RESUMEN

N6-Methyladenosine (m6A) modification and its regulators play critical roles in human cancers, but their functions and regulatory mechanisms in adenocarcinoma of the esophagogastric junction (AEG) remain unclear. Here, we identified that IGF2BP3 is the most significantly up-regulated m6A regulator in AEG tumors versus paired normal adjacent tissues from the expression profile of m6A regulators in a large cohort of AEG patients. Silencing IGF2BP3 inhibits AEG progression in vitro and in vivo. By profiling transcriptome-wide targets of IGF2BP3 and the m6A methylome in AEG, we found that IGF2BP3-mediated stabilization and enhanced expression of m6A-modified targets, including targets of the cell cycle pathway, such as CDC25A, CDK4, and E2F1, are critical for AEG progression. Mechanistically, the increased m6A modification of CDC25A accelerates the G1-S transition. Clinically, up-regulated IGF2BP3, METTL3, and CDC25A show a strong positive correlation in TCGA pan-cancer, including AEG. In conclusion, our study highlights the role of post-transcriptional regulation in modulating AEG tumor progression and elucidates the functional importance of the m6A/IGF2BP3/CDC25A axis in AEG cells.

Asunto(s)

Adenocarcinoma , Adenosina , Ciclo Celular , Neoplasias Esofágicas , Proteínas de Unión al ARN , Fosfatasas cdc25 , Humanos , Fosfatasas cdc25/metabolismo , Fosfatasas cdc25/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenosina/análogos & derivados , Adenosina/metabolismo , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Animales , Unión Esofagogástrica/metabolismo , Unión Esofagogástrica/patología , Línea Celular Tumoral , Ratones , Regulación Neoplásica de la Expresión Génica , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Ratones Desnudos , Metiltransferasas/metabolismo , Metiltransferasas/genética

RESUMEN

BACKGROUND: Genome instability (GI) is a hallmark of esophageal squamous cell carcinoma (ESCC) while factors affecting GI remain unclear. METHODS: Here, we aimed to characterize genomic events representing specific mechanisms of GI based on 201 ESCC samples and validated our findings at the patient, single-cell and cancer cell-line levels, including a newly generated multi-omics dataset of the trial NCT04006041. RESULTS: A two-gene (AHNAK and AHNAK2) mutation signature was identified to define the "AHNAK1/2-mutant" cancer subtype. Single-cell-assisted multi-omics analysis showed that this subtype had a higher neoantigen load, active antigen presentation, and proficient CD8 + T cell infiltrations, which were validated at pan-cancer levels. Mechanistically, AHNAK1/2-mutant ESCC was characterized by impaired response of TGF-ß and the inefficient alternative end-join repair (Alt-EJ) that might promote GI. Knockdown of AHNAK in ESCC cell lines resulted in more Alt-EJ events and increased sensitivities to cisplatin. Furthermore, this two-gene signature accurately predicted better responses to DNA-damaging therapy in various clinical settings (HR ≈ 0.25). The two-gene signature predicted higher pCR rates in ESCCs receiving neoadjuvant immunotherapy-involved treatment. Finally, a molecular classification scheme was built and outperformed established molecular typing models in the prognosis stratification of ESCC patients. CONCLUSION: Our study extended our understanding of the AHNAK family in promoting GI and selecting treatment responders of ESCC.

Asunto(s)

Neoplasias Esofágicas , Inmunoterapia , Proteínas de la Membrana , Proteínas de Neoplasias , Factor de Crecimiento Transformador beta , Animales , Femenino , Humanos , Masculino , Ratones , Línea Celular Tumoral , Proteínas del Citoesqueleto , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/inmunología , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/terapia , Carcinoma de Células Escamosas de Esófago/inmunología , Carcinoma de Células Escamosas de Esófago/patología , Inmunoterapia/métodos , Proteínas de la Membrana/genética , Mutación , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Pronóstico , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo

RESUMEN

Esophageal cancer is a poor prognosis cancer characterized by intrinsic or acquired resistance to chemotherapeutic agents. The primary determinants of treatment failure are unknown. Expression of an anti-viral protein, myxovirus resistance protein A (MxA) is de-regulated in many cancers, including esophageal cancer, and its activity has been linked to apoptosis. This study has assessed whether MxA expression can influence the response of esophageal cancer cells to the chemotherapeutic agents 5-fluorouracil (5-FU) or oxaliplatin. MxA protein was differentially expressed in a panel of five esophageal cancer cell lines. KYSE450 and KYSE140 cells did not express MxA and were apoptosis incompetent. FLO-1, KYSE270, and OE21 cells expressed MxA, were more drug-sensitive and were apoptosis competent. MxA was artificially overexpressed in cell lines with no endogenous expression (KYSE450 and KYSE140). This increased the resistance of KYSE450 but not KYSE140 cells. Both cell lines remained apoptosis incompetent. We then evaluated siRNA knockdown of MxA in FLO-1 cells and CRISPR knockout in OE21 cells. Knockdown of MxA significantly increased drug sensitivity and caspase-3 activation in FLO-1 cells. OE21-MX1KO cells were also more drug-sensitive, but in contrast to FLO-1 cells, caspase-3 activation was reduced. Collectively these data indicate that MxA can promote resistance to chemotherapy, but this does not always correspond with effects on apoptosis. Effects on apoptosis are cell line specific, suggesting that other co-operating pathways determine the overall impact of MxA. Importantly, in cancer cells that overexpress the protein, drug sensitivity can be improved by interfering with MxA.

