Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent cancers worldwide, characterized by a dismal prognosis and elusive therapeutic targets. Dysregulated cholesterol metabolism is a critical hallmark of cancer cells, facilitating tumor progression. Here, we used whole genome sequencing data from several ESCC cohorts to identify the important role of squalene epoxidase (SQLE) in promoting ESCC tumorigenesis and metastasis. Specifically, our findings highlight the significance of 2,3-oxidosqualene, an intermediate metabolite of cholesterol biosynthesis, synthesized by SQLE and metabolized by lanosterol synthase (LSS), as a key regulator of ESCC progression. Mechanistically, the interaction between 2,3-oxidosqualene and vinculin enhances the nuclear accumulation of Yes-associated protein 1 (YAP), thereby increasing YAP/TEAD-dependent gene expression and accelerating both tumor growth and metastasis. In a 4-nitroquinoline 1-oxide (4-NQO)-induced ESCC mouse model, overexpression of Sqle resulted in accelerated tumorigenesis compared to wild-type controls, highlighting the pivotal role of SQLE in vivo. Furthermore, elevated SQLE expression in ESCC patients correlates with a poorer prognoses, suggesting potential therapeutic avenues for treatment. In conclusion, our study elucidates the oncogenic function of 2,3-oxidosqualene as a naturally occurring metabolite and proposes modulation of its levels as a promising therapeutic strategy for ESCC.

Tristetraprolin (TTP) can inhibit the abnormal proliferation of malignant tumors but there are no studies involving TTP and esophageal squamous cell carcinoma (ESCC). We aimed to determine the effect of TTP on ESCC cell proliferation and to elucidate the underlying mechanism.

The human ESCC cell line, KYSE-510, and the human ESCC cell line, KYSE-150, stably infected with tetracycline-inducible expression (Tet-on-TTP and Tet-on-EV, respectively) were screened with puromycin. After Tet-on-TTP KYSE-150 cells were treated with different concentrations of doxycycline [Dox] (0, 0.5, and 1 ug/mL), the levels of TTP mRNA and protein expression were detected by real-time fluorescent quantitative PCR and western blotting, respectively. The effects of TTP on proliferation and migration were estimated by CCK-8 and Transwell assays, respectively. Cell apoptosis and cell cycle were measured by flow cytometry. Cellular apoptosis-related gene protein expression was determined by western blotting.

TTP overexpression significantly inhibited KYSE-510 and KYSE-150 proliferation. TTP overexpression also significantly inhibited KYSE-150 migration. In addition, TTP expression upregulation promoted the KYSE-150 apoptosis and induced cell cycle arrest in the G2 phase, downregulated Bcl-2 expression, and upregulated Bax expression.

TTP inhibited ESCC cell proliferation, promoted ESCC cell apoptosis, and arrested cell cycle progression in the G2 phase.

Polyploid Giant Cancer Cells (PGCCs) play a critical role in tumor progression due to their distinctive biological behaviors. However, the mechanisms by which PGCCs regulate their composition and structure to adapt to dynamic environments during their formation remain poorly understood. In this study, we used multicolor labeling of major organelles in esophageal squamous cell carcinoma (ESCC) cells combined with high- and super-resolution time-lapse imaging to monitor induced PGCCs in three dimensions. In addition to abnormal PGCC division, we observed nuclear dynamics and transient cell-in-cell formations. PGCCs exhibited cell cycle abnormalities, including prolonged G1/S transitions, asynchronous micronuclei, and intranuclear mitosis. Notably, early progeny continued dividing despite cell cycle dysregulation, resulting in asymmetric offspring. Quantitative analysis of subcellular structures revealed asymmetric inheritance of organelles, particularly mitochondria and the Golgi apparatus, in recurrent cells. These adaptive mechanisms in PGCCs may also be relevant in the context of anticancer treatments, contributing to the heterogeneity of recurrent tumors arising from early PGCC progeny populations.

Effective biomarkers for esophageal carcinoma (ESCA) are currently lacking. Here, we examined the role of minichromosome maintenance complex component 8 (MCM8) as a diagnostic and prognostic marker in ESCA and its association with m6a methylation and angiogenesis, and constructed a competing endogenous RNA (ceRNA) network.

Clinical data and gene expression profiles were obtained from The Cancer Genome Atlas and Gene Expression Omnibus datasets. Differential gene expression analysis was performed using DESeq2 and limma packages. The prognostic significance of MCM8 expression regarding overall survival (OS) was examined using the Cox proportional hazards model. Receiver Operating Characteristic (ROC) analysis was used to assess the diagnostic potential of MCM8. MCM8 expression in ESCA tissues was evaluated by immunohistochemical staining on a tissue microarray. Pearson correlation analysis identified co-expressed genes, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. The GEPIA online tool was used to examine the relationship between MCM8 and m6a methylation as well as angiogenesis-related genes. MicroRNA and long noncoding RNA predictions were made using miRWalk, MicroT-CDS, ENCORI, and miRNet tools to construct the ceRNA network.

MCM8 was significantly overexpressed in tumor tissues and showed high diagnostic accuracy in the ROC analysis with an area under the curve of 0.920. Kaplan-Meier survival analysis revealed that high MCM8 expression correlated with poorer OS and disease-specific survival. Pearson correlation analysis identified a significant correlation between MCM8 and several m6a methylation-related genes such as HNRNPA2B1 and YTHDF1, as well as PTK2, an angiogenesis-related gene. A ceRNA network including MCM8, PURPL/hsa-miR- 135a- 5p/MCM8 was successfully predicted and constructed.

MCM8 is a promising biomarker in ESCA and it is associated with m6a methylation and angiogenesis, showing potential as a therapeutic target. The ceRNA network provided insight into the pathogenesis of ESCA.

Field cancerization defined by multiple development of squamous cell carcinomas (SCCs) in upper aerodigestive tract was explained by excessive alcohol intake. A dysfunctional mitochondrial aldehyde dehydrogenase 2 (Aldh2) delays the clearance of acetaldehyde, a genotoxic alcohol metabolite, and increases SCC risks. TP53 plays key roles in squamous carcinogenesis. However, the mechanism of alcohol-mediated squamous field cancerization has not been clearly elucidated.

