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OBJECTIVE: To explore the underlying molecular mechanism of Notch1/cadherin 5 (CDH5) pathway in modulating in cell malignant behaviors of gastric cancer (GC). METHODS: We performed bioinformatic analyses to screen the potential target genes of Notch1 from cadherins in GC. Western blot and RT-PCR were conducted to detect CDH5 expression in GC tissues and cells. We utilized chromatin immunoprecipitation (CHIP) assays to assess the interaction of Notch1 with CDH5 gene. The effects of Notch1/CDH5 axis on the proliferation, invasion, migration and vasculogenic mimicry in GC cells were evaluated by EdU, wound healing, transwell, and tubule formation assays. RESULTS: Significantly increased CDH5 expression was found in GC tissues compared with paracancerous tissues and associated to clinical stage and poor overall survival (OS) in patients with GC. Notch1 positively regulate the expression of CDH5 in GC cells. CHIP assays validated that CDH5 was a direct target of Notch1. In addition, Notch1 upregulation enhanced the proliferation, migration, invasion and vasculogenic mimicry capacity of GC cells, which could be attenuated by CDH5 silencing. CONCLUSIONS: These results indicated Notch1 upregulation enhanced GC malignant behaviors by triggering CDH5, suggesting that targeting Notch1/CDH5 axis could be a potential therapeutic strategy for GC progression.
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RNA-binding proteins (RBPs) play critical roles in genome regulation. In this study, we explored the latent function of KPNA2, which is an essential member of the RBP family, in the regulation of alternative splicing (AS) in gastric cancer (GC). We analyzed the role of KPNA2 in regulating differential expression and AS via RNA sequencing (RNA-seq) and improved RNA immunoprecipitation sequencing (iRIP-seq). Clinical specimens were used to analyze the associations between KPNA2 expression and clinicopathological characteristics. CCK8 assays, transwell assays and wound healing assays were performed to explore the effect of KPNA2/WDR62 on GC cell progression. KPNA2 was shown to be highly expressed in GC cells and tissues and associated with lymph node metastases. KPNA2 promoted the proliferation, migration and invasion of GC cells and primarily regulated exon skipping, alternative 3's splice sites (A3SSs), alternative 5' splice sites (A5SSs), and cassette exons. We further revealed that KPNA2 participated in biological processes related to cell proliferation, and the immune response in GC via the regulation of transcription. In addition, KPNA2 preferentially bound to intron regions. Notably, KPNA2 regulated the A3SS AS mode of WDR62, and upregulation of WDR62 reversed the KPNA2 downregulation-induced inhibition of GC cell proliferation, migration and invasion. Finally, we discovered that the AS of immune-related molecules could be regulated by KPNA2. Overall, our results demonstrated for the first time that KPNA2 functions as an oncogenic splicing factor in GC that regulated the AS and differential expression of GC-related genes, and KPNA2 may be a potential target for GC treatment.
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Processamento Alternativo , Movimento Celular , Proliferação de Células , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Neoplasias Gástricas , alfa Carioferinas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/metabolismo , Proliferação de Células/genética , alfa Carioferinas/genética , alfa Carioferinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Masculino , Pessoa de Meia-Idade , Metástase LinfáticaRESUMO
BACKGROUND AND STUDY AIMS: Immunotherapy has emerged as a hot topic in cancer treatment in recent years and has also shown potential in the treatment of Helicobacter pylori-associated gastric cancer. However, there is still a need to identify potential immunotherapy targets. MATERIAL AND METHODS: We used the GSE116312 dataset of Helicobacter pylori-associated gastric cancer to identify differentially expressed genes, which were then overlapped with immune genes from the ImmPort database. The identified immune genes were used to classify gastric cancer samples and evaluate the relationship between classification and tumor mutations, as well as immune infiltration. An immune gene-based prognostic model was constructed, and the expression levels of the genes involved in constructing the model were explored in the tumor immune microenvironment. RESULTS: We successfully identified 60 immune genes and classified gastric cancer samples into two subtypes, which showed differences in prognosis, tumor mutations, immune checkpoint expression, and immune cell infiltration. Subsequently, we constructed an immune prognostic model consisting of THBS1 and PDGFD, which showed significant associations with macrophages and fibroblasts. CONCLUSION: We identified abnormal expression of THBS1 and PDGFD in cancer-associated fibroblasts (CAFs) within the tumor immune microenvironment, suggesting their potential as therapeutic targets.