Asunto(s)

Antineoplásicos , Apoptosis , Resistencia a Antineoplásicos , Neoplasias Esofágicas , Fluorouracilo , Proteínas de Resistencia a Mixovirus , Humanos , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proteínas de Resistencia a Mixovirus/genética , Proteínas de Resistencia a Mixovirus/metabolismo , Resistencia a Antineoplásicos/genética , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Oxaliplatino/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos

RESUMEN

OBJECTIVES: Esophageal squamous cell carcinoma (ESCC) is a malignant tumor with high incidence and mortality rates worldwide. This study aimed to investigate the correlation between LINC-PINT polymorphisms and ESCC risk in the Hainan Han population. METHODS: A total of 391 patients with ESCC and 452 healthy controls were enrolled to evaluate the effect of LINC-PINT SNPs (single nucleotide polymorphisms) on ESCC susceptibility. Associations were evaluated by calculating odds ratios (OR) and 95% confidence intervals (CIs). Multifactor dimensionality reduction analysis was performed to explore the association between SNP-SNP interactions and ESCC susceptibility. We further determined the correlation between clinical indicators and SNP in patients with ESCC. RESULTS: Our study showed that rs157916 (OR 0.63, p = 0.011) and rs157928 (OR 0.80, p = 0.021) were associated with a decreased risk of ESCC. Stratified analysis indicated that rs157916 could decrease the risk of ESCC in people aged >64 years, in males, and non-drinkers (OR 0.58, p = 0.042; OR 0.58, p = 0.010; OR 0.62, p = 0.025, respectively). Rs16873842 was related to a decreased risk of ESCC in males (OR 0.70, p = 0.015). Rs7801029 was associated with ESCC risk in females (OR 0.39, p = 0.033) and non-drinkers (OR 0.68, p = 0.040). Rs7781295 decreased the ESCC risk in smokers (OR 0.58, p = 0.046) and drinkers (OR 0.58, p = 0.046). In addition, rs157928 played a protective role in ESCC risk in females (OR 0.39, p = 0.033) and non-smokers (OR 0.32, p = 0.006). Additionally, the best predictive model for ESCC was a combination of rs157916, rs16873842, rs7801029, rs7781295, rs28662387, and rs157928. CONCLUSION: Our study revealed that LINC-PINT polymorphisms were associated with ESCC risk.

Asunto(s)

Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , ARN Largo no Codificante , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios de Casos y Controles , China/epidemiología , Neoplasias Esofágicas/etnología , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago/etnología , Carcinoma de Células Escamosas de Esófago/genética , Factores de Riesgo , ARN Largo no Codificante/genética , Pueblos del Este de Asia/genética , Etnicidad/genética

RESUMEN

N6-methyladenosine (m6A) methylation, as a new regulatory mechanism, has been reported to be involved in diverse biological processes in recent years. Wilms tumor 1-associated protein (WTAP), as the key member of m6A methylation, has been proven to participate in tumorigenesis. Here, we studied the expression of WTAP and its potential mechanism involved in the development of esophageal squamous cell carcinoma (ESCC). We detected the expression of WTAP and its correlation with clinicopathological features, and we determined the function of WTAP on ESCC cells by MTS assay, colony formation, scratch wound healing assay, Transwell assay, and subcutaneous xenograft assay. We used mRNA sequencing technology to screen candidate downstream targets for WTAP and investigated the underlying mechanism of CCND1 in ESCC promotion through a series of rescue assays. An elevated expression of WTAP in ESCC malignancy indicated a worse prognosis. WTAP promoted the proliferation and metastasis of ESCC cells, and CCND1 was identified as the potential downstream effecter of WTAP. Moreover, WTAP modulated ESCC progression through a MAPK pathway-dependent pattern. Our research suggested that WTAP promoted both proliferation and metastasis of ESCC by accelerating the expression of CCND1 via the MAPK signaling pathway, indicating that WTAP may be a candidate prognostic biomarker for ESCC and also will be a promising strategy for ESCC cancer therapy.