We developed a novel genetically engineered mouse strain KTPA-/- (Krt5CreERT2; Trp53loxp/loxp; Aldh2-/-) featuring Aldh2-loss concurrent with epithelial-specific Trp53 deletion. These mice were given 10%-EtOH, and we evaluated the development of squamous cell carcinogenesis histologically and genetically.

Widespread multifocal rete ridges (RRs), characterized by downward growth of proliferative preneoplastic cells, were found only in Aldh2+/- and Aldh2-/- mice with keratin5-specific Trp53 deletion (KTPA+/- and KTPA-/- mice, respectively), and alcohol drinking apparently increased RR formation rate. SCC occurred only in KTPA-/- (Aldh2 loss/TP53 loss) mice with alcohol drinking (15/18: 83%). Total alcohol consumption volume was significantly higher in KTPA-/- (Aldh2 loss/TP53 loss) mice with SCCs than those without SCCs. Further, target sequence revealed the occurrence of genetic abnormalities including Trp53 mutations in the esophageal epithelium of Aldh2-/- mice with alcohol drinking, suggesting direct mutagenic effects of alcohol drinking to the esophageal epithelium.

This study provides for the first time the evidence that alcohol drinking, Aldh2 dysfunction and Trp53 loss cooperate in squamous field cancerization. Alcohol consumption volume affects the SCCs development, even in the same genotype.

Endoscopic laryngopharyngeal surgery is an effective treatment for superficial laryngopharyngeal cancer, particularly in cases with prior esophageal cancer treatment. Despite its frequent application, reports on the risk factors for postoperative complications are limited. This study aimed to identify the risk factors for pneumonia after endoscopic laryngopharyngeal surgery and to examine the variations in pneumonia incidence among the types of prior esophageal cancer treatment.

Patients who had a history of esophageal cancer treatment and subsequently underwent endoscopic laryngopharyngeal surgery for superficial pharyngolaryngeal cancer were retrospectively analyzed. We examined the association between postoperative pneumonia and several factors, including number of lesions; diameter of the resected lesion; and type of previous esophageal cancer treatment, such as endoscopic submucosal dissection, chemoradiotherapy, and esophagectomy.

The study included 79 patients who had a mean age of 67.4 years. Postoperative pneumonia occurred in 16.4%. Multivariate analysis showed that the pneumonia incidence significantly increased in cases with multiple lesions (OR 4.794, 95% CI 1.133-20.288, p = 0.033) and larger diameter of the resected lesion (OR 7.047, 95% CI 1.791-27.730, p = 0.005). Importantly, compared with other treatments, prior esophagectomy for esophageal cancer did not increase the pneumonia incidence.

Multiple lesions and larger lesion diameter were the significant predictors of postoperative pneumonia. Moreover, endoscopic laryngopharyngeal surgery can be safely performed even in patients who have previously undergone esophageal cancer surgery, although careful monitoring remains necessary.

Clones harboring cancer driver mutations can expand in normal tissues, known as somatic mosaicism, and can be influenced by age and environmental and germline factors. Somatic mosaicism in the blood predicts the risk of hematological malignancies; however, the relevance of somatic mosaicism to solid tumors remains unclear, in part because of limited sample availability. Lifestyle habits, including alcohol consumption and tobacco smoking, and pathogenic germline variants increase the risk of developing esophageal squamous cell carcinoma (ESCC). Because somatic mosaicism in the esophagus is known to be associated with aging and lifestyle habits and considering the contiguity of squamous epithelium from the esophagus to the oral cavity, we noninvasively collected buccal mucosa samples from patients with and without ESCC using swabs of different sizes and conducted deep error-corrected sequencing of 26 cancer driver genes to obtain comprehensive landscapes of tissue remodeling by driver-mutant clones. We found that the number of mutations increased with drinking, but only in individuals with germline risks. Moreover, across positively selected genes in the buccal mucosa, mutations increased with age and smoking regardless of germline risks, whereas drinking affected only those with germline risks. The buccal mucosa of patients with ESCC was extensively remodeled, and models predicting the presence of ESCC demonstrated high accuracy with smaller swab sizes, possibly because of their higher sensitivity in detecting small mutant clones. In conclusion, we showed that buccal mucosal remodeling reflects lifestyle and germline risks, as well as age, which might be exploited for noninvasive risk assessment of ESCC.

Tumor metabolism has emerged as a critical target in cancer therapy, revolutionizing our understanding of how cancer cells grow, survive, and respond to treatment. Historically, cancer research focused on genetic mutations driving tumorigenesis, but in recent decades, metabolic reprogramming has been recognized as a hallmark of cancer. The TP53 inducible glycolysis and apoptosis regulator, or TIGAR, affects a wide range of cellular and molecular processes and plays a key role in cancer cell metabolism by regulating the balance between glycolysis and antioxidant defense mechanisms. Cancer cells often exhibit a shift towards aerobic glycolysis (the Warburg effect), which allows rapid energy production and gives rise to biosynthetic intermediates for proliferation. By inhibiting glycolysis, TIGAR can reduce the proliferation rate of cancer cells, particularly in early-stage tumors or specific tissue types. This metabolic shift may limit the resources available for rapid cell division, thereby exerting a tumor-suppressive effect. However, this metabolic shift also leads to increased levels of reactive oxygen species (ROS), which can damage the cell if not properly managed. TIGAR helps protect cancer cells from excessive ROS by promoting the pentose phosphate pathway (PPP), which generates NADPH-a key molecule involved in antioxidant defense. Through its actions, TIGAR decreases the glycolytic flux while increasing the diversion of glucose-6-phosphate into the PPP. This reduces ROS levels and supports biosynthesis and cell survival by maintaining the balance of nucleotides and lipids. The role of TIGAR has been emerging as a prognostic and potential therapeutic target in different types of cancers. This review highlights the role of TIGAR in different types of cancer, evaluating its potential role as a diagnostic marker and a therapeutic target.