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Infecções por Helicobacter , Helicobacter pylori , Fator de Crescimento Derivado de Plaquetas , Neoplasias Gástricas , Trombospondina 1 , Microambiente Tumoral , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Humanos , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Helicobacter pylori/imunologia , Helicobacter pylori/genética , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/complicações , Trombospondina 1/genética , Prognóstico , Fator de Crescimento Derivado de Plaquetas/genética , Fator de Crescimento Derivado de Plaquetas/metabolismo , Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/metabolismo , Mutação , LinfocinasRESUMO
Background: Observational studies have previously demonstrated a significant relationship among both metabolic syndrome (Mets) and colorectal cancer (CRC). Whether there is a causal link remains controversial. Objective: To clarify whether Mets and their components have a causal effect on colorectal cancer, we have carried out a bidirectional Mendelian randomization analysis (MR). Methods: This study started from genome-wide association data for Mets and its 5 components (hypertension, waist circumference, fasting blood glucose, serum triglycerides, and serum high-density lipoprotein cholesterol) and colorectal cancer. Mendelian randomization (MR) techniques were used in the study to examine their associations. Results: After Benjamini-Hochberg multiple corrections, genetically predicted significant causal link exists between WC (waist circumference) and CRC. The OR was 1.35 (95 % CI: 1.08-1.69; p = 0.0096). Other Mets components (HBP, FBG, TG, HDL), on the other hand, found no evidence of a genetic link between CRC and Mets. In addition, MR results showed that CRC was not causally related to either Mets or the components. We get the same result in the validated dataset. Conclusion: According to the bidirectional MR investigation shows a significant causal relationship among obesity and CRC in the Mets component but no causal relationship in the opposite direction.
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Gastrointestinal cancer is a common malignancy with high mortality and poor prognosis. Therefore, developing novel effective markers and therapeutic targets for gastrointestinal cancer is currently a challenging and popular topic in oncology research. Accumulating studies have reported that N6-methyladenosine is the most abundant epigenetic modification in eukaryotes. N6-methyladenosine plays an essential role in regulating RNA expression and metabolism, including splicing, translation, stability, decay, and transport. FTO, the earliest demethylase discovered to maintain the balance of N6-adenosine methylation, is abnormally expressed in many tumors. In this review, we discuss the molecular structure and substrate selectivity of FTO. we focus on the role of FTO in gastrointestinal tumor proliferation, migration, invasion, apoptosis, autophagy, immune microenvironment, and its molecular mechanisms. We also discuss its potential in the treatment of gastrointestinal cancers.
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Environmental tobacco smoke (ETS) exposure has been proven to induce digestive diseases such as hepatic steatosis, cirrhosis, and gastrointestinal cancer, yet little is known about the link between ETS exposure and constipation. This study aimed to investigate the impact of ETS exposure on the risk of chronic constipation in adults aged 20 years or older. This is a cross-sectional study based on population. A total number of 7705 participants from the National Health and Nutrition Examination Survey (NHANES) 2005-2010 were included. Cotinine, an alkaloid found in tobacco, serves as a reliable and precise biomarker for measuring exposure to ETS. Hence, the categorization of exposure to ETS was conducted based on serum cotinine levels, resulting in four distinct categories. The association between ETS exposure and the risk of constipation was assessed using multivariable restricted cubic spline and logistic regression with odds ratio (OR) and 95% confidence interval (CI). The weighted prevalence of constipation in this study was estimated to be 7.51% based on stool consistency, or 3.11% based on stool frequency. The fully adjusted models indicated a positive correlation between exposure to ETS and constipation as measured by stool frequency, among adults with poor dietary quality (OR (95% CI): moderate exposure: 2.49 (1.05, 5.94); high exposure: 2.36(1.13, 4.95), P for trend = 0.03), while no significant difference was observed in the subgroup with a higher healthy eating index. Furthermore, the log10-transformed serum cotinine level exhibited a non-linear inverted U-shaped association with constipation in individuals with poor dietary quality (P overall = 0.0207, P non-linear = 0.0427). Conversely, a J-shaped non-linear relationship was observed in the subgroup with a higher healthy eating index (P overall = 0.0028, P non-linear = 0.0036). Our results show that ETS exposure appears to be positively associated with stool frequency-related chronic constipation in adults with poor dietary quality.
