Pathogenesis Of Gastric Cancer Research Articles

A potential target of GXYLT2 affecting the prognosis of gastric cancer by enhancing the EMT process: A clinical retrospective study.

The present study aimed to investigate glucoside xylosyltransferase 2 (GXYLT2) as a potential prognostic marker for gastric cancer (GC). The expression levels of GXYLT2, Notch1, E-cadherin and vimentin in GC and adjacent tissues were detected by Elivision™️ Plus immunohistochemistry. The relationship between GXYLT2, Notch1, E-cadherin and vimentin, and clinicopathological parameters was also analyzed. Univariate and multivariate Cox regression analyses were conducted to evaluate the effect of GXYLT2 on survival. The results revealed that GC tissues exhibited a marked increase in GXYLT2, Notch1 and vimentin, and a marked reduction in E-cadherin. The expression of GXYLT2 was related to the differentiation degree of GC and the pathological tumor-node-metastasis (pTNM) stage; the expression of Notch1 was related to the vascular and nerve infiltration of GC; and E-cadherin and vimentin expression were related to patient age, tumor size, tumor differentiation degree, depth of infiltration, lymph node metastasis and pTNM stage. Positive associations existed between GXYLT2 and Notch1 expression, GXYLT2 and vimentin expression, and Notch1 and vimentin expression. Furthermore, the Kaplan-Meier analysis showed that survival and prognosis were associated with factors such as GXYLT2 protein levels, pTNM stage, tumor dimensions, depth of infiltration and lymph node metastasis. Through Cox regression analysis, GXYLT2 was identified as an independent predictor for GC. In conclusion, GXYLT2 may be related to the pathogenesis of GC, and its abnormal expression could be associated with epithelial-mesenchymal transition. Consequently, GXYLT2 may be considered a promising prognostic marker in the context of GC.

Gastrointestinal Microbiota in Gastric Cancer: Potential Mechanisms and Clinical Applications-A Literature Review.

Emerging evidence highlights the crucial role of gastrointestinal microbiota in the pathogenesis of gastric cancer. Helicobacter pylori (H. pylori) infection stands out as a primary pathogenic factor. However, interventions such as anti-H. pylori therapy, gastric surgeries, immunotherapy, and chronic inflammation significantly remodel the gastric microbiome, implicating a broader spectrum of microorganisms in cancer development. These microbial populations can modulate gastric carcinogenesis through various mechanisms, including sustained chronic inflammation, bacterial genotoxins, alterations in short-chain fatty acids, elevated gastrointestinal bile acids, impaired mucus barrier function, and increased concentrations of N-nitrosamines and lactic acid. The dynamic changes in gut microbiota also critically influence the outcomes of anti-cancer therapies by modifying drug bioavailability and metabolism, thus affecting therapeutic efficacy and side effect profiles. Additionally, the effectiveness of radiotherapy can be significantly impacted by gut microbiota alterations. Novel therapeutic strategies targeting the microbiome, such as dietary interventions, probiotic and synbiotic supplementation, and fecal microbiota transplantation, are showing promise in cancer treatment. Understanding the intricate relationship between the gut microbiota and gastric cancer is essential for developing new, evidence-based approaches to the prevention and treatment of this malignancy.

Integrated Analysis of Serum and Tissue microRNA Transcriptome for Biomarker Discovery in Gastric Cancer.

Gastric cancer (GC) poses a significant global health challenge, demanding a detailed exploration of its molecular landscape. Studies suggest that exposure to environmental pollutants can lead to changes in microRNA (miRNA) expression patterns, which may contribute to the development and progression of GC. MiRNAs have emerged as crucial regulators implicated in GC pathogenesis. The largest GC serum miRNA dataset to date, comprising 1417 non-cancer controls and 1417 GC samples was used. We conducted a comprehensive analysis of miRNA expression profiles. Differential expression analysis, co-expression network construction, and machine learning models were employed to identify key serum miRNAs and their association with clinical parameters. Weighted Gene Co-expression Network Analysis (WGCNA) and immune infiltration analysis were used to validate the importance of the key miRNA. A total of 1766 differentially expressed miRNAs were identified, with miR-1290, miR-1246, and miR-451a among the top up-regulated, and miR-6875-5p, miR-6784-5p, miR-1228-5p, and miR-6765-5p among the top down-regulated. WGCNA revealed that modules M1 and M5 were significantly associated with GC subtypes and disease status. MiRNA-target gene network analysis identified prognostically significant genes TP53, EMCN, CBX8, and ALDH1A3. Machine learning models LASSO, SVM, randomforest, and XGBOOST demonstrated the diagnostic potential of miRNA profiles. Tissue and serum miR-187 emerged as an independent prognostic factor, influencing patient survival across clinical parameters. Gene expression and immune cell infiltration were different in tissues stratified by miR-187 expression. In summary, the integration of differential gene expression, co-expression analysis, and immune cell profiling provided insights into the molecular intricacies of GC progression.

