Esophageal Carcinogenesis Research Articles

Decreased Expression of NRF2 Target Genes after Alcohol Exposure in the Background Esophageal Mucosa of Patients with Esophageal Squamous Cell Carcinoma.

Patients with esophageal squamous cell carcinoma (ESCC) might have a specific mechanism for the carcinogenesis by alcohol consumption in the background esophageal mucosa, and nuclear factor erythroid 2-related factor 2 (NRF2), which plays a protective role against esophageal carcinogenesis, and barrier dysfunction might be associated with this phenomenon. This study aimed to confirm this hypothesis. Twenty patients with superficial ESCCs (ESCC patients) and 20 age- and sex-matched patients without ESCC (non-ESCC patients) were enrolled. Biopsy samples were obtained from non-neoplastic esophageal mucosa: one for histological evaluation, one for quantitative real-time polymerase chain reaction (PCR), and two for the mini-Ussing chamber system to measure transepithelial electrical resistance (TEER) and, thereafter, for PCR. The TEER after acetaldehyde or both acetaldehyde and ethanol exposure did not differ significantly between ESCC and non-ESCC patients. Unlike non-ESCC patients, mRNA levels of NRF2 target genes and claudin4 in ESCC patients tended to decrease after the exposure, with a significant difference between no exposure and both acetaldehyde and ethanol exposure in NRF2 target genes (p < 0.05). Furthermore, in ESCC patients, the decreased tendency of mRNA levels of NRF2 target genes after the exposure was more pronounced in high-risk states, such as aldehyde dehydrogenase 2 (ALDH2) Lys alleles (Glu/Lys + Lys/Lys), Lugol-voiding lesion grade C, and drinking history. In conclusion, the protective role of NRF2 against carcinogenesis from alcohol exposure might be disrupted in the background esophageal mucosa of ESCC patients, which might lead to a high incidence of metachronous ESCC.

YKL-40/osteopontin-integrin β 4-p70S6K axis induced by interaction with macrophages was involved in early carcinogenesis of esophagus

YKL-40/osteopontin-integrin β 4-p70S6K axis induced by interaction with macrophages was involved in early carcinogenesis of esophagus

Acetyltransferase P300 Inhibits the Proliferation, Invasion, and Migration of Esophageal Cancer via Survivin Acetylation

Background: Esophageal cancer is one of the primary death causes leading by cancer in the world, which is high morbidity and mortality. Epigenetic acetylation modification participates in and regulates the proliferation, invasion, and metastasis of various tumor cells, and the acetylation modification of tumor proteins involved by acetyltransferases may be one of the important mechanisms of esophageal carcinogenesis. The aim of this study was to investigate the correlation of acetyltransferase P300 and Survivin acetylation in esophageal cancer pathogenesis and its molecular mechanism. Methods: Fifty-five cases of esophageal cancer tissues and adjacent cancer tissues were collected, Survivin and P300 protein expression was measured by immunohistochemistry (SP) and protein blotting (Western Blot); Survivin acetylated protein levels were measured by coimmunoprecipitation (Co-IP); bioinformatics predicted the relationship between P300 and Survivin as the substrate, and fluorescence immunohistochemistry (IF) to verify the localization and expression of Survivin and P300 in esophageal cancer tissues; the correlation of Survivin acetylation, P300 and clinical cases characteristics was analyzed by statistics. P300 siRNA sequences were structured and transfected into EC109 cells. P300 protein expression and Survivin acetylated protein levels were determined by Co-IP. Cell viability was determined by the MTT assay, Scratch healing and Transwell chamber assay examined cell migration and invasion ability. Results: Survivin and P300 protein expression was significantly increased in human esophageal cancer tissues and EC109 cells. The Survivin protein was acetylated in esophageal cancer tissues and EC109 cells, and its protein acetylation rate was significantly increased; bioinformatics predicted that the acetyltransferase P300 could catalyze the acetylation of Survivin as a substrate, and the fluorescence immunohistochemistry confirmed that both Survivin and P300 simultaneously showed a high expression state in cancer tissues; Survivin acetylation and P300 expression; Survivin acetylation and P300 were closely related with esophageal cancer stage, tissue differentiation and lymph node metastasis. The vitro experiments showed that P300 RNA interference in esophageal cancer cells can significantly reduce the Survivin protein acetylation level, while inhibiting the survival, migration and invasion capacity of EC109 cells. Conclusion: P300 has a correlation with Survivin acetylation in the lespathological process of esophageal cancer, P300 may be an important upstream molecule of Survivin acetylation and has an important potential value in the diagnosis and treatment of esophageal cancer.