A computer-aided detection (CAD) system for early esophagus carcinoma identification during endoscopy with narrow-band imaging (NBI) was evaluated in a large-scale, prospective, tandem, randomized controlled trial to assess its effectiveness. The study was registered at the Chinese Clinical Trial Registry (ChiCTR2100050654, 2021/09/01). Involving 3400 patients were randomly assigned to either routine (routine-first) or CAD-assisted (CAD-first) NBI endoscopy, followed by the other procedure, with targeted biopsies taken at the end of the second examination. The primary outcome was the diagnosis of 1 or more neoplastic lesion of esophagus during the first examination. The CAD-first group demonstrated a significantly higher neoplastic lesion detection rate (3.12%) compared to the routine-first group (1.59%) with a relative detection ratio of 1.96 (P = 0.0047). Subgroup analysis revealed a higher detection rate in junior endoscopists using CAD-first, while no significant difference was observed for senior endoscopists. The CAD system significantly improved esophageal neoplasm detection, particularly benefiting junior endoscopists.

Oral potentially malignant disorders (OPMDs), such as oral lichen planus (OLP) and oral leukoplakia (OLK), are clinical conditions associated with the risk of developing oral squamous cell carcinoma; however, no standardized treatment guidelines exist. Mutations in specific genes, known as oral cancer driver gene mutations (ODGMs), are responsible for carcinogenesis. We aimed to analyze the ODGMs in OPMDs and investigate their clinical correlations. We investigated 41 cases of OPMDs, including OLP and OLK, and performed next-generation sequencing using a custom gene panel targeting whole exons of TP53, HRAS, PIK3CA, NOTCH1, CDKN2A, FBXW7, and BRAF. We detected ODGMs in four OLK cases and one OLP case. All ODGM-positive OLK cases were located in the tongue, a site associated with a higher risk of malignant transformation compared with those in other oral sites. Moreover, ODGMs were significantly associated with alcohol consumption. While there was a tendency for mutations to increase with higher grades, we found no significant correlation between the presence of ODGMs and oral epithelial dysplasia (OED) grade. Notably, in the case of OLP with ODGM, the lesion histopathologically developed OED during the follow-up period, indicating an increased risk of cancer development and that cases with identified ODGMs require early surgical excision. These findings suggest that ODGM analysis may predict the risk of cancer development in OPMDs that are difficult to diagnose using histopathological examination alone.

There is a currently an unmet need for non-invasive methods to predict the risk of esophageal squamous cell carcinoma (ESCC). Previously, we found that specific soft palate morphologies are strongly associated with increased ESCC risk. However, there is currently no artificial intelligence (AI) system that utilizes oral images for ESCC risk assessment. Here, we evaluated three AI models and three fine-tuning approaches with regard to their ESCC predictive power. Our dataset contained 539 cases, which were subdivided into 221 high-risk cases (2491 images) and 318 non-high-risk cases (2524 images). We used 480 cases (4295 images) for the training dataset, and the rest for validation. The Bilinear convolutional neural network (CNN) model (especially when pre-trained on fractal images) demonstrated diagnostic precision that was comparable to or better than other models for distinguishing between high-risk and non-high-risk groups. In addition, when tested with a small number of images containing soft palate data, the model showed high precision: the best AUC model had 0.91 (sensitivity 0.86, specificity 0.79). This study presents a significant advance in the development of an AI-based non-invasive screening tool for the identification of high-risk ESCC patients. The approach may be particularly suitable for institutes with limited medical imaging resources.

Esophageal cancer (EC) is one of the deadliest malignancies worldwide. Gynostemma pentaphyllum Thunb. Makino (GpM) has been used in traditional Chinese medicine as a treatment for tumors and hyperlipidemia. Nevertheless, the active components and underlying mechanisms of anti-EC effects of GpM remain elusive.

This study aims to determine the major active ingredients of GpM in the treatment of EC and to explore their molecular mechanisms by using network pharmacology, molecular docking, and in vitro experiments.

Firstly, active ingredients and potential targets of GpM, as well as targets of EC, were screened in relevant databases to construct a compound-target network and a protein-protein interaction (PPI) network that narrowed down the pool of ingredients and targets. This was followed by gene ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Next, molecular docking, ADME and toxicity risk prediction, cell viability assays, in vitro scratch assays, Transwell cell invasion assays, and Western blotting analysis were subsequently applied to validate the results of the network analysis.

The screening produced a total of 21 active ingredients and 167 ingredient-related targets for GpM, along with 2653 targets for EC. The PPI network analysis highlighted three targets of interest, namely AKT1, TP53, and VEGFA, and the compound-target network identified three possible active ingredients: quercetin, rhamnazin, and isofucosterol. GO and EKGG indicated that the mechanism of action might be related to the PI3K/AKT signaling pathway as well as the regulation of cell motility and cell migration. Molecular docking and pharmacokinetic analyses suggest that quercetin and isoprostanoid sterols may have therapeutic value and safety for EC. The in vitro experiments confirmed that GpM can inhibit EC cell proliferation, migration, and invasion and suppress PI3K and AKT phosphorylation.

Our findings indicate that GpM exerts its anti-tumor effect on EC by inhibiting EC cell migration and invasion via downregulation of the PI3K/AKT signaling pathway. Hence, we have reason to believe that GpM could be a promising candidate for the treatment of EC.

Circular RNA (circRNA) plays a significant role in esophagus squamous cell carcinoma (ESCC) progression. Nevertheless, circ-TTC17 roles in ESCC have not fully understood.