Integrin β5, a noninvasive diagnostic biomarker, is associated with unfavorable prognosis and immunotherapy efficacy in gastric cancer

BackgroundIntegrin β5 (ITGB5) is a pivotal player in the pathogenesis of gastric cancer (GC). We aimed to explore the potential value of ITGB5 as a predictor of diagnosis and immunotherapy in gastric cancer.MethodsThe expression of ITGB5 in GC was assessed using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and verified through quantitative polymerase chain reaction (qPCR) and immunohistochemistry. Kaplan-Meier curves were conducted to evaluate the prognostic significance. The immune cells infiltration, tumor mutational burden (TMB), and immunophenoscore (IPS) were examined using CIBERSORT, TIMER, and TISIDB. In addition, colony formation, scratch assays, and transwell assays were employed to determine the impact on tumor progression and metastasis. CD276 expression was detected by western blotting following the knockdown of ITGB5. ELISA was utilized to measure serum ITGB5 levels.ResultsThe expression of ITGB5 in GC tissue surpassed that in normal tissue, it might contribute to GC pathogenesis through pathways including PI3K-AKT, ECM-receptor interaction, and TGF-beta. The elevated ITGB5 expression is associated with poor prognosis in GC patients. In addition, a strong positive association between ITGB5 overexpression and the infiltration levels of macrophages and monocytes, and it significantly influenced immune response. Moreover, lower expression of ITGB5 was associated with better immunotherapy efficacy. Subsequent investigation demonstrated that silencing of ITGB5 suppressed the proliferation and migration of GC cell lines in vitro. ITGB5 expression was positively correlated with CD276 expression and the knockdown of ITGB5 resulted a notable decrease CD276 expression. Futhermore, a significantly high level of serum ITGB5 was observed in GC patients. The combined assessment of ITGB5, CEA, and CA19-9 improved the diagnostic accuracy.ConclusionsITGB5 potentially serve as both a diagnostic biomarker and therapeutic target in managing GC.

Investigating Full-Length circRNA Transcripts to Reveal circRNAMediated Regulation of Competing Endogenous RNAs in Gastric Cancer

Background: Circular RNAs (circRNAs) play important regulatory roles in the progression of gastric cancer (GC), but the exact mechanisms governing their regulation remain incompletely understood. Prior studies typically used back-spliced junctions (BSJs) to represent a range of circRNA isoforms, overlooking the prevalence of alternative splicing (AS) events within circRNAs, which could lead to unreliable or even incorrect conclusions in subsequent analyses, hindering our comprehension of the specific functions of circRNAs in GC. Objective: This study aimed to explore the potential functional roles of the dysregulated circRNA transcripts in GC and provide new biomarkers and effective novel therapeutic strategies for GC treatment. Methods: RNA-seq data with rRNA depletion and RNase R treatment was employed to characterize the expression profiles of circRNAs in GC, and RNA-seq data only with rRNA depletion was employed to identify differentially expressed mRNAs in GC. Based on the full-sequence information and accurate isoform-level quantification of circRNA transcripts calculated by the CircAST tool, we performed a series of bioinformatic analyses. A circRNA-miRNA-hub gene regulatory network was constructed to reveal the circRNA-mediated regulation of competing endogenous RNAs in GC, and then the protein-protein interaction (PPI) network was built to identify hub genes. Results: A total of 18,398 circular transcripts were successfully reconstructed in the samples. Herein, 351 upregulated and 177 downregulated circRNA transcripts were identified. Functional enrichment analysis revealed that their parental genes were strongly associated with GC. After several screening steps, 19 dysregulated circRNA transcripts, 40 related miRNAs, and 65 target genes (mRNAs) were selected to construct the ceRNA network. Through PPI analysis, five hub genes (COL5A2, PDGFRB, SPARC, COL1A2, and COL4A1) were excavated. All these hub genes may play vital roles in gastric cancer cell proliferation and invasion. Conclusion: Our study revealed a comprehensive profile of full-length circRNA transcripts in GC, which could provide potential prognostic biomarkers and targets for GC treatment. The results would be helpful for further studies on the biological roles of circRNAs in GC and offer new mechanistic insights into the pathogenesis of GC.

