in High-Risk Regions.

OBJECTIVE: This study constructs, calibrates, and verifies a mathematical simulation model designed to project the natural history of ESCC and is intended to serve as a platform for testing the benefits and cost-effectiveness of primary and secondary ESCC prevention alternatives. METHODS: The mathematical model illustrates the natural history of ESCC as a sequence of transitions among health states, including the primary health states (e.g., normal mucosa, precancerous lesions, and undetected and detected cancer). Using established calibration approaches, the parameter sets related to progression rates between health states were optimized to lead the model outputs to match the observed data (specifically, the prevalence of precancerous lesions and incidence of ESCC from the published literature in Chinese high-risk regions). As illustrative examples of clinical and policy application, the calibrated and validated model retrospectively simulate the potential benefit of two reported ESCC screening programs. RESULTS: Nearly 1,000 good-fitting parameter sets were identified from 1,000,000 simulated sets. Model outcomes had sufficient calibration fit to the calibration targets. Additionally, the verification analyses showed reasonable external consistency between the model-predicted effectiveness of ESCC screening and the reported data from clinical trials. CONCLUSIONS: This parameterized mathematical model offers a tool for future research investigating benefits, costs, and cost-effectiveness related to ESCC prevention and treatment.

Up-regulation of circ-SMAD7 inhibits tumor proliferation and migration in esophageal squamous cell carcinoma.

BACKGROUND: Increasing evidences demonstrate that circular RNAs (circRNAs) play an important role in the development and progression of human cancers. Nevertheless, the functions and molecular mechanism of circRNAs in esophageal squamous cell carcinoma (ESCC) tumorigenesis are largely unknown. The purpose of this research is to investigate the expression and potential role of a new circular RNA named circ-SMAD7 on ESCC carcinogenesis. MATERIALS AND METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure circ-SMAD7 expression amount in both ESCC plasmas and tissues. Then the correlation between the expression of circ-SMAD7 and clinicopathological features was analyzed. Furthermore, by loss-of-function and gain-of-function experiments in ESCC cells, a functional analysis of circ-SMAD7 on ESCC cell proliferation and migration was performed. RESULTS: The expression of circ-SMAD7 was validated to be significantly down-regulated in ESCC plasmas in comparison with normal controls, showing a high negative correlation with TNM stage (P = 0.000) and lymphatic metastasis (P = 0.000). Moreover, circ-SMAD7 was significantly down-regulated in ESCC tissues compared to adjacent normal tissues. Furthermore, Loss-of-function and gain-of-function experiments revealed that the expression level of circ-SMAD7 affected the proliferation and migration of ESCC cell lines. CONCLUSION: Our study firstly exposed that over-expressioncirc-SMAD7, an influential regulator in cancer progression, can inhibit tumor proliferation and migration in ESCC and have the potential of becoming a biomarker for the diagnosis and therapy of ESCC.

MicroRNA-384 inhibits the progression of esophageal squamous cell carcinoma through blockade of the LIMK1/cofilin signaling pathway by binding to LIMK1.

INTRODUCTION: Esophageal squamous cell carcinoma (ESCC) represents an aggressive malignancy often accompanied with a poor prognosis. Owing to the poor mortality and morbidity rates associated with this malignancy, a deeper understanding of the finer molecular changes that occur in ESCC is required in order to identify novel potential targets for early detection and therapy. At present the mechanism by which ESCC functions on a molecular level is not fully understood. Hence, the aim of the present study was to ascertain as to whether microRNA-384 (miR-384) influences the progression of ESCC. MATERIAL AND METHODS: Bioinformatics analysis was initially conducted to identify ESCC-related differentially expressed genes and predict regulatory miRs. After the target relationship between miR-384 and LIMK1 had been verified, the expression of miR-384 and LIMK1 in the EC9706 cell line was altered in an attempt to investigate the regulatory roles of miR-384 in the expression of the LIMK1/cofilin signaling pathway-related genes, cell proliferation, invasion, cell cycle distribution and apoptosis, in addition to lymph node metastasis (LNM) and tumor growth in nude mice. RESULTS: Microarray-based gene expression profiling indicated that miR-384 affected the progression of ESCC through the LIMK1-mediated LIMK1/cofilin signaling pathway. Furthermore, miR-384 and Bax were observed to be poorly expressed, while LIMK1, cofilin and Bcl-2 were highly expressed in ESCC. The obtained evidences indicating that miR-384 targeted and negatively regulated LIMK1. Upregulation of miR-384 or LIMK1 inhibition was determined to block the LIMK1/cofilin signaling pathway, repress cell proliferation, invasion, cell cycle, LNM and tumor growth, while promote cell apoptosis in ESCC. CONCLUSION: Collectively, based on the key findings of the study, miR-384 could sequester LIMK1, which acts to suppress activation of the LIMK1/cofilin signaling pathway, thus ultimately inhibiting the development and progression of ESCC.