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Poluição por Fumaça de Tabaco , Adulto , Humanos , Poluição por Fumaça de Tabaco/análise , Inquéritos Nutricionais , Cotinina , Estudos Transversais , Constipação Intestinal/epidemiologia , Exposição AmbientalRESUMO
Background: Due to the abnormal angiogenesis, cancer stem cells (CSCs) in esophageal cancer (EC) have the characteristics of a hypoxic microenvironment. However, they can resist hypoxia-induced apoptosis. the molecular mechanism underlying the resistance of esophageal CSCs to hypoxia-induced apoptosis is currently unclear. Therefore, this study will investigate the molecular mechanism based on CHOP-mediated endoplasmic reticulum stress. Methods: CD44+CD24- cells in EC9706 cells were screened by fluorescence-activated cell sorting (FACS). To clarify which apoptosis pathway esophageal CSCs resist hypoxia-induced cell apoptosis through, the effects of hypoxia on apoptosis were detected by nuclear staining, flow cytometry, and JC-1 reagent, the effects of hypoxia on the expression of apoptosis-related proteins were detected by western blotting (WB) assay and quantitative polymerase chain reaction (qPCR) assay. To clarify the mechanisms of CD44+CD24- cells resistance to hypoxia-induced apoptosis is achieved by inhibiting the activation of endoplasmic reticulum stress (ERS) pathway, silenced CHOP and PERK cell lines of EC9706 cells and overexpressed CHOP and PERK cell lines of CD44+CD24- cells were constructed, the effects of hypoxia on apoptosis, cell cycle, and mitochondrial membrane potential were detected by flow cytometry and JC-1 reagent. WB assay and qPCR assay were used to detect the expressions of apoptosis-related proteins and ERS-related proteins. Results: Hypoxia significantly induce apoptosis and cycle arrest of EC9706 cells (P<0.05), but did not affect apoptosis and cycle of CD44+CD24- cells (P>0.05). Hypoxia considerably induced the activation of mitochondrial and ERS apoptosis pathways in EC9706 cells (P<0.05), but did not affect Fas receptor apoptosis pathways (P>0.05). The three apoptosis pathways were not affected by hypoxia in CD44+CD24- cells (P>0.05). Silencing the CHOP and PERK gene inhibited hypoxia-induced apoptosis of EC9706 cells (P<0.05). CHOP and PERK overexpression promoted hypoxia-induced apoptosis of CD44+CD24- cells (P<0.05), whereas mitochondrial membrane permeability inhibitors inhibited hypoxia-induced apoptosis of CD44+CD24- cells overexpressed CHOP gene. Conclusions: CD44+CD24- tumor stem cells in EC resist to hypoxia-induced apoptosis by the inhibition of ERS-mediated mitochondrial apoptosis pathway, which suggested that ERS pathway can serve as a potential target for reducing EC treatment resistance in clinical treatment.
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Objectives: The advanced gastric adenocarcinoma (GAC) patients (stage III/IV) with surgery may have inconsistent prognoses due to different demographic and clinicopathological factors. In this retrospective study, we developed clinical prediction models for estimating the overall survival (OS) and cancer-specific survival (CSS) in advanced GAC patients with surgery. Methods: A retrospective analysis was conducted using the Surveillance, Epidemiology, and End Results (SEER) database. The total population from 2004 to 2015 was divided into four levels according to age, of which 179 were younger than 45 years old, 695 were 45-59 years old, 1064 were 60-74 years old, and 708 were older than 75 years old. There were 1,712 men and 934 women. Univariate and multivariate Cox regression analyses were performed to identify prognostic factors for OS and CSS. Nomograms were constructed to predict the 1-, 3-, and 5-year OS and CSS. The models' calibration and discrimination efficiency were validated. Discrimination and accuracy were evaluated using the consistency index, area under the receiver operating characteristic curve, and calibration plots; and clinical usefulness was assessed using decision curve analysis. Cross-validation was also conducted to evaluate the accuracy and stability of the models. Prognostic factors identified by Cox regression were analyzed using Kaplan-Meier survival analysis. Results: A total of 2,646 patients were included in our OS study. Age, primary site, differentiation grade, AJCC 6th_TNM stage, chemotherapy, radiotherapy, and number of regional nodes examined were identified as prognostic factors for OS in advanced GAC patients with surgery (P < 0.05). A total of 2,369 patients were included in our CSS study. Age, primary site, differentiation grade, AJCC 6th_TNM stage, chemotherapy, radiotherapy, and number of regional nodes examined were identified as risk factors for CSS in these patients (P < 0.05). These factors were used to construct the nomogram to predict the 1-, 3-, and 5-year OS and CSS of advanced GAC patients with surgery. The consistency index and area under the receiver operating characteristic curve demonstrated that the models effectively differentiated between events and nonevents. The calibration plots for 1-, 3-, and 5-year OS and CSS probability showed good consistence between the predicted and the actual events. The decision curve analysis indicated that the nomogram had higher clinical predictive value and more significant net gain than AJCC 6th_TNM stage in predicting OS and CSS of advanced GAC patients with surgery. Cross-validation also revealed good accuracy and stability of the models. Conclusion: The developed predictive models provided available prognostic estimates for advanced GAC patients with surgery. Our findings suggested that both OS and CSS can benefit from chemotherapy or radiotherapy in these patients.
