ALYREF expression correlated with upregulated YBX1 and HIF1α, contributing to cell migration in gastric cancer.

Integrated bioinformatics and tissue-based validation reveal the oncogenic role of hsa_circ_0043256 and hsa_circ_0004789 in gastric cancer

TMEM176A drives anti-apoptotic signaling through TGM2-mediated ERK activation in gastric cancer.

Combining multi-omics analysis and network toxicology to explore the role and underlying mechanisms of an environmental pollutant in gastric cancer: A study of Diisononyl Phthalate.

Tumor-derived C4BPA promotes macrophage M2-like polarization through C5a -C5aR1-STAT3 axis and drives gastric cancer progression.

ERβ-PIK3R2 axis promotes estrogen-driven gastric cancer progression.

ObjectivesChromobox 4 (CBX4), a polycomb protein family member linked to tumor pathogenesis via dysregulation, has an incompletely defined role in gastric cancer (GC). The study aimed to investigate the role and mechanism of CBX4 in GC progression and evaluate its potential as a therapeutic target.MethodsCBX4 expression was assessed in GC tissues vs. adjacent non-cancerous tissues and in GC cell lines vs. normal gastric mucosal epithelial cells. Clinicopathological correlations were analyzed. Functional impacts of CBX4 were determined using knockdown and overexpression models in vitro (cell proliferation, migration, invasion) and in vivo (xenograft tumorigenesis in nude mice). Mechanistic studies evaluated β-catenin levels (total and nuclear) and transcriptional activity following CBX4 modulation. The functional dependency on Wnt/β-catenin signaling was tested using the pharmacological inhibitor XAV939 in CBX4-overexpressing cells.ResultsCBX4 expression was significantly upregulated in GC tissues and cell lines. Elevated CBX4 levels strongly correlated with aggressive tumor characteristics, including larger tumor size, lymph node metastasis, and advanced Tumor, Node, Metastasis (TNM) stage. Functionally, CBX4 knockdown suppressed GC cell proliferation, migration, invasion in vitro, and tumorigenesis in vivo. Conversely, CBX4 overexpression enhanced these malignant traits. Mechanistically, CBX4 depletion reduced total and nuclear β-catenin levels and inhibited its transcriptional activity, while CBX4 overexpression had the opposite effect. Critically, XAV939-mediated inhibition of Wnt/β-catenin signaling attenuated the oncogenic effects induced by CBX4 overexpression.ConclusionCBX4 upregulation promotes GC progression via β-catenin signaling activation. The CBX4/β-catenin axis emerges as a promising therapeutic target, offering potential for the development of precision treatment strategies in GC management.

Cancer-associated fibroblasts (CAFs) play a pivotal role in Gastric cancer (GC) progression and immune modulation. This study aimed to identify CAF subtypes using single-cell analysis and evaluate their prognostic and therapeutic relevance in GC. CAF gene sets were derived from 13 single-cell datasets and quantified via ssGSEA in bulk transcriptomic cohorts (TCGA and GEO). Consensus clustering defined CAF-based subtypes. Immune infiltration was evaluated using CIBERSORT, xCell, MCPcounter, and ESTIMATE. Immunotherapy response was predicted using TIDE and ImmuCellAI. Chemotherapeutic sensitivity was assessed via PRISM, CTRP, and GDSC databases. Hub genes were identified by WGCNA, and a prognostic model was constructed and validated in external cohorts and at the single-cell level. Two CAF subtypes, FA_H and FA_L, were identified. FA_H was associated with poor prognosis, higher M2 macrophage infiltration, and immunosuppressive pathways, while FA_L correlated with improved survival and stronger predicted response to immune checkpoint inhibitors. Dasatinib was predicted as a potential therapeutic agent specifically for FA_H subtype. A five-gene prognostic model (COL1A2, NDN, SPARC, VCAN, TCEAL7) showed consistent predictive performance across datasets. Functional validation confirmed upregulation of TCEAL7 in CAFs and its role in promoting GC cell invasion. Single-cell-based CAF subtyping defines clinically relevant heterogeneity in GC. The FA_H subtype may serve as both a prognostic biomarker and therapeutic target, particularly for dasatinib-based or immunomodulatory strategies.