Comprehensive analysis reveals that P4HA3 is a prognostic and diagnostic gastric cancer biomarker that can predict immunotherapy efficacy

Gastric cancer (GC) is one of the most challenging malignant tumors worldwide, primarily because of its high incidence and mortality rates. Prolyl 4-hydroxylase subunit alpha 3 (P4HA3) has been established as a pivotal factor for facilitating cell proliferation, invasion, and metastasis across multiple human tumors. Nevertheless, the precise role of P4HA3in GC has not been fully elucidated. In this study, we used data from The Cancer Genome Atlas (TCGA) to examine the role of P4HA3 as a potential biomarker for predicting immunotherapy response in patients with GC. Our comprehensive analysis of data from the TCGA, TIMER, and other databases revealed a significant association between elevated P4HA3 expression in GC and adverse prognostic outcomes. Furthermore, we confirmed that P4HA3 expression was strongly correlated with immune infiltrating cells, immune infiltration markers, the tumor mutational burden (TMB), microsatellite instability (MSI), the immune score, the stromal score, and immune checkpoints, thus highlighting P4HA3 as a crucial and dependable therapeutic target within the context of immune-based antitumor strategies. Our findings suggest that P4HA3 may function as an immune-related biomarker in the pathogenesis and treatment of GC, indicating that P4HA3 is a promising prognostic and therapeutic target for this malignancy.

Causal relationship between circulating immune cells and gastric cancer: a bidirectional Mendelian randomization analysis using UK Biobank and FinnGen datasets.

The role of immune cells in cancer pathogenesis remains controversial due to conflicting reports, potentially arising from various confounding factors. Emerging evidence suggests that cancer can also influence immune cell populations and functions, making it challenging to investigate their causal relationship. Traditional observational studies often fail to eliminate all confounding factors and are prone to reverse causality. Therefore, we employ Mendelian randomization (MR) to determine the causal relationship between immune cells and cancer, as this method can identify causal relationships independent of confounding factors and avoid reverse causality. Genome-wide association study (GWAS) summary statistics on immune traits, encompassing 310 immune cell phenotypes, were obtained from 3,757 European individuals, with peripheral blood immune cells tested using flow cytometry. GWAS summary statistics for gastric cancer were derived from 476,116 European individuals across two large-scale biobanks: the UK Biobank and FinnGen. Gastric cancer was identified by the International Classification of Diseases, 9th Revision (ICD-9), and 10th Revision (ICD-10) codes. Significant single nucleotide polymorphisms (SNPs) for immune traits were extracted at a threshold of P<1×10-5, while a threshold of P<5×10-8 was used for gastric cancer GWAS data. Linkage imbalance-based clumping was performed to obtain independent SNPs, and those with F<10 were excluded to mitigate weak instrument bias. Phenoscanner V2 was used to exclude SNPs directly associated with potential confounders or outcomes. Two-sample MR was conducted using five MR methods, with inverse-variance-weighted (IVW) as the primary analysis method. A false discovery rate (FDR) correction was used to reduce the likelihood of type 1 errors. In addition, we conducted MR-Egger intercept tests and Cochran's Q tests. The numbers of CD4-CD8- T cells and IgD-CD27- B cells were positively correlated with the development of gastric cancer, with odds ratios (ORs) of 1.15 [95% confidence interval (CI), 1.07-1.24; P<0.001; PFDR=0.041; IVW method] and 1.07 (95% CI, 1.03-1.11; P=0.001; PFDR=0.187; IVW method), respectively. However, the percentage of IgD+CD24- B cells in lymphocytes were negatively associated with the development of gastric cancer (OR =0.90; 95% CI, 0.84-0.96; P=0.002; PFDR=0.187; IVW method). MR analysis of the above three immune cell phenotypes showed no significant heterogeneity or horizontal pleiotropy. In the reverse MR analysis, gastric cancer was not causally associated with any of the immune cell phenotypes. Circulating CD4-CD8- T cells and IgD-CD27- B cells are positively correlated with the development of gastric cancer, while the percentage of IgD+CD24- B cells in lymphocytes are negatively correlated. These findings provide insight into the relationship between immune cells and gastric cancer pathogenesis and may serve as a basis for the development of immunotherapies for gastric cancer.