Metformin suppresses the esophageal carcinogenesis in rats treated with NMBzA through inhibiting AMPK/mTOR signaling pathway.

Metformin is a widely used antidiabetic drug for the management of type 2 diabetes mellitus. Recently, epidemiological studies demonstrate that metformin has anticancer effects on esophageal squamous cell carcinoma (ESCC) and other cancers. However, the effects and potential mechanisms of metformin on ESCC remain elusive. In this study, we used N-nitroso-N-methylbenzylamine (NMBzA), a special carcinogen for esophagi, to develop a rat ESCC model, in which the carcinogenesis progression of ESCC in rat was induced and promoted. We investigated the effects of metformin on carcinogenesis of ESCC in this model. Our results revealed that metformin significantly decreased the incidence and precancerous lesions of ESCC and inhibited proliferation and promoted apoptosis of esophageal epithelial cells in rat treated with NMBzA. Moreover, metformin also increased apoptosis and inhibited migration, colony formation and tumor sphere formation of human ESCC cells in vitro. Immunohistochemistry and western blotting showed that without interfering the metabolism of NMBzA, metformin inhibited the inflammation of esophagi via reducing the expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6). Treatment of metformin led to activation of AMP-activated protein kinase (AMPK) and attenuated signaling of the downstream molecules such as p-mTOR, p-p70S6K and cyclin D1 expression both in vivo and in vitro. Taken together, our study demonstrated that metformin suppressed the carcinogenesis of ESCC through inhibiting AMPK/mammalian target of the rapamycin (mTOR) signaling pathway, resulting in its chemopreventive effects on the carcinogenesis of ESCC.

p-Hydroxylcinnamaldehyde slows the progression of 4NQO-induced oesophageal tumourigenesis via the RhoA-MAPK signaling pathway.

p-Hydroxylcinnamaldehyde isolated from the Cochinchina momordica seed (CMSP) has been identified to inhibit growth and metastasis in oesophageal squamous cell carcinoma (ESCC) by inducing differentiation. The aim of the present study was to evaluate the effect and underlying mechanism of CMSP on 4-nitroquinoline 1-oxide (4NQO)-induced oesophageal tumourigenesis. In the present study, a mouse model of oesophageal preneoplastic lesions was established by providing 4NQO-containing drinking water to C57BL/6 mice. The effect of CMSP on tumourigenesis induced by the chemical mutagen and the effect of CMSP on immune function were investigated. The results showed that the incidence and pathological stage of atypical hyperplasia in oesophageal tissues were significantly reduced in CMSP-treated mice compared with untreated mice. Immunohistochemistry and pull-down assay results revealed that the expression levels of p-ERK1/2, p-SAPK/JNK, and GTP-RhoA were significantly decreased in the oesophageal tissue of CMSP-treated mice. In addition, the proportions of CD4+ T cells, CD8+ T cells, and NK cells were increased, while the proportion of CD4+ CD25+ regulatory T cells (Tregs) was decreased, in the peripheral blood of CMSP-treated mice. These results indicated that CMSP could hamper 4NQO-induced oesophageal tumourigenesis by regulating the RhoA-ERK/JNK signaling pathway and promoting immune system function, thus providing a new potential strategy for treating preneoplastic lesions of the oesophagus.