Asunto(s)

Proliferación Celular , Ciclina D1 , Progresión de la Enfermedad , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Sistema de Señalización de MAP Quinasas , Humanos , Ciclina D1/metabolismo , Ciclina D1/genética , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/metabolismo , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Animales , Línea Celular Tumoral , Ratones , Masculino , Regulación Neoplásica de la Expresión Génica , Pronóstico , Femenino , Factores de Empalme de ARN/genética , Factores de Empalme de ARN/metabolismo , Movimiento Celular , Ratones Desnudos , Persona de Mediana Edad , Proteínas de Ciclo Celular

RESUMEN

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is often diagnosed at advanced stages due to the inherent limitations of current screening methodologies. Central to evaluating tumor invasion and prognostic assessment in ESCC is the integrity of the basement membrane (BM). However, current research on the implications of BM-related genes (BMRGs) in diagnosing ESCC remains sparse. METHODS: We performed a comprehensive analysis using single-cell RNA-sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) database, alongside gene expression profiles acquired from GEO and The Cancer Genome Atlas (TCGA) databases. This identified differentially expressed BMRGs in ESCC. Employing LASSO, RF, and SVM-RFE, we selected potential BM biomarkers and crafted a diagnostic nomogram for ESCC, validated by ROC curves and AUC values. We also explored immune infiltration and biological mechanisms through consensus clustering and GSVA, and utilized single cell trajectory analysis and GSCALite to study gene distributions and pathways. In vitro experiments further elucidated the role of these genes in ESCC carcinogenesis. RESULTS: Here, we discovered that ESCC cell types exhibited markedly elevated BM-related scores. Our analysis pinpointed seven BM genes upregulated and linked to immune infiltration, showcasing unique gene expression profiles and varying immune cell densities across the BM-related subtypes. Furthermore, a robust positive correlation was observed between these genes expression and EMT activity. The knockdown of BGN significantly suppressed cell proliferation, migration, invasion, while also augmenting cell viability following chemotherapy drug treatment. CONCLUSION: Our study identified seven key BMRGs (BGN, LAMB3, SPARC, MMP1, LUM, COL4A1, and NELL2) and established a diagnostic nomogram for ESCC. Of noteworthy significance is the discovery of BGN as a promising drug target, indicating a novel strategy for future clinical combination therapies in ESCC.

Asunto(s)

Membrana Basal , Biomarcadores de Tumor , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Genómica , Humanos , Carcinoma de Células Escamosas de Esófago/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/diagnóstico , Biomarcadores de Tumor/genética , Membrana Basal/metabolismo , Genómica/métodos , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica

RESUMEN

Gastroesophageal adenocarcinoma (GEAC) poses a significant challenge due to its poor prognosis and limited treatment options. Recently, Cancer/testis antigens (CTAs) have emerged as potential therapy targets due to their high expression in tumor cells and their immunogenic nature. We aimed to explore the expression and co-expression of CTAs in GEAC. We analyzed 63 GEAC patients initially and validated our findings in 329 patients from The Cancer Genome Atlas (TCGA) database. CTA expression was measured after RNA sequencing, while clinical information, including survival outcomes and treatment details, was collected from an institutional database. Co-expression patterns among CTAs were determined using Spearman correlation analysis. The majority of the study cohort were male (87%), Caucasian (94%), and had stage IV disease (64%). CTAs were highly prevalent, ranging from 58 to 19%. The MAGE gene family showed the highest expression, consistent across both cohorts. The correlation matrix revealed a distinct cluster of significantly co-expressed genes, including MAGEA3, NY-ESO-1, and others (0.27 ≤ r ≤ 0.73). Survival analysis revealed that individual CTAs were associated with poorer survival outcomes in patients not receiving immunotherapy while showing potential for improved survival in those undergoing immunotherapy, although these findings lacked robust reliability. Our study provides a comprehensive characterization of CTA expression and co-expression in GEAC. The strong correlation among CTAs like MAGE, NY-ESO-1, and GAGE suggests a potential for therapies targeting multiple CTAs simultaneously. Further research, including prospective trials, is warranted to assess the prognostic value of CTAs and their suitability as therapeutic targets.