Reducing metastasis ability of gastric cancer cell line by targeting MMP16 using miR-193a-5p and 5-FU

PurposeCo-administration of microRNAs and chemotherapy drugs effectively treats several cancers. The current study sought to investigate the function of matrix metalloproteinase 16 (MMP16) and miR-193a-5p in the pathogenesis of gastric cancer (GC). Materials/methodsSixty-five surgical patients, 15 receiving 5-fluorouracil (5-FU), provided GC and adjacent non-cancerous tissue. Following that, qPCR was used to assess the expression levels of MMP16 and miR-193a-5p in GC cells. The impact of miR-193a-5p and 5-FU administration on MMP16 mRNA expression was evaluated using qRT-PCR and Western blotting. MTT and Scratch tests were also conducted to assess their effects on cell viability and migration. Moreover, a rescue experiment using an MTT assay was performed. Using flow cytometry, the apoptotic rate was calculated. Finally, it was evaluated how MMP16 and miR-193a-5p related to the clinicopathological characteristics of the patients. ResultsThe current study found that while MMP16 expression increased in GC patients (P ​< ​0.0001), miR-193a-5p expression significantly decreased (P ​< ​0.001). MMP16 down-regulation was another effect of miR-193a-5p replacement, particularly when 5-FU was added (P ​< ​0.01). In addition, this study found that miR-193a-5p, by concentrating on MMP16, decreased the migration of GC cells brought on by MMP16. In GC cell lines, miR-193 and 5-FU induce apoptosis, with the 5-FU being more pronounced when combined with mir-193, according to flow cytometry results. A strong correlation was also found between clinicopathological traits associated with MMP16 and miR-193a-5p. ConclusionsThese findings suggest that miR-193a-5p, in conjunction with 5-FU, down-regulates MMP16 in GC, where it suppresses tumor growth.

Investigation of the Mechanism of SEMA5A and Its Associated Autophagy-Related Genes in Gastric Cancer.

Semaphorin 5A (SEMA5A) and autophagy-related genes (ARGs) are pivotal in the pathogenesis of gastric cancer (GC). However, the potential regulatory role of SEMA5A in autophagy via its associated ARGs and the underlying molecular mechanisms remain unresolved. GC-related datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were analyzed to identify differentially expressed genes (DEGs) between GC and control samples. The intersection of DEGs with ARGs produced candidate genes, which were further analyzed using Spearman correlation with SEMA5A to identify signature genes. Stratification of GC samples based on signature gene expression, followed by Kaplan-Meier survival analysis, identified key genes. Subsequent analyses, including gene set enrichment analysis (GSEA), immune infiltration, and immune checkpoint evaluation, were conducted on the key genes and SEMA5A. The mRNA expression level was quantified using real-time quantitative polymerase chain reaction (RT-qPCR). Ninety candidate genes were identified for Spearman correlation with SEMA5A, revealing TNFSF11, BMP6, ITPR1, and DLC1 with correlation coefficients exceeding 0.3. Survival analysis underscored DLC1 and BMP6 as key genes due to significant prognostic differences. GSEA implicated SEMA5A, BMP6, and DLC1 in the ECM receptor interaction pathway. Immune infiltration analysis indicated a negative correlation of SEMA5A and BMP6 with M1 macrophages, while DLC1 exhibited the strongest association with the immune checkpoint PDCD1LG2 (p < 0.05, cor = 0.43). The mRNA expression level of SEMA5A was significantly upregulated in AGS parental cells compared to GES-1 cells (p < 0.01), whereas DLC1 and BMP6 mRNA levels were markedly downregulated in AGS parental cells relative to GES-1 (p < 0.0001). ARGs BMP6 and DLC1, associated with SEMA5A, were identified, and their prognostic significance in GC was demonstrated. Additionally, their regulatory mechanisms were further elucidated through immune infiltration analysis and molecular network construction, providing a theoretical foundation for future research on the molecular mechanisms in patients with GC.

LncRNA HAGLR regulates gastric cancer progression by regulating the miR-20a-5p/E2F1 axis.