Our previous studies found that Menin was highly expressed in gastric cancer (GC) and could promote GC progression. Tumor microenvironment (TME), including cancer-associated fibroblasts (CAFs) and their exosomes plays pivotal roles in GC. It remains unclear whether exosomes derived from CAFs influence GC by delivering Menin. Primary CAFs and normal fibroblasts (NFs) were isolated from fresh GC tissues, and co-cultured with GC cells. After Men1 expression in CAFs and NFs was modulated, exosomes were extracted via ultracentrifugation and mixed with GC cells. Next, GC cell biological behaviors were assessed in vitro. A nude mouse model of lung metastasis was established, and a small animal in vivo imaging system was used to monitor the effects of exosomes on metastasis. HSPA6/JNK/JunD pathway components and EMT-related molecules were detected by Western blot. Menin was highly expressed in CAFs and in their exosomes. Co-culturing of CAFs with GC cells promoted the proliferation, invasion and migration of GC cells. After Men1 was knocked down in CAFs, exosomes derived from these CAFs inhibited the progression of GC both in vitro and in vivo. Conversely, after overexpressing Men1, exosomes from NFs promoted the progression of GC both in vitro and in vivo. The HSPA6/JNK/JunD pathway and EMT in GC cells were activated when GC cells were co-cultured with CAFs or exosomes from Menin-overexpressing NFs. CAFs can promote GC progression by delivering Menin-containing exosomes, which activates the HSPA6/JNK/JunD pathway and induces EMT. Targeting Menin within CAFs and GC cells and blocking the delivery of Menin by exosomes may provide novel strategies for GC treatment.

The lipopolysaccharide (LPS) of Helicobacter pylori (HP) is a critical virulence factor in gastric cancer development. As a toxic component of the HP cytoderm, HP LPS causes persistent inflammatory injury to the gastric mucosa. Although HP lipopolysaccharide exhibits weaker endotoxic activity, it still promotes gastric cancer progression by inducing chronic inflammation and enhancing cellular proliferation. However, the specific signaling pathways involved are not fully understood. GES-1, HGC-27, and MKN-45 cells were treated with LPS from HP and E. coli. Western blotting and a luciferase reporter assay were used to analyze MDM2 expression and transcriptional activity. Cell proliferation, migration, and invasion were evaluated through colony formation, scratch wound healing, and transwell assays. Immunohistochemistry was used to examine MDM2 and p53 expression, while immunofluorescence detected regulatory T cells. Gastric cancer mouse models were also used to confirm MDM2's role in gastric cancer. HP infection resulted in elevated MDM2 levels in gastric precancerous lesions and cancers. HP LPS enhances MDM2 expression in GC cells. This effect is mediated through TLR4/MAPK/AP-1, which promotes the proliferation and invasion of gastric cancer cells. In addition, MDM2 participated in Tregs infiltration and promoted the maintenance of an immunosuppressive tumor microenvironment in gastric cancer. HP LPS enhances MDM2 expression in GC cells through the TLR4/MAPK/AP-1 pathway. MDM2 mediates the protumor effects of HP LPS by promoting tumor cell proliferation and regulating Treg-mediated immune suppression. Our study deepens the understanding of gastric cancer progression and identifies MDM2 as an effective therapeutic target.

Helicobacter pylori is a globally prevalent pathogen implicated in multiple gastrointestinal malignancies. While its role in gastric cancer is well established, its association with extragastric malignancies such as gallbladder carcinoma (GBC), pancreatic carcinoma (PC), and colorectal carcinoma (CRC) remains contentious. To evaluate the prevalence of H. pylori in gallbladder, pancreatic, and colorectal malignancies and to assess its potential associations. This prospective observational study was conducted between January 2023 and March 2025 at a tertiary hospital in India. Seventy-six histologically confirmed cases of GBC (n = 42), CRC (n = 24), and PC (n = 10) underwent immunohistochemistry testing for H. pylori. The data were analyzed using SPSS v26.0; P < 0.05 was considered statistically significant. The overall prevalence of H. pylori was 22.4%. It was detected in 26.2% of GBC, 8.3% of CRC, and 40% of PC cases. However, no statistically significant association was found between H. pylori presence and any malignancy type (P > 0.05). Although H. pylori was detected in a subset of GBC, PC, and CRC cases, the association was not statistically significant. Further multicenter studies with larger cohorts are necessary to explore potential etiological roles.