Asunto(s)

Adenocarcinoma , Antígenos de Neoplasias , Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Masculino , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidad , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/mortalidad , Neoplasias Gástricas/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidad , Femenino , Persona de Mediana Edad , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Pronóstico , Regulación Neoplásica de la Expresión Génica , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/biosíntesis , Adulto

RESUMEN

Preclinical studies suggest that simultaneous HER2/VEGF blockade may have cooperative effects in gastroesophageal adenocarcinomas. In a single-arm investigator initiated clinical trial for patients with untreated advanced HER2+ gastroesophageal adenocarcinoma, bevacizumab was added to standard of care capecitabine, oxaliplatin, and trastuzumab in 36 patients (NCT01191697). Primary endpoint was objective response rate and secondary endpoints included safety, duration of response, progression free survival, and overall survival. The study met its primary endpoint with an objective response rate of 81% (95% CI 65-92%). Median progression free and overall survival were 14.0 (95% CI, 11.3-36.4) and 23.2 months (95% CI, 16.6-36.4), respectively. The median duration of response was 14.9 months. The regimen was well tolerated without unexpected or severe toxicities. In post-hoc ctDNA analysis, baseline ctDNA features were prognostic: Higher tumor fraction and alternative MAPK drivers portended worse outcomes. ctDNA at resistance identified oncogenic mutations and these were detectable 2-8 cycles prior to radiographic progression. Capecitabine, oxaliplatin, trastuzumab and bevacizumab shows robust clinical activity in HER2+ gastroesophageal adenocarcinoma. Combination of VEGF inhibitors with chemoimmunotherapy and anti-PD1 regimens is warranted.

Asunto(s)

Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Capecitabina , ADN Tumoral Circulante , Neoplasias Esofágicas , Oxaliplatino , Receptor ErbB-2 , Neoplasias Gástricas , Trastuzumab , Humanos , Trastuzumab/uso terapéutico , Trastuzumab/administración & dosificación , Capecitabina/administración & dosificación , Capecitabina/uso terapéutico , Femenino , Persona de Mediana Edad , Bevacizumab/uso terapéutico , Bevacizumab/administración & dosificación , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Anciano , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Oxaliplatino/administración & dosificación , Oxaliplatino/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Masculino , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Adulto , Unión Esofagogástrica/patología , Resultado del Tratamiento , Supervivencia sin Progresión

RESUMEN

Single-cell RNA sequencing (scRNA-Seq) technology provides the scope to gain insight into the interplay between intrinsic cellular processes as well as transcriptional and behavioral changes in gene-gene interactions across varying conditions. The high level of scarcity of scRNA-seq data, however, poses a significant challenge for analysis. We propose a complete differential co-expression (DCE) analysis framework for scRNA-Seq data to extract network modules and identify hub-genes. The performance of our method has been shown to be satisfactory after validation using an scRNA-Seq esophageal squamous cell carcinoma (ESCC) dataset. From comparison with four other existing hub-gene finding methods, it has been observed that our method performs better in the majority of cases and has the ability to identify unique potential biomarkers that were not detected by the other methods. The potential biomarker genes identified by our framework, differential co-expression analysis method for single-cell RNA sequencing data (scDiffCoAM), have been validated both statistically and biologically.

Asunto(s)

Biomarcadores de Tumor , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Regulación Neoplásica de la Expresión Génica , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Humanos , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Análisis de la Célula Individual/métodos , Biomarcadores de Tumor/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Análisis de Secuencia de ARN/métodos , Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes/genética , RNA-Seq/métodos , Análisis de Expresión Génica de una Sola Célula

RESUMEN

N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG) and Helicobacter pylori might synergistically promote the malignant transformation of human esophageal epithelial cells (HEECs) through inducing DNA double-strand breaks (DSBs) and inhibition of PAXX protein expression. The long noncoding RNA (lncRNA) TUG1 is associated with multiple cancers, and its overexpression can promote cancer by interfering with the functions of oncogenes. LncRNA TUG1 is also associated with DNA methyltransferase 1 (DNMT1) and the epithelial signaling pathway of H. pylori infection. To explore the role of LncRNA TUG1 in the malignant transformation of HEECs induced by H.pylori + MNNG, a stable strain of HEECs with LncRNA TUG1 knockdown (LncRNA TUG1-KD) was constructed using RNA interference technology with lentivirus as a vector. Set up negative controls LncRNA TUG1-NC (null carrier lentivirus was selected to transfect HEECs) and block controls (normal HEECs without exposure). H. pylori + MNNG were added to the LncRNA TUG1-KD and LncRNA TUG1-NC groups for 6 h and then passaged until their malignant transformation. From each group, cells in the early, intermediate, and late stages of malignant transformation were used for the alkaline comet assay and determination of protein expression, including γ-H2AX and PAXX, by western blotting assay to assess DNA damage and repair processes. Clone formation assay in soft agar and nude mouse xenograft model was used to assess malignancy. This study suggests that H. pylori + MNNG promotes the malignant transformation of HEECs by inducing DNA DSBs and inhibiting PAXX expression, and this effect may be alleviated by LncRNA TUG1 knockdown. It elucidates the pathogenesis of EC from the perspective of the combined effect of epigenetic and environmental carcinogens, offering new insights for the comprehensive prevention and treatment of EC.