Gastric cancer (GC) stands as a prevalent and challenging malignancy within the gastrointestinal tract. The potential of long non-coding RNAs (lncRNAs) as biomarkers and therapeutic targets in oncology has garnered immense research interest. This study aims to elucidate the relevance, biological roles, and mechanistic pathways of LncRNA HAGLR in the context of GC. The assessments of cell proliferation, migration, and invasion were executed using CCK-8, wound healing, and Transwell assays. The interactions between HAGLR, miR-20a-5p, and E2F1 were appraised through luciferase reporter assays, fluorescence in situ hybridization (FISH), and RNA immunoprecipitation (RIP). A tumor xenograft model provided in vivo validation for in vitro findings. Elevated levels of HAGLR in GC cells and tissue specimens were linked to worse patient outcomes. The inhibition of HAGLR led to a decrease in GC cell proliferation, migration, and invasion, whereas its activation prompted contrary effects. The impact of HAGLR on cell migration and invasion was notably associated with epithelial-mesenchymal transition (EMT). Through bioinformatics, luciferase reporter assays, FISH, RIP, and Western blot analyses, it was revealed that HAGLR acts as a molecular sponge for miR-20a-5p, consequently augmenting E2F1 levels. The data suggest that the HAGLR/miR-20a-5p/E2F1 regulatory cascade is implicated in GC pathogenesis, offering a novel therapeutic avenue for GC management.

Development and validation of a hypoxia- and mitochondrial dysfunction- related prognostic model based on integrated single-cell and bulk RNA sequencing analyses in gastric cancer.

Gastric cancer (GC) remains a major global health threat ranking as the fifth most prevalent cancer. Hypoxia, a characteristic feature of solid tumors, significantly contributes to the malignant progression of GC. Mitochondria are the major target of hypoxic injury that promotes mitochondrial dysfunction during the development of cancers including GC. However, the gene signature and prognostic model based on hypoxia- and mitochondrial dysfunction-related genes (HMDRGs) in the prediction of GC prognosis have not yet been established. The gene expression profile datasets of stomach cancer patients were retrieved from The Cancer Genome Atlas and the Gene Expression Omnibus databases. Prognostic genes were selected using Least Absolute Shrinkage andSelection Operator Cox (LASSO-Cox) regression analysis to construct a prognostic model. Immune infiltration was evaluated through ESTIMATE, CIBERSORT, and ssGSEA analyses. Tumor immune dysfunction and exclusion (TIDE) and immunophenoscore (IPS) were utilized to explore implications for immunotherapy. Furthermore, in vitro experiments were conducted to validate the functional roles of HMDRGs in GC cell malignancy. In this study, five HMDRGs (ZFP36, SERPINE1, DUSP1, CAV1, and AKAP12) were identified for developing a prognostic model in GC. This model stratifies GC patients into high- and low-risk groups based on median risk scores. A nomogram predicting overall survival (OS) was constructed and showed consistent results with observed OS. Immune infiltration analysis indicated that individuals in the high-risk group tend to exhibit increased immune cell infiltration. Additionally, analysis of cancer immunotherapy responses revealed that high-risk group patients exhibit poorer responses to cancer immunotherapy compared to the low-risk group. Immunohistochemistry (IHC) staining indicated that the expression levels of HMDRGs were remarkably correlated with GC, of which, SERPINE1 displayed the most pronounced up-regulation, while ZFP36 exhibited the most notable down-regulation in GC patients. Furthermore, in vitro investigation validated that SERPINE1 and ZFP36 contribute to the malignant processes of GC cells correlated with mitochondrial dysfunction. This study presents a novel and efficient approach to evaluate GC prognosis and immunotherapy efficacy, and also provides insights into understanding the pathogenesis of GC.

Unraveling the influence of LncRNA in gastric cancer pathogenesis: a comprehensive review focus on signaling pathways interplay.

Gastric cancers (GCs) are among the most common and fatal malignancies in the world. Despite our increasing understanding of the molecular mechanisms underlying GC, further biomarkers are still needed for more in-depth examination, focused prognosis, and treatment. GC is one among the long non-coding RNAs, or lncRNAs, that have emerged as key regulators of the pathophysiology of cancer. This comprehensive review focuses on the diverse functions of long noncoding RNAs (lncRNAs) in the development of GC and their interactions with important intracellular signaling pathways. LncRNAs affect GC-related carcinogenic signaling cascades including pathways for EGFR, PI3K/AKT/mTOR, p53, Wnt/β-catenin, JAK/STAT, Hedgehog, NF-κB, and hypoxia-inducible factor. Dysregulated long non-coding RNA (lncRNA) expression has been associated with multiple characteristics of cancer, such as extended growth, apoptosis resistance, enhanced invasion and metastasis, angiogenesis, and therapy resistance. For instance, lncRNAs such as HOTAIR, MALAT1, and H19 promote the development of GC via altering these pathways. Beyond their main roles, GC lncRNAs exhibit potential as diagnostic and prognostic biomarkers. The overview discusses CRISPR/Cas9 genome-modifying methods, antisense oligonucleotides, small molecules, and RNA interference as potential therapeutic approaches to regulate the expression of long noncoding RNAs (lncRNAs). An in-depth discussion of the intricate functions that lncRNAs play in the development of the majority of stomach malignancies is provided in this review. It provides the groundwork for future translational research in lncRNA-based whole processes toward GC by highlighting their carcinogenic effects, regulatory roles in significant signaling cascades, and practical scientific uses as biomarkers and therapeutic targets.