Tumour suppressor role of microRNA-335-5p in esophageal squamous cell carcinoma by targeting TTK (Mps1)

BackgroundEsophageal cancer is an aggressive malignancy. miR-335-5p is reported to possess both tumour suppressor and tumour promoter activities in different cancers. ObjectivesWe investigated the role of miR-335-5p in esophageal cancer by expression and functional studies. Materials and methodsThe role of miR-335-5p in ESCC was evaluated using MTT assay, cell cycle analysis, colony formation assay, scratch assay, matrigel invasion, and migration assay. ResultsOur expression studies showed a significantly decreased expression of tissue and circulating miR-335-5p in esophageal cancer. Our results herein report a key tumour suppressive role of miR-335-5p in esophageal carcinogenesis by inhibiting proliferation, migration, and invasion in ESCC cells. Using RNA-seq and Insilico analysis we found TTK to be a newly identified direct target and confirmed it by using luciferase assay. ConclusionOverall, our expression and functional analysis results demonstrated herein point towards the potential role of miR-335-5p in esophageal tumorigenesis. Moreover, this is the first report showing TTK as a downstream target of miR-335-5p.

Meta-Analysis of Esophageal Cancer Transcriptomes Using Independent Component Analysis.

Independent Component Analysis is a matrix factorization method for data dimension reduction. ICA has been widely applied for the analysis of transcriptomic data for blind separation of biological, environmental, and technical factors affecting gene expression. The study aimed to analyze the publicly available esophageal cancer data using the ICA for identification and comprehensive analysis of reproducible signaling pathways and molecular signatures involved in this cancer type. In this study, four independent esophageal cancer transcriptomic datasets from GEO databases were used. A bioinformatics tool « BiODICA—Independent Component Analysis of Big Omics Data» was applied to compute independent components (ICs). Gene Set Enrichment Analysis (GSEA) and ToppGene uncovered the most significantly enriched pathways. Construction and visualization of gene networks and graphs were performed using the Cytoscape, and HPRD database. The correlation graph between decompositions into 30 ICs was built with absolute correlation values exceeding 0.3. Clusters of components—pseudocliques were observed in the structure of the correlation graph. The top 1,000 most contributing genes of each ICs in the pseudocliques were mapped to the PPI network to construct associated signaling pathways. Some cliques were composed of densely interconnected nodes and included components common to most cancer types (such as cell cycle and extracellular matrix signals), while others were specific to EC. The results of this investigation may reveal potential biomarkers of esophageal carcinogenesis, functional subsystems dysregulated in the tumor cells, and be helpful in predicting the early development of a tumor.

Mutant clones in normal epithelium outcompete and eliminate emerging tumours.

Human epithelial tissues accumulate cancer-driver mutations with age1-9, yet tumour formation remains rare. The positive selection of these mutations suggests that they alter the behaviour and fitness of proliferating cells10-12. Thus, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less competitive neighbours11-14. However, little is known about how such dynamic competition in normal epithelia influences early tumorigenesis. Here we show that the majority of newly formed oesophageal tumours are eliminated through competition with mutant clones in the adjacent normal epithelium. We followed the fate of nascent, microscopic, pre-malignant tumours in a mouse model of oesophageal carcinogenesisand found that most were rapidly lost with no indication of tumour cell death, decreased proliferation or an anti-tumour immune response. However, deep sequencing of ten-day-old and one-year-old tumours showed evidence of selection on the surviving neoplasms. Induction of highly competitive clones in transgenic mice increased early tumour removal, whereas pharmacological inhibition of clonal competition reduced tumour loss. These results support a model in which survival of early neoplasms depends on their competitive fitness relative to that of mutant clones in the surrounding normal tissue. Mutant clones in normal epithelium have an unexpected anti-tumorigenic role in purging early tumours through cell competition, thereby preserving tissue integrity.