Ubiquitin carboxyl-terminal hydrolase L3 (UCHL3) is a deubiquitinating enzyme involved in various cancers, yet its role in gastric cancer (GC) requires further exploration. This study primarily investigates the expression, function, and mechanisms of UCHL3 in GC. Clinical samples and bioinformatics analysis indicated that UCHL3 is overexpressed in GC tissues compared to adjacent normal tissues, with higher expression levels correlating with worse prognosis. Functional assays demonstrated that UCHL3 promotes GC cell proliferation, invasion, and migration, accelerates cell cycle progression, and induces epithelial–mesenchymal transition (EMT). In vivo studies using a cell line-derived xenograft (CDX) model confirmed that UCHL3 enhances GC proliferation, and its therapeutic potential was validated in patient-derived xenografts (PDX). Mechanistically, transcriptomic analysis and validation experiments identified the AKT/CCND1 signaling pathway as a key mediator of UCHL3-driven GC progression. Co-immunoprecipitation (Co-IP) and liquid chromatography-mass spectrometry identified potential UCHL3-binding proteins, notably the AKT activator ENO1. Molecular docking simulations, Co-IP, and GST-pull down assays further confirmed the interaction, mapping the binding regions between UCHL3 (AA 179-230) and ENO1 (AA 140-434). Cycloheximide (CHX) and in vivo ubiquitination assays demonstrated that UCHL3 deubiquitinates and stabilizes ENO1, thus extending its half-life, while UCHL3 inhibition produced the opposite effect. A C95A point mutation significantly impaired UCHL3’s deubiquitination function on ENO1. Further studies revealed UCHL3 removes K48-linked polyubiquitin chains from ENO1 at lysine 92, activating the AKT/CCND1 signaling pathway. In addition, the small-molecule inhibitor TCID, specific for UCHL3, inhibited this deubiquitination, counteracting pro-tumorigenic effects. In vitro and in vivo experiments demonstrated that TCID increased the sensitivity of GC cells to CDK4/6 inhibitors palbociclib. These findings suggest that UCHL3 contributes to GC progression and represents a promising therapeutic target for GC treatment.

BackgroundGrowth factor receptor-bound protein 14 (GRB14) has emerged as a significant regulator in cancer progression and prognosis across certain cancer types. Nevertheless, its role in gastric cancer (GC) remain poorly characterized.MethodsWe conducted a comprehensive investigation of GRB14 in GC, integrating bioinformatics analysis with experimental validation. The prognostic significance and functional profile of GRB14 was evaluated through survival analysis and GSEA. Additionally, we analyzed the variations in immune cell infiltration and responses to immunotherapy between groups with low and high expression levels of GRB14. To confirm GRB14 expression in GC tissues, we utilized RT-qPCR, western blot and immunohistochemistry (IHC) analysis. Subsequently, functional experiments were then employed to evaluate the functional role of GRB14 in GC cells.ResultsAnalysis of the TCGA_stomach adenocarcinoma (TCGA_STAD) cohort revealed notable GRB14 upregulation in GC tissues, which was subsequently validated through RT-qPCR, western blot and IHC analyses. Elevated GRB14 expression were found to correlate with poor clinical outcomes. GSEA results showed that the vitamin digestion and absorption, and retinol metabolism pathways were obviously inactivated in the high GRB14 expression group. Moreover, this group exhibited notably lower immune score, stromal score, ESTIMATE score, but higher tumor purity compared to the low GRB14 expression group. Meanwhile, patients in the high GRB14 expression group exhibited significant M2 macrophage infiltration and elevated TIDE scores, suggesting that high GRB14 expression may be linked to an immunosuppressive tumor microenvironment. Functional studies demonstrated that GRB14 deficiency remarkably reduced GC cell proliferation, migration and invasion, but induced cell apoptosis.ConclusionThis evidence highlights that GRB14 may serve as a potential candidate for both prognostic evaluation and therapeutic intervention in GC.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12672-025-03771-x.

Gastric cancer (GC) ranks among the most prevalent malignancies worldwide and is associated with high mortality rates. Ephrin-B2 (EFNB2), a membrane-bound ligand that interacts with Eph receptor tyrosine kinases, has been implicated in various cancer-related biological processes; however, its precise role in GC remains poorly understood. By integrating data from multiple public databases with immunohistochemical analyses of tissue microarrays, significant upregulation of EFNB2 expression in GC specimens compared with paired adjacent normal tissue was demonstrated. Elevated EFNB2 levels were associated with the poor overall survival and disease-free survival in patients with GC. EFNB2 knockdown inhibited cellular proliferation and viability, increased apoptosis, and induced cell cycle arrest at the G0/G1 phase in GC cells. By contrast, EFNB2 overexpression resulted in the opposite oncogenic effects. Mechanistically, rescue experiments identified the Wnt/β-catenin signaling cascade as the primary molecular pathway mediating EFNB2-driven tumorigenic effects. These results were further validated in vivo using cell-derived xenograft models, which confirmed the key role of Wnt/β-catenin pathway activation in EFNB2-induced tumor progression. Collectively, these results suggested that EFNB2 represents a promising molecular target for therapeutic intervention in GC.