Comprehensive landscape of integrator complex subunits and their association with prognosis and tumor microenvironment in gastric cancer.

The integrator complex (INT) is a multiprotein assembly in gene transcription. Although several subunits of INT complex have been implicated in multiple cancers, the complex's role in gastric cancer (GC) is poorly understood. The gene expressions, prognostic values, and the associations with microsatellite instability (MSI) of INT subunits were confirmed by GEO and The Cancer Genome Atlas (TCGA) databases. cBioPortal, GeneMANIA, TISIDB, and MCPcounter algorithm were adopted to investigate the mutation frequency, protein-protein interaction network, and the association with immune cells of INT subunits in GC. Additionally, in vitro experiments were performed to confirm the role of INTS11 in pathogenesis of GC. The mRNA expression levels of INTS2/4/5/7/8/9/10/11/12/13/14 were significantly elevated both in GSE183904 and TCGA datasets. Through functional enrichment analysis, the functions of INT subunits were mainly associated with snRNA processing, INT, and DNA-directed 5'-3' RNA polymerase activity. Moreover, these INT subunit expressions were associated with tumor-infiltrating lymphocytes and MSI in GC. In vitro experiments demonstrated that knockdown of the catalytic core INTS11 in GC cells inhibits cell proliferation ability. INTS11 overexpression showed opposite effects. Our data demonstrate that the INT complex might act as an oncogene and can be used as a prognosis biomarker for GC.

Increased ONECUT2 induced by Helicobacter pylori promotes gastric cancer cell stemness via an AKT-related pathway

Helicobacter pylori (HP) infection initiates and promotes gastric carcinogenesis. ONECUT2 shows promise for tumor diagnosis, prognosis, and treatment. This study explored ONECUT2’s role and the specific mechanism underlying HP infection-associated gastric carcinogenesis to suggest a basis for targeting ONECUT2 as a therapeutic strategy for gastric cancer (GC). Multidimensional data supported an association between ONECUT2, HP infection, and GC pathogenesis. HP infection upregulated ONECUT2 transcriptional activity via NFκB. In vitro and in vivo experiments demonstrated that ONECUT2 increased the stemness of GC cells. ONECUT2 was also shown to inhibit PPP2R4 transcription, resulting in reduced PP2A activity, which in turn increased AKT/β-catenin phosphorylation. AKT/β-catenin phosphorylation facilitates β-catenin translocation to the nucleus, initiating transcription of downstream stemness-associated genes in GC cells. HP infection upregulated the reduction of AKT and β-catenin phosphorylation triggered by ONECUT2 downregulation via ONECUT2 induction. Clinical survival analysis indicated that high ONECUT2 expression may indicate poor prognosis in GC. This study highlights a critical role played by ONECUT2 in promoting HP infection-associated GC by enhancing cell stemness through the PPP2R4/AKT/β-catenin signaling pathway. These findings suggest promising therapeutic strategies and potential targets for GC treatment.

The role of dysregulated metabolism and associated genes in gastric cancer initiation and development.