Asunto(s)

Transformación Celular Neoplásica , Daño del ADN , Células Epiteliales , Helicobacter pylori , Metilnitronitrosoguanidina , ARN Largo no Codificante , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Metilnitronitrosoguanidina/toxicidad , Humanos , Transformación Celular Neoplásica/genética , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Animales , Neoplasias Esofágicas/genética , Ratones , Esófago/patología , Esófago/efectos de los fármacos , Infecciones por Helicobacter , Ratones Desnudos

RESUMEN

Benign and malignant diseases of the upper gastrointestinal tract show gender-specific differences. The frequent gastroesophageal reflux disease is a prime example: men have an erosive reflux disease more often than women and are also younger at the time of onset. The rate of progression to a metaplastic Barrett's esophagus is also higher in men. In the case of achalasia, there are indications that surgical treatment by laparoscopic Heller's myotomy and semifundoplication 180° according to Dor leads to a markedly better improvement in the symptoms in women compared to men, although they showed a more pronounced dilation of the tubular esophagus. The female hormone status influences the localization and histopathology of adenocarcinoma of the esophagogastric junction and gastric carcinoma. Premenopausal and postmenopausal carcinomas differ significantly in women. In addition, high microsatellite instability (MSI high) is more frequent in women and is associated with a generally significantly better prognosis. The MSI high gastric carcinomas of women show better survival than MSI high carcinomas of men. The future inclusion of gender-specific aspects in studies of the upper gastrointestinal tract is desirable in order to generate adequate data and to enable differentiated treatment stratification in the future.

Asunto(s)

Esófago de Barrett , Humanos , Femenino , Masculino , Factores Sexuales , Esófago de Barrett/patología , Esófago de Barrett/diagnóstico , Esófago de Barrett/terapia , Reflujo Gastroesofágico/patología , Reflujo Gastroesofágico/diagnóstico , Neoplasias Gástricas/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/cirugía , Acalasia del Esófago/patología , Acalasia del Esófago/genética , Acalasia del Esófago/diagnóstico , Acalasia del Esófago/fisiopatología , Acalasia del Esófago/cirugía , Tracto Gastrointestinal Superior/patología , Enfermedades Gastrointestinales/patología , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/cirugía , Neoplasias Esofágicas/genética , Inestabilidad de Microsatélites , Adenocarcinoma/patología , Adenocarcinoma/genética , Adenocarcinoma/cirugía

RESUMEN

INTRODUCTION: Esophageal cancer presents significant challenges due to limited treatment options and poor prognosis, particularly in advanced stages. Dysregulated long non-coding RNAs (lncRNAs) are implicated in cancer progression and treatment resistance. This study investigated the roles of dysregulated lncRNA NONHSAT227443.1, identified through lncRNA-seq, and its downstream target gene MRTFB in esophageal squamous cell carcinoma (ESCC). METHODS: Dysregulated lncRNAs were identified through lncRNA-seq in esophageal cancer tissues with varying chemotherapy response. The regulatory interaction of overexpressed NONHSAT227443.1 was assessed using quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Functional assays, including cell viability, cell proliferation, and flow cytometry analyses, were performed to comprehensively investigate the influence of NONHSAT227443.1 and its downstream molecules on ESCC. RESULTS: NONHSAT227443.1 was significantly overexpressed in paclitaxel plus platinum chemotherapy non-responders and esophageal cancer cell lines. Chemotherapy exposure led to diminished NONHSAT227443.1 expression. NONHSAT227443.1 negatively regulated MRTFB expression, and their combined dysregulation correlated with increased cancer activity, proliferation, and suppressed apoptosis. Diminished MRTFB expression was associated with PI3K/AKT pathway activation. CONCLUSION: Our study provides insights into NONHSAT227443.1 and MRTFB roles in esophageal cancer, contributing to aggressive traits and treatment resistance. NONHSAT227443.1 and MRTFB may serve as potential therapeutic targets to enhance the response to paclitaxel plus platinum chemotherapy in non-responsive cases.

Asunto(s)

Apoptosis , Proliferación Celular , Resistencia a Antineoplásicos , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Regulación Neoplásica de la Expresión Génica , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , ARN Largo no Codificante , Transducción de Señal , Humanos , ARN Largo no Codificante/genética , Resistencia a Antineoplásicos/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Línea Celular Tumoral , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo

RESUMEN

The prognosis for esophageal squamous cell carcinoma (ESCC), a prevalent and aggressive form of cancer, remains poor despite advancements in treatment options. Addressing the gap in comprehensive prognostic information derived from circRNA expression profiles for ESCC, our study aimed to establish a linkage between circRNA expressions and ESCC prognosis. To achieve this, we first developed an optimized prognostic model named T cell-related risk score (TRRS), which integrates T cell-associated features with machine learning algorithms. In parallel, we re-analyzed existing RNA-seq datasets to redefine the expression profiles of circRNAs and mRNAs. Utilizing the TRRS as a foundational "bridge," we identified circRNAs correlated with TRRS, leading to the development of a novel circRNA pair-based prognostic model, the TCRS, which is independent of specific expression levels. Further investigations uncovered two circRNAs, circNLK(5,6,7).1 and circRC3H1(2).1, with potential functional significance. These findings underscore the utility of these risk scores as tools for predicting overall survival and identifying potential therapeutic targets for ESCC patients.