Gastric cancer (GC) remains a major cause of cancer-related mortality, with limited options for early detection and precision therapy. Collagen family members are increasingly recognized as key structural and regulatory components of the tumor microenvironment. Collagen type X alpha 1 chain (COL10A1) appears among the top overexpressed genes in GC and has been linked with tumorigenesis, but its functional role in GC has not been completely elucidated. The oncogenic potential of COL10A1 was assessed in vitro in GC cell lines using adenoviral-mediated overexpression. Functional assays were further performed to evaluate proliferation, apoptosis, migration, invasion, and epithelial–mesenchymal transition (EMT) markers. Intracellular signaling alterations were analyzed by phosphokinase protein profiling and protein–protein interaction network analysis. COL10A1 overexpression significantly increased proliferation and migration, while reducing GC cell apoptosis. It promotes EMT by up-regulating mesenchymal markers (N-cadherin, Vimentin, Snail/Slug) and suppressing epithelial markers such as E-cadherin and β-catenin. Additionally, COL10A1 overexpression activated oncogenic signaling pathways, including the JNK and MAPK cascades, increasing proliferation and tumorigenic potential. Our results showed that COL10A1 functions as a driver for tumor progression by promoting proliferation, migration, and invasion along with EMT through activation of important oncogenic pathways. These findings highlight its biological role in tumor progression and contribute to a better understanding of GC pathogenesis.

Gastric cancer (GC) is a common malignant tumour and a leading cause of cancer-related deaths worldwide. Although the OAS gene family has been implicated in various tumour-related biological processes, its specific role in GC remains unclear. This study integrated bioinformatics analysis of public datasets with experimental validation using clinical GC specimens to investigate the function of the OAS gene family in GC. We found that OAS family members were significantly upregulated in GC and associated with poor patient prognosis. Furthermore, OAS expression levels correlated with genomic mutation profiles and showed positive associations with neutrophil and dendritic cell infiltration in the tumour microenvironment, but negative correlation with B cell infiltration. In vitro functional experiments demonstrated that knockdown of OAS3 or OASL inhibited GC cell proliferation and migration, while overexpression of OASL enhanced these malignant behaviors. RNA-seq analysis revealed upregulation of SFRP4 and JUN and downregulation of ACTA2. KEGG pathway analysis indicated significant enrichment in necroptosis, MAPK signaling, PI3K-Akt signaling, cAMP signaling, viral carcinogenesis, cancer pathways, neutrophil extracellular trap formation, and IL-17 signaling pathways. Additionally, OASL may regulate DNA damage response and metabolic reprogramming. Drug prediction and molecular docking identified chlorendic acid, idarubicin, PHA-848,125, and tosedostat as potential activators of the OAS family due to their strong binding affinity. Conversely, GW842166, NSC 23,766, and metolazone showed high binding affinity for OASL and may inhibit its expression. In summary, The OAS gene family, associated with poor prognosis in gastric cancer, promotes tumour progression and represents a promising therapeutic target.

Comprehensive pan-cancer analysis of USP35 and validation of its role in gastric cancer

Background Dehydrokoline has a wide range of pharmacological activities and exhibits anti-tumor potential effects in a variety of cancer types. Whether it plays a role in gastric cancer remains unclear. Purpose This study aims to explore the mechanism by which liposome nanoparticles (Harmine NPs) coated with “dehydrocardamine” inhibit COX-2 expression by regulating the PTEN/Akt signaling pathway, thereby alleviating the inflammatory response in mice with gastric cancer and providing a new strategy for targeted therapy of gastric cancer. Materials and Methods Mice suffering from gastric cancer were used as models, and Harmine NPs were further prepared and used in experiments to observe the anti-inflammatory response in gastric cancer, explore its effect on PTEN/Akt, and analyze its role in the regulation of COX-2. Results We successfully prepared the Harmine NPs nanocomposite, and the model group was raised for 12 weeks for subsequent animal experiments. The inflammatory factor, Harmine NPs, in the group of mice showed a better improvement in inflammation. Their mucosal muscle layer cells were evenly arranged. While the levels of inflammatory response were reduced, their COX-2 expression and genes and proteins related to the PTEN/Akt signaling pathway were also inhibited. Using SF1670 based on Harmine NPs, it was found that the inhibitory effect of Harmine NPs on PTEN protein expression was reversed. VO-OHpic simulated the inactivation of PTEN and found that the anti-inflammatory effect of Harmine NPs was amplified. After celecoxib, it was confirmed that Harmine NPs can inhibit the expression of COX-2 through the PTEN/Akt signaling pathway to reduce the inflammatory response in gastric cancer mice. Conclusion Harmine NPs are a new type of complex with anti-inflammatory and anti-cancer effects and are expected to become an effective strategy for the treatment of gastric cancer by inhibiting the PTEN/Akt signaling pathway and the COX-2 expression. This treatment method shows potential benefits in the management of gastric cancer inflammation and provides an important theoretical basis for the treatment of gastric cancer inflammation.