850 OBJECTIVE IDENTIFICATION OF OESOPHAGEAL ADENOCARCINOMA USING MASS SPECTROMETRY IMAGING

Abstract Outcomes for oesophageal adenocarcinoma continue to be poor, as patients are often diagnosed too late for curative treatment. New tools to assist early and rapid diagnosis are needed. Tissue phospholipids quantified by mass spectrometry imaging (MSI) can objectively diagnose non-oesophageal cancers from control tissue in minutes. However, whether MSI can objectively identify oesophageal adenocarcinoma is unknown and represents a significant challenge, as this microenvironment is complex with phenotypically similar tissue-types. Methods Desorption electrospray ionisation mass spectrometry imaging (DESI-MSI) and bespoke chemometrics were used to assess the phospholipidomes of oesophageal adenocarcinoma and relevant control tissues, in surgical (discovery) and endoscopic (validation) cohorts. Structural annotations verified by tandem MS fragmentation patterns were performed to understand the characteristics of the key differential phospholipids. Bioinformatics, quantitative polymerase chain reaction, and immunohistochemistry were performed to describe the reprogramming of phospholipogenesis in oesophageal adenocarcinoma. Finally, genetic silencing experiments were performed to understand whether this genetic reprogramming impacts the oesophageal adenocarcinoma phospholipid signature. Results Multivariable models based on tissue phospholipids from 117 patients were highly discriminant for oesophageal adenocarcinoma both in discovery (area-under-curve = 0.97) and validation cohorts (AUC = 1). Cancer samples were enriched for polyunsaturated phosphatidylglycerols with longer acyl chains, with stepwise enrichment in pre-malignant tissues. Expression of fatty acid and glycerophospholipid synthesis genes was significantly upregulated, and characteristics of fatty acid acyls matched phospholipid acyls. Mechanistically, reducing ACLY expression in oesophageal adenocarcinoma cells shortened GPL chains, therefore linking de novo lipogenesis to the oesophageal adenocarcinoma phospholipidome. Conclusion DESI-MSI (i) objectively identified invasive oesophageal adenocarcinoma from a number of pre-malignant tissues (ii) described the characteristics of cancer phospholipids, which have unknown function (iii) unveiled a new mechanism of phospholipidomic reprogramming. These results call for accelerated diagnosis studies using DESI-MSI in the upper gastrointestinal endoscopy suite, as well as functional studies to determine how polyunsaturated phosphatidylglycerols are generated, and how they contribute to oesophageal carcinogenesis.

Dynamic switch of immunity and antitumor effects of metformin in rat spontaneous esophageal carcinogenesis

Chronic inflammation contributes to tumor development by creating a local microenvironment that facilitates neoplastic transformation and potentiates the progression of cancer. Esophageal cancer (EC) is an inflammation-associated malignancy with a poor prognosis. The nature of the switch between chronic inflammation of the esophagus and EC-related immunological changes remains unclear. Here, we examined the dynamic alterations of immune cells at different stages of chronic esophagitis, Barrett’s esophagus (BE) and EC using an esophageal spontaneous carcinogenesis rat model. We also investigated the anticancer effects of metformin. To stimulate EC carcinogenesis, chronic gastroduodenal reflux esophagitis via esophagojejunostomy was induced in 120 rats in metformin-treated and non-treated (control) groups. After 40 weeks, BE and EC developed in 96.7% and 63.3% of the control group, and in 66.7% and 23.3% of the metformin-treated group, respectively. Flow cytometric analysis demonstrated that the balance of M1/M2-polarized or phospho-Stat3-positive macrophages, regulatory T, cytotoxic T, natural killer (NK), NK T cells, and Th17 T cells was dynamically changed at each stage of the disease and were resolved by metformin treatment. These findings clarify the immunity in esophageal carcinogenesis and suggest that metformin could suppress this disease by improving the immunosuppressive tumor microenvironment and immune evasion.