The review delves into the intricate interplay between metabolic dysregulation and the onset and progression of gastric cancer (GC), shedding light on a pivotal aspect of this prevalent malignancy. GC stands as one of the leading causes of cancer-related mortality worldwide, its trajectory influenced by a multitude of factors, among which metabolic dysregulation and aberrant gene expression play significant roles. The article navigates through the fundamental roles of metabolic dysregulation in the genesis of GC, unveiling phenomena such as aberrant glycolysis, epitomized by the Warburg effect, alongside anomalies in lipid and amino acid metabolism. It delineates how these disruptions fuel the cancerous process, facilitating uncontrolled cell proliferation and survival. Furthermore, the intricate nexus between metabolism and the vitality of GC cells is elucidated, underscoring the profound influence of metabolic reprogramming on tumor energy dynamics and the accrual of metabolic by-products, which further perpetuate malignant growth. A pivotal segment of the review entails an exploration of key metabolic-related genes implicated in GC pathogenesis. MYC and TP53 are spotlighted among others, delineating their pivotal roles in driving tumorigenesis through metabolic pathway modulation. These genetic pathways serve as critical nodes in the intricate network orchestrating GC development, providing valuable targets for therapeutic intervention. This review embarks on a forward-looking trajectory, delineating the potential therapeutic avenues stemming from insights into metabolic dysregulation in GC. It underscores the promise of targeted therapies directed towards specific metabolic pathways implicated in tumor progression, alongside the burgeoning potential of combination therapy strategies leveraging both metabolic and conventional anti-cancer modalities. In essence, this comprehensive review serves as a beacon, illuminating the intricate landscape of metabolic dysregulation in GC pathogenesis. Through its nuanced exploration of metabolic aberrations and their genetic underpinnings, it not only enriches our understanding of GC biology but also unveils novel therapeutic vistas poised to revolutionize its clinical management.

Identification and validation of key genes in gastric cancer: insights from in silico analysis, clinical samples, and functional assays.

The underlying mechanisms of gastric cancer (GC) remain unknown. Therefore, in this study, we employed a comprehensive approach, combining computational and experimental methods, to identify potential key genes and unveil the underlying pathogenesis and prognosis of GC. Gene expression profiles from GEO databases (GSE118916, GSE79973, and GSE29272) were analyzed to identify DEGs between GC and normal tissues. A PPI network was constructed using STRING and Cytoscape, followed by hub gene identification with CytoHubba. Investigations included expression and promoter methylation analysis, survival modeling, mutational and miRNA analysis, gene enrichment, drug prediction, and in vitro assays for cellular behaviors. A total of 83 DEGs were identified in the three datasets, comprising 41 up-regulated genes and 42 down-regulated genes. Utilizing the degree and MCC methods, we identified four hub genes that were hypomethylated and up-regulated: COL1A1, COL1A2, COL3A1, and FN1. Subsequent validation of their expression and promoter methylation on clinical GC samples through targeted bisulfite sequencing and RT-qPCR analysis further confirmed the hypomethylation and overexpression of these genes in local GC patients. Furthermore, it was observed that these hub genes regulate tumor proliferation and metastasis in in vivo and exhibited mutations in GC patients. We found four potential diagnostic and prognostic biomarkers, including COL1A1, COL1A2, COL3A1, and FN1 that may be involved in the occurrence and progression of GC.

Helicobacter Pylori-Enhanced hnRNPA2B1 Coordinates with PABPC1 to Promote Non-m6A Translation and Gastric Cancer Progression.

Helicobacter pylori (H. pylori) infection is the primary risk factor for the pathogenesis of gastric cancer (GC). N6-methyladenosine (m6A) plays pivotal roles in mRNA metabolism and hnRNPA2B1 as an m6A reader is shown to exert m6A-dependent mRNA stabilization in cancer. This study aims to explore the role of hnRNPA2B1 in H. pylori-associated GC and its novel molecular mechanism. Multiple datasets and tissue microarray are utilized for assessing hnRNPA2B1 expression in response to H. pylori infection and its clinical prognosis in patients with GC. The roles of hnRNPA2B1 are investigated through a variety of techniques including glucose metabolism analysis, m6A-epitranscriptomic microarray, Ribo-seq, polysome profiling, RIP-seq. In addition, hnRNPA2B1 interaction with poly(A) binding protein cytoplasmic 1 (PABPC1) is validated using mass spectrometry and co-IP. These results show that hnRNPA2B1 is upregulated in GC and correlated with poor prognosis. H. pylori infection induces hnRNPA2B1 upregulation through recruiting NF-κB to its promoter. Intriguingly, cytoplasm-anchored hnRNPA2B1 coordinated PABPC1 to stabilize its relationship with cap-binding eIF4F complex, which facilitated the translation of CIP2A, DLAT and GPX1 independent of m6A modification. In summary, hnRNPA2B1 facilitates the non-m6A translation of epigenetic mRNAs in GC progression by interacting with PABPC1-eIF4F complex and predicts poor prognosis for patients with GC.

Plasma metabolomics and lipidomics reveal potential novel biomarkers in early gastric cancer: An explorative study.