Asunto(s)

Biomarcadores de Tumor , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , ARN Circular , Humanos , ARN Circular/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/inmunología , Neoplasias Esofágicas/diagnóstico , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/mortalidad , Carcinoma de Células Escamosas de Esófago/inmunología , Pronóstico , Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica , Linfocitos T/inmunología , Masculino , Femenino , Aprendizaje Automático , Persona de Mediana Edad

RESUMEN

While whole genome sequencing (WGS) of cell-free DNA (cfDNA) holds enormous promise for detection of molecular residual disease (MRD), its performance is limited by WGS error rate. Here we introduce AccuScan, an efficient cfDNA WGS technology that enables genome-wide error correction at single read-level, achieving an error rate of 4.2 × 10-7, which is about two orders of magnitude lower than a read-centric de-noising method. The application of AccuScan to MRD demonstrated analytical sensitivity down to 10-6 circulating variant allele frequency at 99% sample-level specificity. AccuScan showed 90% landmark sensitivity (within 6 weeks after surgery) and 100% specificity for predicting relapse in colorectal cancer. It also showed 67% sensitivity and 100% specificity in esophageal cancer using samples collected within one week after surgery. When AccuScan was applied to monitor immunotherapy in melanoma patients, the circulating tumor DNA (ctDNA) levels and dynamic profiles were consistent with clinical outcomes. Overall, AccuScan provides a highly accurate WGS solution for MRD detection, empowering ctDNA detection at parts per million range without requiring high sample input or personalized reagents.

Asunto(s)

ADN Tumoral Circulante , Neoplasia Residual , Secuenciación Completa del Genoma , Humanos , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Secuenciación Completa del Genoma/métodos , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Sensibilidad y Especificidad , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/diagnóstico , Melanoma/genética , Melanoma/diagnóstico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/diagnóstico

RESUMEN

In this study, we develop a stacked ensemble model that utilizes cell-free DNA (cfDNA) fragmentomics for the early detection of esophageal squamous cell carcinoma (ESCC). This model incorporates four distinct fragmentomics features derived from whole-genome sequencing (WGS) and advanced machine learning algorithms for robust analysis. It is validated across both an independent validation cohort and an external cohort to ensure its generalizability and effectiveness. Notably, the model maintains its robustness in low-coverage sequencing environments, demonstrating its potentials in clinical settings with limited sequencing resources. With its remarkable sensitivity and specificity, this approach promises to significantly improve the early diagnosis and management of ESCC. This study represents a substantial step forward in the application of cfDNA fragmentomics in cancer diagnostics, emphasizing the need for further research to fully establish its clinical efficacy.

Asunto(s)

Ácidos Nucleicos Libres de Células , Detección Precoz del Cáncer , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/diagnóstico , Carcinoma de Células Escamosas de Esófago/patología , Detección Precoz del Cáncer/métodos , Ácidos Nucleicos Libres de Células/genética , Ácidos Nucleicos Libres de Células/sangre , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/diagnóstico , Aprendizaje Automático , Biomarcadores de Tumor/genética , Femenino , Masculino , Persona de Mediana Edad , Secuenciación Completa del Genoma/métodos , Algoritmos , Anciano

RESUMEN

Many studies have demonstrated the importance of accurately identifying miRNA-disease associations (MDAs) for understanding disease mechanisms. However, the number of known MDAs is significantly fewer than the unknown pairs. Here, we propose RSANMDA, a subview attention network for predicting MDAs. We first extract miRNA and disease features from multiple similarity matrices. Next, using resampling techniques, we generate different subviews from known MDAs. Each subview undergoes multi-head graph attention to capture its features, followed by semantic attention to integrate features across subviews. Finally, combining raw and training features, we use a multilayer scoring perceptron for prediction. In the experimental section, we conducted comparative experiments with other advanced models on both HMDD v2.0 and HMDD v3.2 datasets. We also performed a series of ablation studies and parameter tuning exercises. Comprehensive experiments conclusively demonstrate the superiority of our model. Case studies on lung, breast, and esophageal cancers further validate our method's predictive capability for identifying disease-related miRNAs.