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Liver fibrosis is a chronic inflammatory process characterized by the accumulation of extracellular matrix (ECM), which contributes to cirrhosis and hepatocellular carcinoma. Increasing evidence suggests that the activation of hepatic stellate cells (HSCs) under an inflammatory state leads to the secretion of collagens, which can cause cirrhosis. In this study, we analysed data from the Gene Expression Omnibus (GEO) databases to identify differentially expressed genes (DEGs) between quiescent and fibrotic HSCs. We found that Microfibril Associated Protein 2 (MFAP2) was elevated in carbon tetrachloride (CCl4)-induced liver fibrosis and Transforming Growth Factor-Beta 1 (TGF-ß1)-activated HSCs. Knockdown of MFAP2 inhibited HSC proliferation and partially attenuated TGF-ß-stimulated fibrogenesis markers. Bioinformatics analysis revealed that Fibrillin-1 (FBN1) was correlated with MFAP2, and the expression of FBN1 was significantly upregulated after MFAP2 overexpression. Silencing MFAP2 partially attenuated the activation of HSCs by inhibiting HSC proliferation and decreasing collagen deposits. In vitro results showed that the inhibition of MFAP2 alleviated hepatic fibrosis by inhibiting the activation and inducing the apoptosis of active HSCs in a CCl4-induced mouse model. In conclusion, our results suggest that MFAP2 is a potential target for the clinical treatment of liver fibrosis.
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Microfibrilas , Fator de Crescimento Transformador beta , Animais , Camundongos , Tetracloreto de Carbono/toxicidade , Fibrilina-1/genética , Fibrilina-1/metabolismo , Células Estreladas do Fígado/metabolismo , Fígado/metabolismo , Cirrose Hepática/metabolismo , Microfibrilas/metabolismo , Microfibrilas/patologia , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
BACKGROUND: Dietary carotenoids have been proven to improve intestinal disorders like inflammatory bowel disease and colon cancer, yet little is known about the link between dietary carotenoids and constipation. This study aims to examine the relationship between dietary carotenoids intake and constipation, using data from the National Health and Nutrition Examination Survey (NHANES) 2005-2010. METHODS: A total of 11,722 participants were enrolled. Chronic constipation was defined as type 1 (separate hard lumps, like nuts) and type 2 (sausage-like, but lumpy) in the Bristol stool form scale (BSFS). Carotenoids intake was obtained from the average of two 24-hour dietary recall questionnaires (if only one 24-hour was available, we used it) and divided into quartiles (Q). The prevalence of constipation was calculated across men and women individuals. The relationship between dietary carotenoids intake and constipation in men and women was assessed with weighted logistic regression and smoothed curve fitting after adjusting confounders, with results displayed as weighted odds ratio (OR) with 95% confidence intervals (95% CI). The model was further stratified by age, race, and HEI 2015 scores (with median as cutoff) among men and women. RESULTS: The total weighted prevalence of chronic constipation in this study was 8.08%, 11.11% in women and 5.18% in men. After multivariable adjustment, compared with the lowest intake, participants with the highest dietary lycopene intake (ORQ4 vs. Q1= 0.55, 95% CI: 0.36-0.84, p for trend = 0.01) and total lycopene intake (ORQ4 vs. Q1 = 0.52, 95% CI: 0.34-0.80, p for trend = 0.01) were negatively associated with the risk of chronic constipation in men, whereas increased dietary α-carotene intake reduced the risk of chronic constipation in women (ORQ4 vs. Q1 = 0.69, 95% CI: 0.48-0.98, p for trend = 0.04). Smoothing curve fitting further supported these results and provided evidence of dose-response effects. No association was found between other types of carotenoids and chronic constipation in men and women. CONCLUSIONS: Increasing lycopene intake may improve bowel function in men while increased α-carotene intake may reduce the risk of chronic constipation in women. Further studies are essential to explore the role that the intake of carotenoids plays in chronic constipation.