The levels of circ-TTC17, miR-145-5p and sirtuin 1 (SIRT1) were determined using qRT-PCR. ESCC cell functions were examined by CCK8 assay, flow cytometry, transwell assay and colony formation assay. The relative protein levels of autophagy marker and SIRT1 were determined by western blot (WB). The interactions among circ-TTC17, miR-145-5p, and SIRT1 were verified by dual-luciferase reporter assay and RIP assay.

circ-TTC17 was overexpressed and miR-145-5p was underexpressed in ESCC. circ-TTC17 knockdown restrained ESCC cell proliferation and metastasis, while enhance apoptosis and autophagy-mediated radiosensitivity. Circ-TTC17 could sponge miR-145-5p, and its inhibitor reversed the inhibitory effect of circ-TTC17 knockdown on ESCC cell progression. Additionally, SIRT1 was targeted by miR-145-5p, and SIRT1 overexpression abolished miR-145-5p-mediated the suppressive effect on ESCC cell progression. Also, circ-TTC17 interference reduced ESCC tumor growth via miR-145-5p/SIRT1 axis.

circ-TTC17 promoted ESCC cell growth, metastasis and inhibited autophagy-mediated radiosensitivity by miR-145-5p/SIRT1 axis.

Esophageal cancer (EC) is a malignancy with a poor prognosis and a five-year survival rate of less than 20%. It is the ninth most frequent cancer globally and the sixth leading cause of cancer-related deaths. The incidence of EC has been found to vary significantly by geography, indicating the importance of environmental and lifestyle factors along with genetic factors in the onset of the disease. In this work, we investigated mycotoxin exposure in a case-control study from the Arsi-Bale districts of Oromia regional state in Ethiopia, where there is a high incidence of EC while alcohol and tobacco use - two established risk factors for EC - are very rare.

Internal exposure to 39 mycotoxins and metabolites was assessed by liquid chromatography-tandem mass spectrometry in plasma samples of EC cases (n = 166) and location-matched healthy controls (n = 166) who shared similar dietary sources. Demographic and lifestyle data were collected using structured questionnaires. Principal Component Analysis and machine learning models were used to identify the most relevant demographic, lifestyle, and mycotoxin (co-)exposure variables associated with EC. Multivariate binary logistic regression analysis was used to assess EC risk.

Evidence of mycotoxin exposure was observed in all plasma samples, with 10 different mycotoxins being detected in samples from EC cases, while only 6 different mycotoxins were detected in samples from healthy controls. Ochratoxin A was detected in plasma from all cases and controls, while tenuazonic acid was detected in plasma of 145 (87.3%) cases and 71 (42.8%) controls. Using multivariable logistic regression analysis, exposure to tenuazonic acid (AOR = 1.88 [95% CI: 1.68-2.11]) and to multiple mycotoxins (AOR = 2.54 [95% CI: 2.10-3.07]) were positively associated with EC.

All cases and controls were exposed to at least one mycotoxin. Cases were exposed to a statistically significantly higher number of mycotoxins than controls. Exposure to tenuazonic acid and to multiple mycotoxins were associated with increased risk of EC in the study population. Although aflatoxin B1-lysine and the ratio of sphinganine to sphingosine (as a biomarker of effect to fumonisin exposure) were not assessed in this study, our result emphasizes the need to characterize the effect of mycotoxin co-exposure as part of the exposome and include it in risk assessment, since the current mycotoxin safety levels do not consider the additive or synergistic effects of mycotoxin co-exposure. Moreover, a prospective study design with regular sampling should be considered in this high incidence area of EC in Ethiopia to obtain conclusive results on the role of mycotoxin exposure in the onset and development of the disease.

Esophageal squamous cell carcinoma (ESCC) is among the most prevalent forms of esophageal cancer globally, with a particularly high incidence in developing countries. Notably, Asia accounts for approximately 80% of global esophageal cancer cases, with China alone contributing to 54% of this burden. The primary treatment modality for ESCC remains esophagectomy, primarily employed for locally advanced disease, often in combination with chemotherapy and radiotherapy for advanced-stage cases. Despite significant advancements in surgical techniques and the advent of precision medicine, which has facilitated the development of targeted and immune-based therapies, critical challenges persist, including suboptimal therapeutic efficacy and the emergence of drug resistance. A comprehensive understanding of the current treatment landscape for ESCC is essential to overcoming these barriers and improving patient outcomes.

Understanding the stepwise progression of esophageal squamous cell carcinoma (ESCC) is crucial for developing customized strategies for early detection and optimal clinical management. Herein, we aimed to unravel the transcriptional and immunologic alterations occurring during malignant transformation and identify clinically significant biomarkers of ESCC.

Digital spatial profiling (DSP) was performed on 11 patients with early-stage ESCC (pT1) to explore the transcriptional alterations in epithelial, immune cell, and non-immune cell stromal compartments across regions of distinct histology, including normal tissues, low- and high-grade dysplasia, and cancerous tissues. Furthermore, single-cell spatial transcriptomics was performed using the CosMx Spatial Molecular Imaging (SMI) system on 4 additional patients with pT1 ESCC. Immunohistochemical (IHC) analysis was performed on consecutive histological sections of 20 pT1 ESCCs. Additionally, public bulk and single-cell RNA-sequencing (scRNA-seq) datasets were analyzed, and in vitro and in vivo functional studies were conducted.

Spatial transcriptional reprogramming and dynamic cell signaling pathways that determined ESCC progression were delineated. Increased infiltration of macrophages from normal tissues through dysplasia to cancerous tissues occurred. Macrophage subtypes were characterized using the scRNA-seq dataset. Cell-cell communication analysis of scRNA-seq and SMI data indicated that the migration inhibitory factor (MIF)-CD74 axis may exhibit pro-tumor interactions between macrophages and epithelial cells. DSP, SMI, and IHC data demonstrated that DTX3L expression in epithelial cells and BST2 expression in stromal cells increased gradually with ESCC progression. Functional studies demonstrated that DTX3L or BST2 knockdown inhibited ESCC proliferation and migration and decreased M2 polarization of tumor-associated macrophages.

Spatial profiling comprehensively characterized the molecular and immunological hallmarks from normal tissue to ESCC, guiding the way to a deeper understanding of the tumorigenesis and progression of this disease and contributing to the prevention of ESCC. Within this exploration, we uncovered biomarkers that exhibit a robust correlation with ESCC progression, offering potential new avenues for insightful therapeutic approaches.