Early identification and therapy can significantly improve the outcome for gastric cancer. However, there is still no perfect biomarker available for the detection of early gastric cancer. This study aimed to investigate the alterations in the plasma metabolites of early gastric cancer using metabolomics and lipidomics based on high-performance liquid chromatography-mass spectrometry (HPLC-MS), which detected potential biomarkers that could be used for clinical diagnosis. To investigate the changes in metabolomics and lipidomics, a total of 30 plasma samples were collected, consisting of 15 patients with early gastric cancer and 15 healthy controls. Extensive HPLC-MS-based untargeted metabolomic and lipidomic investigations were conducted. Differential metabolites and metabolic pathways were uncovered through the utilization of statistical analysis and bioinformatics analysis. Candidate biomarker screening was performed using support vector machine-based multivariate receiver operating characteristic analysis. A disturbance was observed in a combined total of 19 metabolites and 67 lipids of the early gastric cancer patients. The analysis of KEGG pathways showed that the early gastric cancer patients experienced disruptions in the arginine biosynthesis pathway, the pathway for alanine, aspartate, and glutamate metabolism, as well as the pathway for glyoxylate and dicarboxylate metabolism. Plasma metabolomics and lipidomics have identified multiple biomarker panels that can effectively differentiate early gastric cancer patients from healthy controls, exhibiting an area under the curve exceeding 0.9. These metabolites and lipids could potentially serve as biomarkers for the screening of early gastric cancer, thereby optimizing the strategy for the detection of early gastric cancer. The disrupted pathways implicated in early gastric cancer provide new clues for additional understanding of gastric cancer's pathogenesis. Nonetheless, large-scale clinical data are required to prove our findings.

The potential contribution of aberrant cathepsin K expression to gastric cancer pathogenesis

The role of cathepsin K (CTSK) expression in the pathogenesis and progression of gastric cancer (GC) remains unclear. Hence, the primary objective of this study is to elucidate the precise expression and biological role of CTSK in GC by employing a combination of bioinformatics analysis and in vitro experiments. Our findings indicated a significant upregulation of CTSK in GC. The bioinformatics analysis revealed that GC patients with a high level of CTSK expression exhibited enrichment of hallmark gene sets associated with angiogenesis, epithelial–mesenchymal transition (EMT), inflammatory response, KRAS signaling up, TNFα signaling via KFκB, IL2-STAT5 signaling, and IL6-JAK-STAT3 signaling. Additionally, these patients demonstrated elevated levels of M2-macrophage infiltration, which was also correlated with a poorer prognosis. The results of in vitro experiments provided confirmation that the over-expression of CTSK leads to an increase in the proliferative and invasive abilities of GC cells. However, further evaluation was necessary to determine the impact of CTSK on the migration capability of these cells. Our findings suggested that CTSK has the potential to facilitate the initiation and progression of GC by augmenting the invasive capacity of GC cells, engaging in tumor-associated EMT, and fostering the establishment of an immunosuppressive tumor microenvironment (TME).

Fruquintinib plus paclitaxel versus placebo plus paclitaxel for gastric or gastroesophageal junction adenocarcinoma: the randomized phase 3 FRUTIGA trial.

The vascular endothelial growth factor pathway plays a key role in the pathogenesis of gastric cancer. In the multicenter, double-blind phase 3 FRUTIGA trial, 703 patients with advanced gastric or gastroesophageal junction adenocarcinoma who progressed on fluorouracil- and platinum-containing chemotherapy were randomized (1:1) to receive fruquintinib (an inhibitor of vascular endothelial growth factor receptor-1/2/3; 4 mg orally, once daily) or placebo for 3 weeks, followed by 1 week off, plus paclitaxel (80 mg/m2 intravenously on days 1/8/15 per cycle). The study results were positive as one of the dual primary endpoints, progression-free survival (PFS), was met (median PFS, 5.6 months in the fruquintinib arm versus 2.7 months in the placebo arm; hazard ratio 0.57; 95% confidence interval 0.48-0.68; P < 0.0001). The other dual primary endpoint, overall survival (OS), was not met (median OS, 9.6 months versus 8.4 months; hazard ratio 0.96, 95% confidence interval 0.81-1.13; P = 0.6064). The most common grade ≥3 adverse events were neutropenia, leukopenia and anemia. Fruquintinib plus paclitaxel as a second-line treatment significantly improved PFS, but not OS, in Chinese patients with advanced gastric or gastroesophageal junction adenocarcinoma and could potentially be another treatment option for these patients. ClinicalTrials.gov registration: NCT03223376 .