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Carotenoides , Constipação Intestinal , Masculino , Adulto , Feminino , Humanos , Licopeno , Estudos Transversais , Inquéritos Nutricionais , Constipação Intestinal/epidemiologia , Constipação Intestinal/prevenção & controleRESUMO
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and its pathophysiological mechanisms remain unknown. IRSp53 family members, such as BAIAP2L1, participate in the progression of multiple tumors. However, the role of BAIAP2L2 in HCC remains unclear. This study comprehensively analyzed the potential role of BAIAP2L2 in HCC using bioinformatic techniques. The expression of BAIAP2L2 in HCC was analyzed using The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), International Cancer Genome Consortium (ICGC), and Human Protein Atlas (HPA) databases and in vitro experiments. In addition, the prognostic value of BAIAP2L2 in HCC was analyzed using the TCGA database. TCGA and GEO database were used to analyze the role of BAIAP2L2 in immune features. We also explored the function of BAIAP2L2 in methylation and cuprotosis. The CellMiner database was used to analyze the relationship between BAIAP2L2 expression and drug sensitivity. Our study revealed that BAIAP2L2 is overexpressed in HCC and promotes the migration and invasion of HCC cells. BAIAP2L2 may affect the prognosis of HCC by regulating immunity, methylation, and cuprotosis. BAIAP2L2 is a novel HCC prognostic gene involved in immune infiltration associated with cuprotosis and may be a potential prognosis and therapeutic target for HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Proteínas de Membrana , Humanos , Biomarcadores , Carcinoma Hepatocelular/genética , Bases de Dados de Proteínas , Neoplasias Hepáticas/genética , Processos Neoplásicos , Prognóstico , Proteínas de Membrana/genéticaRESUMO
Aberrant expression of circRNAs is closely associated with the progression of gastric cancer; however, the specific mechanisms involved remain unclear. Our aim was to identify new gastric cancer biomarkers and explore the molecular mechanisms of gastric cancer progression. Therefore, we analyzed miRNA and circRNA microarrays of paired early-stage gastric cancer samples. Our study identified a new circRNA called hsa_circ_0069382, that had not been reported before and was expressed at low levels in gastric cancer tissues. Our study also included bioinformatics analyses which determined that the high expression of hsa_circ_0069382 regulated the BTG anti-proliferation factor 2 (BTG2)/ focal adhesion kinase (FAK) axis in gastric cancer lines by sponging for miR-15a-5p. Therefore, proliferation, invasion, and migration of gastric cancer is impacted. miR-15a-5p overexpression partially restored the effects of hsa_circ_0069382. This study provides potential new therapeutic options and a future direction to explore for gastric cancer treatment, and biomarkers.