Gastric and esophageal cancers, the predominant forms of upper gastrointestinal malignancies, contribute significantly to global cancer mortality. Routine detection methods, including medical imaging, endoscopic examination, and pathological biopsy, often suffer from drawbacks such as low sensitivity and laborious and complex procedures. Raman spectroscopy is a non-invasive and label-free optical technique that provides highly sensitive biomolecular information to facilitate effective tumor identification. In this work, we report the use of fiber-optic Raman spectroscopy for the accurate and rapid diagnosis of gastric and esophageal cancers. Using a database of 14,000 spectra from 140 ex vivo tissue pieces of both tumor and normal tissue samples, we compare the random forest (RF) and our established Euclidean distance Raman spectroscopy (EDRS) model. The RF analysis achieves a sensitivity of 85.23% and an accuracy of 83.05% in diagnosing gastric tumors. The EDRS algorithm with improved diagnostic transparency further increases the sensitivity to 92.86% and accuracy to 89.29%. When these diagnostic protocols are extended to esophageal tumors, the RF and EDRS models achieve accuracies of 71.27% and 93.18%, respectively. Finally, we demonstrate that fewer than 20 spectra are sufficient to achieve good Raman diagnostic accuracy for both tumor tissues. This optimizes the balance between acquisition time and diagnostic performance. Our work, although conducted on ex vivo tissue models, offers valuable insights for in vivo in situ endoscopic Raman diagnosis of gastric and esophageal cancer lesions in the future. Our study provides a robust, rapid, and convenient method as a new paradigm in in vivo endoscopic medical diagnostics that integrates spectroscopic techniques and a Raman probe for detecting upper gastrointestinal malignancies.

Oesophageal cancer is a public health concern in Ethiopia. Identifying the incidence and demographic profile of the two histological subtypes: oesophageal squamous cell carcinoma (ESCC) and oesophageal adenocarcinoma (EAC) are the key steps in recognizing the disease burden and potential aetiopathological associations.

The aim of this study is to identify the age and gender-specific incidence patterns of the most common subtype of oesophageal cancer in a high-incidence area of Ethiopia.

A retrospective cross-sectional study from a high-incidence oesophageal cancer district in Ethiopia identified 630 cases from the pathology registry of nine hospitals. The patient records were carefully reviewed and data on age, gender, tumour location and histological types was systematically compiled. The patient data were retrieved and descriptive statistics were used to generate results.

ESCC subtype, accounted for constituting 500 (79.437%) cases. A gender disparity was observed, with 62.80% of cases occurring in females and 37.20% in males. This distribution of higher female ESCC incidences aligns with previous findings indicating a regional consistency and probable aetiological factor. Furthermore, ESCC incidence peaked at 40-50 years in females, highlighting an age-related incidence trend. EAC was observed in 67 (51.5%) females and 63 (48.5%) males showing similar prevalence. Spatial analysis revealed that the majority of ESCC cases were located in the lower oesophagus, followed by the middle part, with fewer instances in the upper oesophagus.

This study from Ethiopia identified ESCC as the predominant subtype, with a marked female predominance and age-related gender disparities. EAC with a lesser proportion identified with consistent spatial distribution patterns in both genders provide valuable insights into the epidemiological landscape of this disease. These findings emphasize the urgency of targeted research to uncover the underlying factors.

Genomics studies have detected numerous genetic alterations in esophageal squamous cell carcinoma (ESCC). However, the functions of these mutations largely remain elusive, partially due to a lack of feasible animal models. Here, we report a convenient platform with CRISPR-Cas9-mediated introduction of genetic alterations and orthotopic transplantation to generate a series of primary ESCC models in mice. With this platform, we validate multiple frequently mutated genes, including EP300, FAT1/2/4, KMT2D, NOTCH2, and TGFBR2, as tumor-suppressor genes in ESCC. Among them, TGFBR2 loss dramatically promotes tumorigenesis and multi-organ metastasis. Paradoxically, TGFBR2 deficiency leads to Smad3 activation, and disruption of Smad3 partially restrains the progression of Tgfbr2-mutated tumors. Drug screening with tumor organoids identifies that pinaverium bromide represses Smad3 activity and restrains Tgfbr2-deficient ESCC. Our studies provide a highly efficient platform to investigate the in vivo functions of ESCC-associated mutations and develop potential treatments for this miserable malignancy.

Esophageal squamous cell carcinoma (ESCC) is an aggressive malignant neoplasm, and up to now, the role of long non-coding RNA (lncRNA) AP001885.4 in cancer, including ESCC, is absolutely unclear. The GEPIA database was applied to identify differentially expressed and prognosis-associated genes in esophageal cancer (ESCA). CCK-8, colony formation, Western blot, and qRT-PCR methods were harnessed to investigate the role and mechanism of AP001885.4 in esophageal carcinogenesis. By analyzing TCGA data in the GEPIA database, two lncRNAs were selected. AP001885.4 was overexpressed and positively associated with the unfavorable outcome of ESCC patients, and LINC001786 was under-expressed and negatively linked with the poor prognosis. Knockdown of AP001885.4 suppressed the proliferation and colony formation of ESCC cells. Importantly, the silence of AP001885.4 downregulated c-myc. Mechanically, the knockdown of AP001885.4 reduced METTL3 expression and m6A modification in c-myc mRNA, and METTL3 positively regulated c-myc. Furthermore, the knockdown of AP001885.4 diminished histone lactylation and NF-κB (p65) expression, and the protein lactylation inhibitors (2-DG, 2-deoxy-D-glucose and oxamate) and the NF-κB inhibitor (JSH-23) also lessened c-myc expression. Consequently, our findings suggested that AP001885.4 promoted the proliferation of esophageal squamous cell carcinoma cells by histone lactylation- and NF-κB (p65)-dependent transcription activation and METTL3-mediated mRNA stability of c-myc.