Insilico Insight into the Association between Polycyclic Aromatic Hydrocarbons and Human Toll like Receptor in Progression of Esophageal Carcinogenesis

Cancer creates enormous burden and is a leading cause of death in most of the countries. Esophageal cancer (EC) is one of the most common cancers in the world and has the worst survival of all cancers. Esophageal Squamous Cell Carcinoma (ESCC) and adenocarcinoma are the two main types of esophageal cancer. Exposure of polycyclic aromatic hydrocarbons (PAHs) can be cited as one of the reasons for development of Esophageal Squamous Cell Carcinoma. Toll Like Receptors (TLRs) present in human esophageal epithelial cells may pose a major role in pathogen recognition, activation of innate immunity and cancer. The study attempts to predict the role of carcinogenic PAHs in TLR4 signaling pathway and how it can ultimately result in immuno suppression and development of esophageal cancer by insilico docking evaluation. For the study we retrieved the structure of sixteen PAHs from the PubChem database and the protein model of TLR4 (PDB ID: 4G8A) from protein data bank (PDB). The binding affinity of PAHs to the TLR4 receptor was calculated using molecular docking software Auto Dock1.5. The results showed that Benzo[a]pyrene showed strong interaction toward TLR4 receptor with the highest number of polar contacts along with high binding affinity values. Considering the presence of Benzo[a] pyrene in different environmental, occupational and behavioral sources globally, there is a need for future research on the risk assessment of Benzo[a]pyrene on Esophageal Squamous Cell Carcinoma.

Human papillomavirus (HPV) types 16 and 18 infection and esophageal squamous cell carcinoma: a systematic review and meta-analysis.

The human papillomavirus (HPV) is implicated in the pathogenesis of several cancers among humans. The role of HPV as one of the etiological agents in esophageal carcinogenesis is partially unknown. We assessed whether the available evidence supports the association of HPV with risk and prognosis in patients with esophageal squamous cell carcinomas (ESCCs). For this systematic review and meta-analysis, PubMed, Embase, Cochrane Library, and SCOPUS were searched up to February 2021. The included studies were prospective or retrospective studies that evaluated the incidence, risk, and prognosis of HPV-16/18-related ESCCs in adult subjects. The primary outcome was the incidence rate of ESCC in HPV-16/18 carriers. Secondary outcomes included the risk of ESCCs compared with healthy HPV-16/18 carriers (expressed as odds ratios [ORs] with 95% confidence intervals [CIs]) and the survival of HPV + versus HPV- ESCCs. The search identified 1649 unique citations, of which 145 met the inclusion criteria and were included in the pooled analysis (16,484 patients). The pooled HPV prevalence in ESCCs was 18.2% (95% CI 15.2-21.6%; P < 0.001). A significantly increased ESCC risk was associated with HPV infection (OR = 3.81; 95% CI 2.84-5.11; P < 0.001). Main limitation were methods of HPV detection (DNA only), race of populations included (mainly Asiatic countries) and lack of adjustment for other prognostic factors. The findings suggest that HPV-16/18 is detectable in about 1 on 5 cases of ESCC with different prevalences across the world. It is moderately but significantly associated with a diagnosis of ESCC. Further epidemiological studies are needed to confirm and increase the current knowledge of the subject.

Antitumor Effects of Astaxanthin on Esophageal Squamous Cell Carcinoma by up-Regulation of PPARγ

Esophageal squamous cell carcinoma is a malignant tumor that is difficult to find and has a poor prognosis. The aim of this study is to explore the chemoprevention effect of Astaxanthin (AST) and reveal the possible mechanism of AST on the development of esophageal cancer based on PPARγ. We found that a stable and strong binding between PPARγ molecules and AST molecules using Autodock 4.0 software. AST significantly inhibited the viability of EC109 cells in a dose and time dependent manners (all P < 0.05), and up-regulated the protein expression level of PPARγ from the concentration of 6.25 µM (P < 0.05). Animal experiment showed that AST significantly decreased the incidences of NMBzA-induced esophageal carcinogenesis at 50 mg/kg AST in F344 rats (P < 0.05). AST inhibited the oxidative stress by improving the levels of superoxide dismutase (SOD), total antioxidant capacity (TAOC) and suppressing malondialdehyde (MDA) in serum, and increasing the protein of PPARγ, Bax/Bcl-2, Caspase-3 in esophagus tissue, especially in the 50 mg/kg of AST intervention group (all P < 0.05). In conclusion, our data suggested that protective effect of AST on esophageal cancer by inhibiting oxidative stress, up-regulating PPARγ, and activating the apoptotic pathway, which could provide a basis for clinical application of AST.