Asunto(s)

MicroARNs , Humanos , MicroARNs/genética , Biología Computacional/métodos , Predisposición Genética a la Enfermedad , Redes Neurales de la Computación , Neoplasias de la Mama/genética , Neoplasias Pulmonares/genética , Algoritmos , Neoplasias/genética , Neoplasias Esofágicas/genética

RESUMEN

BACKGROUND: Esophageal cancer is a common malignancy of the digestive tract. Despite remarkable advancements in its treatment, the overall prognosis for patients remains poor. Cuproptosis is a form of programmed cell death that affects the malignant progression of tumors. This study aimed to examine the impact of the cuproptosis-associated gene DKC1 on the malignant progression of esophageal cancer. METHODS: Clinical and RNA sequencing data of patients with esophageal cancer were extracted from The Cancer Genome Atlas (TCGA). Univariate Cox regression analysis was used to identify the differentially expressed genes related to cuproptosis that are associated with prognosis. We then validated the difference in the expression of DKC1 between tumor and normal tissues via three-dimensional multiomics difference analysis. Subsequently, we investigated the association between DKC1 expression and the tumor microenvironment by employing the TIMER2.0 algorithm, which was further validated in 96 single-cell datasets obtained from the TISCH database. Additionally, the functional role of DKC1 in pancarcinoma was assessed through GSEA. Furthermore, a comprehensive pancancer survival map was constructed, and the expression of DKC1 was verified in various molecular subtypes. By utilizing the CellMiner, GDSC, and CTRP databases, we successfully established a connection between DKC1 and drug sensitivity. Finally, the involvement of DKC1 in the progression of esophageal cancer was investigated through in vivo and in vitro experiments. RESULTS: In this study, we identified a copper death-related gene, DKC1, in esophageal cancer. Furthermore, we observed varying levels of DKC1 expression across different tumor types. Additionally, we conducted an analysis to determine the correlation between DKC1 expression and clinical features, revealing its association with common cell cycle pathways and multiple metabolic pathways. Notably, high DKC1 expression was found to indicate poor prognosis in patients with various tumors and to influence drug sensitivity. Moreover, our investigation revealed significant associations between DKC1 expression and the expression of molecules involved in immune regulation and infiltration of lymphocyte subtypes. Ultimately, the increased expression of DKC1 in esophageal cancer tissues was verified using clinical tissue samples. Furthermore, DKC1-mediated promotion of esophageal cancer cell proliferation and migration was confirmed through both in vitro and in vivo experiments. Additionally, it is plausible that DKC1 may play a role in the regulation of cuproptosis. CONCLUSION: In this study, we conducted a systematic analysis of DKC1 and its regulatory factors and experimentally validated its excellent diagnostic and prognostic abilities in various cancers. Further research indicated that DKC1 may reshape the tumor microenvironment (TME), highlighting the potential of DKC1-based cancer treatment and its usefulness in predicting the response to chemotherapy.

Asunto(s)

Proteínas de Ciclo Celular , Neoplasias Esofágicas , Humanos , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Pronóstico , Proteínas de Ciclo Celular/genética , Ratones , Animales , Masculino , Femenino , Microambiente Tumoral/genética , Regulación Neoplásica de la Expresión Génica , Biomarcadores de Tumor/genética , Proliferación Celular/genética , Línea Celular Tumoral , Proteínas Nucleares

RESUMEN

BACKGROUND: Esophageal cancer is one of the most common malignant tumors in the world. It is urgent to prevent the development and progression of esophageal cancer. Cancer stem cells (CSCs) were reported to have the ability to initiate tumorigenesis, and reducing the stem cell-like characteristics of tumors is an important strategy to inhibit the occurrence and development of tumors. miRNAs are key regulators of the stemness of cancer. Here, we aimed to investigate the role and regulatory mechanism of miR-191-3p in the stemness properties of esophageal cancer cells. METHODS: Esophageal cancer cells with stable expression of miR-191-3p were established by lentivirus system. CCK-8 assay, transwell assay, wound healing assay were used to evaluate the effect of miR-191-3p on proliferation and metastasis of esophageal cancer cells. The expression of stemness-related markers (NANOG, OCT4, SOX2), ALDH activity, sphere-forming assay and subcutaneous tumor model in nude mice were performed to evaluate the stemness properties of esophageal cancer cells in vitro and in vivo. Dual-luciferase reporter assay was used to verify the molecular mechanism. RESULT: Here we found that overexpression of miR-191-3p promoted the stemness properties of esophageal cancer cells in vitro and in vivo, including increasing esophageal cancer cell proliferation and metastasis ability, the expression of stemness-related markers NANOG, OCT4, and SOX2, ALDH activity, the number of spheres formed and tumor growth. Bioinformatic analysis and dual-luciferase assay demonstrated that regulator of G protein signaling 1 (RGS1) was the directed target gene of miR-191-3p and attenuated the promotion effect of miR-191-3p on the stemness of esophageal cancer cells. Furthermore, we found that RGS1 knockdown activated the PI3K/AKT pathway by negatively regulating CXCR4 to promote the stemness of esophageal cancer cells. CONCLUSIONS: Our findings revealed that RGS1 targeted by miR-191-3p inhibited the stemness of esophageal cancer cells by suppressing the CXCR4/PI3K/AKT pathway, which provide potential prognostic markers and therapeutic targets in the future.