The tumor microenvironment (TME) is intricately associated with cancer progression, characterized by dynamic interactions among various cellular and molecular components that significantly impact the carcinogenic process. Notably, neutrophils play a crucial dual role in regulating this complex environment. These cells oscillate between promoting and inhibiting tumor activity, responding to a multitude of cytokines, chemokines, and tumor-derived factors. This response modulates immune reactions and affects the proliferation, metastasis, and angiogenesis of cancer cells. A significant aspect of their influence is their interaction with the endoplasmic reticulum (ER) stress responses in cancer cells, markedly altering tumor immunodynamics by modulating the phenotypic plasticity and functionality of neutrophils. Furthermore, neutrophil extracellular traps (NETs) exert a pivotal influence in the progression of malignancies by enhancing inflammation, metastasis, immune suppression, and thrombosis, thereby exacerbating the disease. In the realm of immunotherapy, checkpoint inhibitors targeting PD-L1/PD-1 and CTLA-4 among others have underscored the significant role of neutrophils in enhancing therapeutic responses. Recent research has highlighted the potential of using neutrophils for targeted drug delivery through nanoparticle systems, which precisely control drug release and significantly enhance antitumor efficacy. This review thoroughly examines the diverse functions of neutrophils in cancer treatment, emphasizing their potential in regulating immune therapy responses and as drug delivery carriers, offering innovative perspectives and profound implications for the development of targeted diagnostic and therapeutic strategies in oncology.

To explore the feasibility and application value of texture analysis based on computed tomography (CT) for predicting the differentiation of esophageal squamous cell carcinoma (ESCC). Patients diagnosed with ESCC who underwent chest contrast-enhanced CT before treatment were selected. Based on the pathological results, the patients were stratified into poorly differentiated and moderately well-differentiated groups. FireVoxel software was used to analyze the region of interest based on venous phase CT images. Texture parameters including the mean, median, standard deviation (SD), inhomogeneity, skewness, kurtosis, and entropy were obtained automatically. Differences in the texture parameters and their relationship with the degree of differentiation between the 2 groups were analyzed. The value of CT texture parameters in identifying poor differentiation and moderate-well differentiation of esophageal cancer was analyzed using the ROC curve. A total of 48 patients with ESCC were included, including 24 patients in the poorly differentiated group and 24 patients in the moderate-well-differentiated group. There were negative correlations between SD, inhomogeneity, entropy, and the degree of differentiation of esophageal cancer (P < .05). The correlation of inhomogeneity was the highest (r = -0.505, P < .001). SD, inhomogeneity, and entropy could effectively distinguish between the poorly and moderately well-differentiated groups, with statistically significant differences between the 2 groups (P < .05). The best critical values for SD, inhomogeneity, and entropy were 17.538, 0.017, and 3.917, respectively. The areas under the ROC curve were 0.793, 0.792, and 0.729, respectively, with the SD and inhomogeneity being the best. The application of texture analysis on venous phase CT images holds promise as a method for forecasting the degree of differentiation in esophageal cancers, which could significantly contribute to the preoperative noninvasive evaluation of tumor differentiation.

Esophageal cancer is one of the leading causes of cancer-related deaths worldwide. The identification of residual tumor tissues in the surgical margin of esophageal cancer is essential for the treatment and prognosis of cancer patients. But the current diagnostic methods, either pathological frozen section or paraffin section examination, are laborious, time-consuming, and inconvenient. Raman spectroscopy is a label-free and non-invasive analytical technique that provides molecular information with high specificity. Here, we report the use of a portable Raman system and machine learning algorithms to achieve accurate diagnosis of esophageal tumor tissue in surgically resected specimens. We tested five machine learning-based classification methods, including k-Nearest Neighbors, Adaptive Boosting, Random Forest, Principal Component Analysis-Linear Discriminant Analysis, and Support Vector Machine (SVM). Among them, SVM shows the highest accuracy (88.61 %) in classifying the esophageal tumor and normal tissues. The portable Raman system demonstrates robust measurements with an acceptable focal plane shift of up to 3 mm, which enables large-area Raman mapping on resected tissues. Based on this, we finally achieve successful Raman visualization of tumor boundaries on surgical margin specimens, and the Raman measurement time is less than 5 min. This work provides a robust, convenient, accurate, and cost-effective tool for the diagnosis of esophageal cancer tumors, advancing toward Raman-based clinical intraoperative applications.

Change in mucosal microbiome is associated with various types of cancer in digestive tract. We hypothesized that microbial communities in the esophageal endoscopic wash fluids reflects resident flora in esophageal mucosa that is associated with esophageal carcinoma (EC) risk and/or directly correlates microbiome derived from EC tumor tissue. Studying microbial communities in esophageal endoscopic wash samples would be therefore useful to predict the incidence or risk of EC. We examined microbial communities of the endoscopic wash samples from 45 primary EC and 20 respective non-EC controls using 16S rRNA V3-V4 amplicon sequencing. The result was also compared with microbial communities in matched endoscopic biopsies from EC and non-cancerous esophageal mucosa. Compared with non-EC controls, 6 discriminative bacterial genera were detected in EC patients. Among them, relative abundance ratio of Prevotella and Shuttlewarthia, as well as decrease of genus Prevotella presented good prognostic performance to discriminate EC from controls (area under curve, 0.86, 0.82, respectively). Multivariate analysis showed occurrence of EC was an independent factor associated with decrease of this bacteria. Abundance of genus Prevotella in the esophageal endoscopic wash samples was significantly correlated with the abundance of this bacteria in the matched endoscopic biopsies from non-cancerous esophageal mucosa but not in the EC tissues. Our findings suggest that microbiome composition in the esophageal endoscopic wash samples reflects resident flora in the esophagus and significantly correlates with the incidence of EC.