Analyzing the Expression Level and Associated Clinical Characteristics of miRNA-138 in Esophageal Squamous Cell Carcinoma in Iranian Patients

Background: Esophageal Squamous Cell Carcinoma (ESCC) is the seventh most common and lethal malignancy worldwide with a high incidence in Iran. Esophageal cancer has a poor prognosis and low 5-years survival rate. Despite several studies on esophageal cancer, its underlying mechanism remains unclear. Therefore, it is significant to analyze the molecular factors involved in disease for introducing effective diagnosis and therapeutic approaches. Accordingly, the aberrant expression of miRNA was demonstrated in the etiology of esophageal cancer, and applying them as detecting biomarkers was further considered by researchers. This study aimed to evaluate the expression level of miRNA-138 in the tumor tissues of ESCC and normal adjacent tissues. Objective: In total, 35 samples of tumor and normal tissues of the esophagus were collected from ESCC patients. Methods: Then, RNA extraction was conducted and the expression level of miRNA-138 was assessed in the collected tissue samples, applying real-time RT-PCR. Moreover, the relationship between the miRNA-138 expression level and the patient’s clinical characteristics was assessed. Results: According to the obtained results, the expression of miR-138 was significantly downregulated in the tumor tissues of ESCC, compared to normal adjacent tissues (P&lt;0.05). Additionally, the level of miRNA-138 downregulation was significantly correlated with tumor differentiation degree and metastasis status (P&lt;0.05). Conclusion: The significant downregulation of miRNA-138 in the tumor samples of ESCC indicated the role of this epigenetic alteration in esophageal carcinogenesis. Therefore, applying the miRNA-138 could be considered as a potential molecular biomarker for ESCC diagnosis and screening.

A discussion of the gut microbiome's development, determinants, and dysbiosis in cancers of the esophagus and stomach.

The microbiome refers to a population of microbes that colonize the skin, nasopharynx, oral cavity, gastrointestinal tract, and urogenital tract. The human microbiome consists of bacteria, archaea, fungi, viruses, and phages. Recent advances in genomic sequencing have catalyzed a deeper understanding of complex microbe-microbe and host-microbe interactions. Dysregulation of these interactions, or dysbiosis of the gastrointestinal tract, has been implicated in a growing list of pathologies including nonalcoholic fatty liver disease, cardiovascular disease, obesity, diabetes, depression, Parkinson's disease, autism, and various gastrointestinal cancers. Gastric and esophageal cancer, for example, continue to remain as two of the most common causes of cancer-related deaths worldwide, therefore there is an increased emphasis on investigating the role of dysbiosis on these cancers. In this review, we discuss the development and structure of the gut microbiome, its homeostatic and dysbiotic mechanisms, and the key microbes in esophageal and gastric carcinogenesis with a focus on bacterial biology. Further clarification of these pathways and discovery of diagnostic or therapeutic targets could have broad impacts on global subpopulations. It is important to understand the nature of the gastrointestinal tract microbiome and its potentional risk factors for dysbiosis in order to tailor its application to the individual patient and create an era of highly personalized, precision medicine.

Clinicopathological features of basal cell type dysplasia of esophagus

Objective: To investigate the clinicpathological features of basal cell type dysplasia of the esophagus. Methods: The clinicopathological data of 71 cases of basal cell type dysplasia of esophagus were collected at the People's Liberation Army Joint Logistics Support Force 989 Hospital, from 2009 to 2019, and the histomorphologic characteristics and immunophenotype were evaluated. The relevant literature was reviewed. Results: The ratio of male to female patients was 1.6∶1.0, and the median age was 65 years (range 48-81 years). The tumors were located in the upper segment of the esophagus in four cases (5.6%), the middle segment in 54 cases (76.1%), and the lower segment in 13 cases (18.3%).The median maximal tumor diameter was 12.0 mm (range 3-42 mm). According to Paris Classification, 0-Ⅱb accounted for 42.3% (30/71) of the cases. Under endoscope, the lesions were reddish with abnormal mucosal microvessels. Histologically, the neoplastic cells were small, with a high nuclear-cytoplasmic ratio, similar to basal cells, and uniform in morphology. The structural atypia was characterized by dense and disordered tumor cells, loss of basal cell polarity, and absence of normal squamous differentiation gradient. In 10 cases, the tumors were confined to the lower part of the epithelium. The tumor cells were smaller and more uniform in shape, and extend to the superficial lamina propria. Sixty-one tumors involved at least the entire layer of the upper cortex. There were 31 cases of neoplasms with superficial invasive carcinoma. The types of neoplasms included typical squamous cell carcinoma, basaloid squamous cell carcinoma, small cell neuroendocrine carcinoma, squamous cell carcinoma with sebaceous adenoid carcinoma, and differentiation of glandular/ductal epithelioid carcinoma. Immunohistochemical staining showed that the mutant expression rate of p53 protein was 41.5% (17/41). All 41 cases (100.0%) showed abnormal distribution pattern of Ki-67. According to the initial pathologic diagnosis, there were 18 cases of low grade dysplasia, 12 cases of atypical epithelial cells, and 41 cases of high grade dysplasia and superficially invasive carcinoma. Conclusions: Basal cell type dysplasia has unique morphologic characteristics and represents a tumor subtype in the morphologic lineage of esophageal squamous dysplasia. Tumor cells of basal cell type dysplasia, especially those distributed only in the lower part of the stratified squamous epithelium, may be tumor stem cells at the earliest stage of esophageal carcinogenesis and have multidirectional differentiation potential. When the tumor is confined to the lower part of the stratified squamous epithelium, it does not meet the diagnostic criteria for esophageal squamous dysplasia as defined by the current WHO classification.