Asunto(s)

Neoplasias Esofágicas , Ratones Desnudos , MicroARNs , Células Madre Neoplásicas , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Proteínas RGS , Receptores CXCR4 , Transducción de Señal , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , MicroARNs/metabolismo , MicroARNs/genética , Humanos , Proteínas RGS/metabolismo , Proteínas RGS/genética , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores CXCR4/metabolismo , Receptores CXCR4/genética , Animales , Fosfatidilinositol 3-Quinasas/metabolismo , Línea Celular Tumoral , Ratones , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Ratones Endogámicos BALB C

RESUMEN

BACKGROUND: Previous studies have suggested a potential association between irritability and the risk of various diseases. However, establishing a causal relationship has remained a significant challenge. To address this issue, we employed Mendelian randomization (MR), a sophisticated approach that leverages genotype data to emulate the conditions of randomized controlled trials. This method enables us to investigate the potential causal link between irritability and the susceptibility to esophageal diseases. METHODS: We conducted an extensive multivariable MR analysis using summary-level data from genome-wide association studies (GWAS) encompassing various esophageal diseases, including gastroesophageal reflux disease (GERD), esophageal cancer (EC), and Barrett's esophagus. Both univariable and multivariable MR analyses were performed to elucidate and confirm the causal association between genetically predicted irritability and the incidence of esophageal diseases. RESULTS: Based on our primary causal effects model utilizing MR analyses with the inverse-variance weighted (IVW) method, genetically predicted irritability was identified as a risk factor for GERD (OR = 2.413; 95 % CI: 1.678-3.470; P = 2.03E-06) and Barrett's esophagus (OR = 2.306; 95 % CI: 1.042-5.101; P = 0.039). However, irritability was not found to be associated with the risk of EC, even after adjusting for BMI, smoking initiation, and alcohol consumption. CONCLUSION: The multivariable MR analysis performed in this study demonstrated a causal relationship between irritability and esophageal diseases. It is imperative to acknowledge the need for further large-scale prospective studies to validate these findings.

Asunto(s)

Esófago de Barrett , Neoplasias Esofágicas , Reflujo Gastroesofágico , Estudio de Asociación del Genoma Completo , Genio Irritable , Análisis de la Aleatorización Mendeliana , Humanos , Esófago de Barrett/genética , Reflujo Gastroesofágico/genética , Reflujo Gastroesofágico/epidemiología , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/epidemiología , Factores de Riesgo , Enfermedades del Esófago/genética , Polimorfismo de Nucleótido Simple , Predisposición Genética a la Enfermedad/genética

RESUMEN

BACKGROUND: A minority of patients with MSS tumors present a high tumor mutation burden (TMB) without underlying MMR defects. METHODS: Publicly available genomic series were assessed for identification of patients with MSS gastric gastroesophageal junction, and esophageal adenocarcinomas and a high TMB, defined as more than 10 mutations per Mb. These were compared with MSS cancers and a low TMB for genetic alterations and for survival outcomes. RESULTS: Patients with MSS cancers with high TMB in the MSK series were older but did not differ in other clinicopathologic parameters compared with MSS patients with low TMB. Mutations in tumor suppressors TP53 and APC and oncogenes KRAS and ERBB4 as well as amplifications of ERBB2 were more prevalent in the high TMB group of MSS cancers. Mutations in DDR associated genes, in epigenetic modifiers and in genes associated with immune response were more prevalent in the hIgh TMB group patients. However, high TMB was not associated with an improved survival in MSS gastric/gastroesophageal junction/esophageal adenocarcinomas (Log Rank p = 0.5). CONCLUSION: MSS Gastric/gastroesophageal junction/esophageal adenocarcinomas with TMB above 10 mutations per Mb possess a genomic landscape with increased alteration frequencies in common gastroesophageal cancer genes and pathways.

Asunto(s)

Adenocarcinoma , Neoplasias Esofágicas , Unión Esofagogástrica , Inestabilidad de Microsatélites , Mutación , Neoplasias Gástricas , Humanos , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/mortalidad , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Neoplasias Gástricas/mortalidad , Unión Esofagogástrica/patología , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/mortalidad , Masculino , Femenino , Pronóstico , Persona de Mediana Edad , Anciano , Biomarcadores de Tumor/genética , Anciano de 80 o más Años