Esophageal cancer ranks the seventh in cancer incidence and the sixth in cancer death. Esophageal squamous cell carcinoma (ESCC) accounts for approximately 90% of the total cases of esophageal cancer. Chemotherapy is the most effective drug-based method for treatment of esophageal cancer. However, severe side effects of traditional chemotherapy limit its treatment efficacy. Targeted chemotherapy can deliver chemotherapeutic drugs to cancer cells and specifically kill these cells with reduced side effects. In the work, the bivalent aptamer-DNA carrier (BAD) was designed by using an ESCC cell-specific aptamer as the recognition molecule and a GC base-rich DNA sequence as the drug carrier. With doxorubicin (Dox) as chemotherapeutic drugs, the bivalent aptamer-DNA-Dox conjugate (BADD) was constructed for targeted killing of ESCC cells. Firstly, the truncated A2(35) aptamer with a retained binding ability was obtained through optimization of an intact A2(80) aptamer and was used to fuse with DNA carrier sequences for constructing the BAD through simple DNA hybridization. The results of gel electrophoresis and flow cytometry analysis showed that the BAD was successfully constructed and had a stronger binding affinity than monovalent A2(35). Then, the BAD was loaded with Dox drugs to construct the BADD through noncovalent intercalation. The results of fluorescence spectra and flow cytometry assays showed that the BADD was successfully constructed and can bind to target cells strongly. Confocal imaging further displayed that the BADD can be specifically internalized into target cells and release Dox. The results of CCK-8 assays, Calcein AM/PI staining, and wound healing assays demonstrated that the BADD can specifically kill target cells, but not control cells. Our results demonstrate that the developed BADD can specifically deliver doxorubicin to target ESCC cells and selectively kill these cells, offering a potentially effective strategy for targeted chemotherapy of ESCC.

To assess the efficacy of consensus cluster analysis based on CT radiomics in stratifying risk and predicting postoperative progression-free survival (PFS) in patients diagnosed with esophageal squamous cell carcinoma (ESC).

We conducted a retrospective study involving 546 patients diagnosed with ESC between January 2016 and March 2021. All patients underwent preoperative enhanced CT examinations. From the enhanced CT images, radiomics features were extracted, and a consensus clustering algorithm was applied to group the patients based on these features. Statistical analysis was performed to examine the relationship between the clustering results and gene protein expression, histopathological features, and patients' 3-year PFS. We applied the Kruskal-Wallis test for continuous data, chi-square or Fisher's exact tests for categorical data, and the log-rank test for PFS.

This study identified four groups: Cluster 1 (n = 100, 18.3%), Cluster 2 (n = 197, 36.1%), Cluster 3 (n = 205, 37.5%), and Cluster 4 (n = 44, 8.1%). The cancer gene Breast Cancer Susceptibility Gene 1 (BRCA1) was most highly expressed in Cluster 4 (75%), showing significant differences between the four subtypes with a P-value of 0.035. The expression of programmed death-1 (PD-1) was highest in Cluster 1 (51%), with a P-value of 0.022. Vascular invasion occurred most frequently in Cluster 2 (28.9%), with a P-value of 0.022. The majority of patients with stage T3-4 were in Cluster 2 (67%), with a P-value of 0.003. Kaplan-Meier survival analysis revealed significant differences in PFS between the four groups (P = 0.013). Among them, patients in Cluster 1 had the best prognosis, while those in Cluster 2 had the worst.

This study highlights the effectiveness of consensus clustering analysis based on enhanced CT radiomics features in identifying associations between radiomics features, histopathological characteristics, and prognosis in different clusters. These findings provide valuable insights for clinicians in accurately and effectively evaluating the prognosis of esophageal cancer.

Gastrointestinal cancer is the most fatal cancer worldwide. The etiology of gastrointestinal cancer has yet to be fully characterized. Alcohol consumption, obesity, tobacco, Helicobacter pylori and gastrointestinal disorders, including gastroesophageal reflux disease, gastric ulcer, colon polyps and non-alcoholic fatty liver disease are among the several risks factors for gastrointestinal cancers. Phycocyanin which is abundant in Spirulina. Phycocyanin, a member of phycobiliprotein family with intense blue color, is an anti-diabetic, neuroprotective, anti-oxidative, anti-inflammatory, and anticancer compound. Evidence exists supporting that phycocyanin has antitumor effects, exerting its pharmacological effects by targeting a variety of cellular and molecular processes, i.e., apoptosis, cell-cycle arrest, migration and Wnt/β-catenin signaling. Phycocyanin has also been applied in treatment of several gastrointestinal disorders such as, gastric ulcer, ulcerative colitis and fatty liver that is known as a risk factor for progression to cancer. Herein, we summarize various cellular and molecular pathways that are affected by phycocyanin, its efficacy upon combined drug treatment, and the potential for nanotechnology in its gastrointestinal cancer therapy.

Describe the accurate locations of lymph node recurrence (LNR) of Chinese patients with postoperative thoracic esophageal squamous cell carcinoma (ESCC) is essential for determining the need for further surveillance protocols and treatments. The authors aimed to evaluate the patterns of postoperative ESCC and its current risk stratification with LNR.

This population-based cohort study included a retrospective review of the medical records and image material of patients with ESCC who underwent LNR after radical surgery between January 2013 and September 2022, with a median follow-up time of 5.71 years. Clinical features were extracted from these records, and survival analysis was performed. The primary endpoint was the accurate location and range of LNR according to the nomenclature of the Japanese Society for Esophageal Diseases. The second endpoints was to explore the related factors of recurrence range and overall survival.

A total of 3268 lymph node regions were recurrence from 1129 patients, with a mean of 2.89 regions per patient. No.104, 106, and 107 was the most common recurrence of thoracic ESCC with an LNR rate higher than 15%. In upper thoracic ESCC, No.105 was a common recurrence site and abdominal LNR was rare. In lower thoracic ESCC, retroperitoneal lymph node was a unique regions (15.4%). Anastomotic recurrence is an important recurrence pattern in patients with postoperative esophageal cancer, with an incidence of 24.5%. Rates of LNR in range of lymph node dissection was low (13.9%). The median time of LRT was 20.0 (1.5-184.0) months. High range of recurrence was associated with significantly poorer OS in patients. Multiple linear regression analysis identified demonstrated N stage, tumor differentiation, adjuvant radiotherapy, and total lymph nodes removed were association with recurrence range for patients.