Bile acids are risk factors for esophageal carcinogenesis

Bile acids are risk factors for esophageal carcinogenesis

Innate Immune Cells in the Esophageal Tumor Microenvironment

Esophageal cancer (EC) is one of the most common mucosa-associated tumors, and is characterized by aggressiveness, poor prognosis, and unfavorable patient survival rates. As an organ directly exposed to the risk of foodborne infection, the esophageal mucosa harbors distinct populations of innate immune cells, which play vital roles in both maintenance of esophageal homeostasis and immune defense and surveillance during mucosal anti-infection and anti-tumor responses. In this review, we highlight recent progress in research into innate immune cells in the microenvironment of EC, including lymphatic lineages, such as natural killer and γδT cells, and myeloid lineages, including macrophages, dendritic cells, neutrophils, myeloid-derived suppressor cells, mast cells and eosinophils. Further, putative innate immune cellular and molecular mechanisms involved in tumor occurrence and progression are discussed, to highlight potential directions for the development of new biomarkers and effective intervention targets, which can hopefully be applied in long-term multilevel clinical EC treatment. Fully understanding the innate immunological mechanisms involved in esophageal mucosa carcinogenesis is of great significance for clinical immunotherapy and prognosis prediction for patients with EC.

Metallothionein MT1M Suppresses Carcinogenesis of Esophageal Carcinoma Cells through Inhibition of the Epithelial-Mesenchymal Transition and the SOD1/PI3K Axis.

Metallothionein (MT1M) belongs to a family of cysteine-rich cytosolic protein and has been reported to be a tumor suppressor gene in multiple cancers. However, its role in esophageal carcinoma carcinogenesis remains unclear. In this study, MT1M expression was correlated with tumor type, stage, drinking and smoking history, as well as patient survival. We also studied the regulation and biological function of MT1M in esophageal squamous cell carcinoma (ESCC). We have found that MT1M is significantly downregulated in ESCC tissues compared with adjacent non-cancer tissues. Furthermore, restoration of expression by treatment with the demethylation agent A + T showed that MT1M downregulation might be closely related to hypermethylation in its promoter region. Over-expression of MT1M in ESCC cells significantly altered cell morphology, induced apoptosis, and reduced colony formation, cell viability, migration and epithelial-mesenchymal transition. Moreover, based on reactive oxygen species (ROS) levels, a superoxide dismutase 1 (SOD1) activity assay and protein analysis, we verified that the tumor-suppressive function of MT1M was at least partially caused by its upregulation of ROS levels, downregulation of SOD1 activity and phosphorylation of the SOD1 downstream pathway PI3K/AKT. In conclusion, our results demonstrated that MT1M was a novel tumor-suppressor in ESCC and may be disrupted by promoter CpG methylation during esophageal carcinogenesis.

MiRNAs Involved in Esophageal Carcinogenesis and miRNA-Related Therapeutic Perspectives in Esophageal Carcinoma.