Gastric cancer (GC) remains a leading cause of cancer mortality. E3 ubiquitin ligases, as central regulators of protein stability and signaling within the ubiquitin-proteasome system, have been implicated in tumor progression, but their functional roles in GC are not well established. We integrated bioinformatics analysis of TCGA and GEO datasets, in vitro experiments (including cell proliferation, migration, and apoptosis assays), and computational modeling to identify key prognostic factors in GC. We established two molecular subtypes (E3GC1/E3GC2) with distinct clinical outcomes and developed a 10-gene prognostic signature. The model showed moderate predictive accuracy (AUC: 0.61-0.71) and was validated externally. MMRN1 was upregulated in GC cells and its knockdown significantly inhibited malignant phenotypes. Critically, drug sensitivity analysis revealed high-risk patients were more sensitive to proteasome inhibitors (bortezomib), while low-risk patients responded better to taxane-based chemotherapy (docetaxel). Molecular docking predicted a high-confidence interaction between MMRN1 and NEDD4L, suggesting potential ubiquitination regulation. MMRN1 drives GC cell proliferation and migration in vitro and may be regulated by NEDD4L-mediated ubiquitination. Our study provides a foundation for E3 ligase-based patient stratification and personalized therapy selection in GC. While this study provides comprehensive multi-omics evidence supporting the role of MMRN1 in GC progression, its clinical translation is limited by the lack of in vivo validation and direct experimental evidence of NEDD4L-MMRN1 physical interaction. Further studies using animal models and clinical specimens are warranted to confirm these findings.

BackgroundProcollagen-lysine 2-oxoglutarate 5-dioxygenase 1 (PLOD1) is important for extracellular matrix formation and is involved in a variety of diseases, including cancer; however, its role in gastric cancer (GC) remains elusive. Therefore, this study aimed to explore the mechanistic importance of PLOD1 as a regulator of GC.MethodsWe examined the potential function and prognostic efficiency of PLOD1 in GC using a variety of bioinformatics methods. In vitro, we assessed the ability of PLOD1 to regulate GC by CCK-8 assay, Transwell assay, and Elisa assay analysis. Furthermore, we evaluated the effect of PLOD1 on the immune escape of GC cells by CCK-8 assay, flow cytometry, and Elisa assay.ResultsAnalysis of PLOD1 expression in gastric cancer and other cancers in public databases as well as survival showed that low expression of PLOD1 has better survival, while the AUC area under the ROC curve of this gene showed that this gene has better prognostic value. Meanwhile, the results of correlation analysis between PLOD1 and 60 immune checkpoints showed that the gene was positively correlated with immune checkpoint genes, and one of the genes with the largest correlation was CD276, and the pearson’s correlation between PLOD1 and cancer immune cycle was also calculated, and the relationship between PLOD1 and the immune microenvironment was evaluated, and the enrichment of the immune infiltration analysis into a larger number of immune cells among which the importance of PLOD1 was determined. Differential gene analysis was then performed on the gastric cancer dataset, using the differential genes to perform WGCNA network co-expression analysis with the PLOD1 gene, and then pathway enrichment analysis was performed on these differential genes, enriching for cancer-related pathways and cell cycle signaling pathways. Two key genes were then obtained in the analysis with glycolysis, while drug sensitivity analysis was performed, yielding multiple potential drugs such as AZD7545, BRD-K03911514 and BRD-K14844214. Furthermore, in vitro experiments further demonstrated that PLOD1 increased the proliferation and migration ability of GC cells by promoting immune escape.ConclusionsThe results of this study suggest that PLOD1 is an important regulator of GC progression and participates in the immune escape process of GC, which is expected to be a potential target for GC treatment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12672-025-03774-8.