Supraclavicular and upper mediastinums lymph nodes were common recurrence site for ESCC patients, and careful initial staging and surveillance are needed. Thorough lymph node dissection may reduce the range of regional recurrence.

Targeting DNA damage response (DDR) pathway is a cutting-edge strategy. It has been reported that Schlafen-11 (SLFN11) contributes to increase chemosensitivity by participating in DDR. However, the detailed mechanism is unclear.

To investigate the role of SLFN11 in DDR and the application of synthetic lethal in esophageal cancer with SLFN11 defects.

To reach the purpose, eight esophageal squamous carcinoma cell lines, 142 esophageal dysplasia (ED) and 1007 primary esophageal squamous cell carcinoma (ESCC) samples and various techniques were utilized, including methylation-specific polymerase chain reaction, CRISPR/Cas9 technique, Western blot, colony formation assay, and xenograft mouse model.

Methylation of SLFN11 was exhibited in 9.15% of (13/142) ED and 25.62% of primary (258/1007) ESCC cases, and its expression was regulated by promoter region methylation. SLFN11 methylation was significantly associated with tumor differentiation and tumor size (both P < 0.05). However, no significant associations were observed between promoter region methylation and age, gender, smoking, alcohol consumption, TNM stage, or lymph node metastasis. Utilizing DNA damaged model induced by low dose cisplatin, SLFN11 was found to activate non-homologous end-joining and ATR/CHK1 signaling pathways, while inhibiting the ATM/CHK2 signaling pathway. Epigenetic silencing of SLFN11 was found to sensitize the ESCC cells to ATM inhibitor (AZD0156), both in vitro and in vivo.

SLFN11 is frequently methylated in human ESCC. Methylation of SLFN11 is sensitive marker of ATM inhibitor in ESCC.

Basal progenitor cells are crucial for maintaining foregut (the esophagus and forestomach) homeostasis. When their function is dysregulated, it can promote inflammation and tumorigenesis. However, the mechanisms underlying these processes remain largely unclear. Here, we employ genetic mouse models to reveal that Jag1/2 regulate esophageal homeostasis and foregut tumorigenesis by modulating the function of basal progenitor cells. Deletion of Jag1/2 in mice disrupts esophageal and forestomach epithelial homeostasis. Mechanistically, Jag1/2 deficiency impairs activation of Notch signaling, leading to reduced squamous epithelial differentiation and expansion of basal progenitor cells. Moreover, Jag1/2 deficiency exacerbates the deoxycholic acid (DCA)-induced squamous epithelial injury and accelerates the initiation of squamous cell carcinoma (SCC) in the forestomach. Importantly, expression levels of JAG1/2 are lower in the early stages of human esophageal squamous cell carcinoma (ESCC) carcinogenesis. Collectively, our study demonstrates that Jag1/2 are important for maintaining esophageal and forestomach homeostasis and the onset of foregut SCC.

Rat model of N-nitrosomethylbenzylamine (NMBzA)-induced esophageal squamous cell carcinoma (ESCC) is routinely used to study ESCC initiation, progression and new therapeutic strategies. However, the model is time-consuming and malignant tumor incidences are low. Here, we report the usage of multi-kinase inhibitor sorafenib as a tumor promoter to establish an efficient two-stage NMBzA-induced rat ESCC carcinogenesis model, resulting in increments of tumor incidences and shortened tumor formation times. By establishing the model and applying whole-genome sequencing, we discover that benign papillomas and malignant ESCCs harbor most of the "driver" events found in rat ESCCs (e.g. recurrent mutations in Ras family, the Hippo and Notch pathways and histone modifier genes) and the mutational landscapes of rat and human ESCCs overlap extensively. We generate tumor cell lines derived from NMBzA-induced papillomas and ESCCs, showing that papilloma cells retain more characteristics of normal epithelial cells than carcinoma cells, especially their exhibitions of normal rat cell karyotypes and inabilities of forming tumors in immunodeficient mice. Three-dimensional (3-D) organoid cultures and single cell RNA sequencing (scRNA-seq) indicate that, when compared to control- and papilloma-organoids, ESCC-organoids display salient abnormalities at tissue and single-cell levels. Multi-omic analyses indicate that NMBzA-induced rat ESCCs are accompanied by progressive hyperactivations of the FAT-Hippo-YAP1 axis and siRNA or inhibitors of YAP1 block the growth of rat ESCCs. Taken together, these studies provide a framework of using an effective rat ESCC model to investigate multilevel functional genomics of ESCC carcinogenesis, which justify targeting YAP1 as a therapeutic strategy for ESCC.

Syndecan-binding protein (SDCBP) was reported to stimulate the advancement of esophageal squamous cell carcinoma (ESCC) and could potentially be a target for ESCC treatment. There is a growing corpus of research on the anti-tumor effects of iron chelators; however, very few studies have addressed the involvement of dexrazoxane in cancer. In this study, structure-based virtual screening was employed to select drugs targeting SDCBP from the Food and Drug Administration (FDA)-approved drug databases. The sepharose 4B beads pull-down assay revealed that dexrazoxane targeted SDCBP by interacting with its PDZ1 domain. Additionally, dexrazoxane inhibited ESCC cell proliferation and anchorage-independent colony formation via SDCBP. ESCC cell apoptosis and G2 phase arrest were induced as measured by the flow cytometry assay. Subsequent research revealed that dexrazoxane attenuated the binding ability between SDCBP and EGFR in an immunoprecipitation assay. Furthermore, dexrazoxane impaired EGFR membrane localization and inactivated the EGFR/PI3K/Akt pathway. In vivo, xenograft mouse experiments indicated that dexrazoxane suppressed ESCC tumor growth. These data indicate that dexrazoxane might be established as a potential anti-cancer agent in ESCC by targeting SDCBP.