MicroRNAs (miRNAs) are small non-coding RNAs that play a pivotal role in many aspects of cell biology, including cancer development. Within esophageal cancer, miRNAs have been proved to be involved in all phases of carcinogenesis, from initiation to metastatic spread. Several miRNAs have been found to be dysregulated in esophageal premalignant lesions, namely Barrett’s esophagus, Barrett’s dysplasia, and squamous dysplasia. Furthermore, numerous studies have investigated the alteration in the expression levels of many oncomiRNAs and tumor suppressor miRNAs in esophageal squamous cell carcinoma and esophageal adenocarcinoma, thus proving how miRNAs are able modulate crucial regulatory pathways of cancer development. Considering these findings, miRNAs may have a role not only as a diagnostic and prognostic tool, but also as predictive biomarker of response to anti-cancer therapies and as potential therapeutic targets. This review aims to summarize several studies on the matter, focusing on the possible diagnostic–therapeutic implications.

Expression of CD44 and CD133 stem cell markers in squamous cell carcinoma of esophagus.

Role of cancer stem cells in the esophageal carcinogenesis is not clear. To assess the expression of CD44 and CD133 cancer stem cell markers in esophageal squamous cell carcinoma (ESCC) and its predisposing lesions by immunohistochemistry. Prospective study as a part of an intramural research project. Tissues samples were obtained with endoscopic biopsy and from surgically resected esophageal specimens. Fifty cases each of histopathologically diagnosed cases of esophageal squamous cell carcinoma and its predisposing lesions (mild, moderate, and severe dysplasia and esophagitis) were evaluated for stem cell marker CD44 and C133 by immunohistochemistry using a scoring system. Chi-square test, analysis of variance (ANOVA), post-hoc tests (Tukey-HSD) were used as appropriate for data analysis. Two sided P < 0.05 was considered as significant. CD44 expression was significantly higher in ESCC as compared to dysplasia and esophagitis (mean IS 7.92 ± 1.45 vs. 6.34 ± 0.80 vs 5.15 ± 0.86 respectively, P < 0.001). CD133 expression was also significantly higher in ESCC as compared to dysplasia (mean IS 6.82 ± 1.57 vs. 1.00 ± 0.00 respectively, P < 0.001) while esophagitis showed no expression. CD44 and CD133 expressions were significantly higher in poorly differentiated ESCC than moderately differentiated and well differentiated lesions (CD44 mean IS 6.94 ± 1.44 vs 8.17 ± 1.38 vs. 8.63 ± 1.02 respectively, P < 0.001 and CD 133 mean IRS 5.63 ± 0.81 vs 6.00 ± 00 vs. 9.0 ± 00 respectively, P < 0.001). Significantly higher expression of CD44 and CD133 cancer stem cell markers in ESCC as compared to its predisposing lesions (esophagitis and dysplasia) suggests its role in esophageal carcinogenesis.

The prevalence of esophageal cancer after caustic and pesticide ingestion: A nationwide cohort study.

Habits such as smoking and alcohol drinking and existing esophageal malfunction are considered the main risk factors for esophageal carcinogenesis. Caustic ingestion of acidic or alkaline agents or strong irritants can induce severe esophageal corrosive injury and increase esophageal cancer risk. We studied the relationship between esophageal carcinoma and acute detergent or pesticide poisoning by using nationwide health insurance data. Methodology/Principle findings: We compared a pesticide/detergent intoxication cohort (N = 21,840) and an age- and gender-matched control cohort (N = 21,840) identified from the National Health Insurance Research Database between 2000 and 2011. We used the multivariable Cox proportional model to determine esophageal carcinoma risk. The overall incidence density of esophageal cancer was 1.66 per 10,000 person-years in the comparison cohort and 4.36 per 10,000 person-years in the pesticide/detergent intoxication cohort. The corresponding adjusted hazard ratio (HR) for esophageal cancer was 2.33 (95% confidence interval [CI] = 1.41-3.86) in the pesticide/detergent intoxication cohort compared with the control cohort. Patients with corrosive and detergent intoxication did not have a higher risk of esophageal cancer (adjusted HR = 0.98, 95% CI = 0.29-3.33) than those without pesticide/detergent intoxication. However, patients with pesticide intoxication had a significantly higher risk of esophageal cancer (adjusted HR = 2.52, 95% CI = 1.52-4.18) than those without pesticide/detergent intoxication. Conclusion: In the present study, after adjusting for conventional risk factors, we observed that pesticide intoxication could exert substantial effects through increased esophageal cancer risk. However, patients with detergent intoxication may not have an increased risk of esophageal cancer.