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BACKGROUND: The global burden of hepatocellular carcinoma (HCC) is increasing, negatively impacting social health and economies. The discovery of novel and valuable biomarkers for the early diagnosis and therapeutic guidance of HCC is urgently needed. METHODS: Extracellular matrix (ECM)-related gene sets, transcriptome data and mutation profiles were downloaded from the Matrisome Project and The Cancer Genome Atlas (TCGA)-LIHC datasets. Coexpression analysis was initially performed with the aim of identifying ECM-related lncRNAs (r > 0.4, p < 0.001). The screened lncRNAs were subjected to univariate analysis to obtain a series of prognosis-related lncRNA sets, which were incorporated into least absolute selection and shrinkage operator (LASSO) regression for signature establishment. Following the grouping of LIHC samples according to risk score, the correlations between the signature and clinicopathological, tumour immune infiltration, and mutational characteristics as well as therapeutic response were also analysed. lncRNA expression levels used for modelling were finally examined at the cellular and tissue levels by real-time PCR. All analyses were based on R software. RESULTS: AL031985.3 and MKLN1-AS were ultimately identified as signature-related lncRNAs, and both were significantly upregulated in HCC tissue samples and cell lines. The prognostic value of the signature reflected by the AUC value was superior to that of age, sex, grade and stage. Correlation analysis results demonstrated that high-risk groups exhibited significant enrichment of immune cells (DCs, macrophages and Tregs) and increased expression levels of all immune checkpoint genes. Prominent differences in clinicopathological profiles, immune functions, tumour mutation burden (TMB) and drug sensitivity were noted between the two risk groups. CONCLUSIONS: Our signature represents a valuable predictive tool in the prognostic management of HCC patients. Further validation of the mechanisms involved is needed.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , RNA Longo não Codificante , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Prognóstico , RNA Longo não Codificante/metabolismoRESUMO
Gastric cancer is a leading cause of tumor-associated death worldwide. Metastasis and chemoresistance are crucial barriers for gastric cancer treatment. The Forkhead Box M1 (FOXM1) transcription factor has been reported as a promising treatment target for various types of tumors, but its effects on gastric cancer progression are not fully understood. In the present study, we found that FOXM1 expression levels were significantly up-regulated in human gastric cancer cell lines and tissues, and its expression was much higher in patients with metastasis. We then found that suppressing FOXM1 with its inhibitor thiostrepton (THIO) significantly reduced the proliferation of gastric cancer cells, while induced G0/G1 and apoptosis. Moreover, reactive oxygen species (ROS) production, mitochondrial impair and autophagy were remarkably provoked in gastric cancer cells treated with THIO, which were required for the regulation of apoptotic cell death. Furthermore, THIO exposure considerably suppressed the migration, invasion and angiogenesis in gastric cancer cells. The inhibitory effects of THIO on tumor growth and metastasis were confirmed in an established gastric cancer xenograft mouse model without detectable toxicity. Intriguingly, our in vitro studies showed that the anti-cancer effects of THIO on gastric cancer were almost abolished upon FOXM1 over-expression, indicating the necessity of FOXM1 suppression in THIO-inhibited tumor growth. In addition, higher FOXM1 expression was detected in gastric cancer cells with chemoresistance. Both in vitro and in vivo studies illustrated that THIO strongly promoted the drug-resistant gastric cancer cells to chemotherapies, proved by the considerably decreased cell proliferation and epithelial-mesenchymal transition (EMT) process. Together, these findings revealed that FOXM1 was a promising therapeutic target for gastric cancer treatment, and THIO exerted potential as an therapeutic agent for the disease.
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Neoplasias Gástricas , Tioestreptona , Animais , Humanos , Camundongos , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/metabolismo , Regulação Neoplásica da Expressão Gênica , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Tioestreptona/farmacologia , Tioestreptona/uso terapêuticoRESUMO
Background: Abnormal glucose and lipid metabolism plays a critical role in gastric carcinogenesis and development. Hence, we presented a systematic analysis of glucose and lipid metabolism-related genes to explore their function and prognostic value in gastric cancer (GC). Methods: The consensus clustering algorithm was used to identify the molecular subtypes based on glucose and lipid metabolism-related genes. Subsequently, cox regression analysis and lasso regression analysis were utilized to establish a risk prediction model. A clinical nomogram was constructed to assist prognosis assessment. In addition, ESTIMATE and single-sample gene set enrichment analysis (ssGSEA) algorithms were performed to evaluate the immune infiltration of the metabolic model, and GSEA was used for enrichment analysis of the metabolic signature. Finally, we explored the association between the risk model and anti-cancer therapy for the purpose of clinical application for GC treatment. Results: GC samples were divided into 2 subtypes based on glucose and lipid metabolism-related genes, patients in cluster 2 had a better overall survival (OS) than those in cluster 1. Fifty-two genes were identified by univariable regression analysis. Finally, a 13-gene metabolic signature (CACNA1H, CHST1, IGFBP3, NASP, STC1, VCAN, NUP205, NUP43, PGM2L1, CAV1, ELOVL4, PRKAA2, TNFAIP8L3) was successfully constructed that demonstrated good performance in different datasets, as well as an independent hazardous factor for prognosis. In addition, the nomogram constructed with the clinical variables showed higher predictive efficacy for predicting the 1-, 3-, and 5-year OS. The 13-gene metabolic signature was significantly associated with immune scores and immune cell infiltration in high-risk group. Moreover, GSEA analysis revealed that cancer- and immune-related pathways were enriched in the high-risk group. Finally, our results indicated that there might exist an immunosuppressive status in the high-risk groups. Conclusions: This study demonstrated that glucose and lipid metabolism-related genes were significantly associated with prognosis. Meanwhile, it will provide novel insights into exploring the immunoregulation roles of these genes.
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Gastric cancer is a gastrointestinal tumor with high morbidity and mortality rates. Several factors influence its progression, cell death being an important element. In this review, we summarized the effects of necrosis, apoptosis, necroptosis, pyroptosis, ferroptosis, and eight less common cell death modalities on gastric cancer cells and the tumor microenvironment, detailed the molecular mechanisms of various cell death and their major regulatory pathways in gastric cancer, explored the prevalence and complexity of cell death in gastric cancer progression and highlighted the potentials of cell death-related therapies in gastric cancer.
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NFE2L3, also known as NFE2L3, is a nuclear transcription factor associated with the pathogenesis and progression of human tumors. To systematically and comprehensively investigate the role of NFE2L3 in tumors, a pan-cancer analysis was performed using multi-omics data, including gene expression analysis, diagnostic and prognostic analysis, epigenetic methylation analysis, gene alteration analysis, immune feature analysis, functional enrichment analysis, and tumor cell functional status analysis. Furthermore, the molecular mechanism of NFE2L3 in liver hepatocellular carcinoma (LIHC) was explored. The relationship between NFE2L3 expression and survival prognosis of patients with LIHC was analyzed and a nomogram prediction model was constructed. Our study showed that NFE2L3 expression was upregulated in most cancers, suggesting that NFE2L3 may play an important role in promoting cancer progression. NFE2L3 expression is closely related to DNA methylation, genetic alteration, immune signature, and tumor cell functional status in pan-cancers. Furthermore, NFE2L3 was demonstrated to be an independent risk factor for LIHC, and the nomogram model based on NFE2L3 expression had good prediction efficiency for the overall survival of patients with LIHC. In summary, our study indicated that NFE2L3 may be an important molecular biomarker for the diagnosis and prognosis of pan-cancer. NFE2L3 is expected to be a potential molecular target for the treatment of tumors.
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The lack of new drugs and resistance to existing drugs are serious problems in gastric cancer(GC) treatment. The research found polyphenols possess anti-Helicobacter pylori(Hp) and antitumor activities and may be used in the research and development of drugs for cancer prevention and treatment. However, polyphenols are affected by their chemical structures and physical properties, which leads to relatively low bioavailability and bioactivity in vivo. The intestinal flora can improve the absorption, utilization, and biological activity of polyphenols, whereas polyphenol compounds can increase the richness of the intestinal flora, reduce the activity of carcinogenic bacteria, stabilize the proportion of core flora, and maintain homeostasis of the intestinal microenvironment. Our review summarizes the gastrointestinal flora-mediated mechanisms of polyphenol against GC.
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Microbioma Gastrointestinal , Neoplasias Gástricas , Disponibilidade Biológica , Humanos , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Microambiente TumoralRESUMO
Ubiquitin binding enzyme E2S (UBE2S) is a member of ubiquitin binding enzyme family involved in a variety of biological functions, including cell cycle regulation, apoptosis, and regulation of the ubiquitination of proteins, which are closely correlated with the development of various tumors. However, its role in gastric cancer (GC) remains unknown. In this study, we found that UBE2S was upregulated in GC tissues and cells. Further, its high expression positively correlated with the tumor stage and indicated a poor prognosis. Knockout of UBE2S by CRISPR/Cas9-mediated strategy suppressed the growth of GC in vitro and in vivo. Moreover, RNA-Seq-based transcriptome analysis and tandem mass tag (TMT)-based quantitative proteomics analysis was performed for exploring the underlying mechanism. The multi-omics and verification results showed that UBE2S knockout-induced apoptosis and proliferation inhibition of GC cells was related to upregulation of FAS and the activation of the FAS-mediated apoptotic pathway. Moreover, a negative correlation between UBE2S and FAS expression was observed in GC tissue samples. Finally, the ubiquitination assay confirmed that knockout of UBE2S might activate endogenous FAS by inhibiting ubiquitination and degradation of p53 in GC cells. Collectively, UBE2S is expected to be a novel prognostic biomarker and potential therapeutic target for GC.