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Abstract Background Exosomes, as extracellular membrane vesicles, play important roles in intercellular communication and can influence tumour progression. Circular RNAs (circRNAs) have been reported in various malignancies and are also important components of exosomes. However, the role of exosomal circRNAs in gastric cancer (GC) progression has not been completely clarified. Methods The exosomal circRNAs enriched in GC were identified using exosomal circRNA sequencing. The biological function of circMAN1A2 in GC was investigated using a series of in vitro and in vivo experiments. PKH-67 staining was used to label the exosomes. The molecular mechanism of exosomal circMAN1A2 was investigated via mass spectrometry, immunoprecipitation, Western blot, and single-cell RNA-sequencing data analyses. Results In our study, we determined that circMAN1A2 (hsa_circ_0000118) was enriched in GC-derived exosomes. Higher circMAN1A2 expression was related to poor survival in GC patients (HR = 2.917, p = 0.0120). Exosomal circMAN1A2 promoted GC progression in vitro and in vivo and suppressed the antitumour activity of T cells. Moreover, circMAN1A2 bound to SFPQ in GC cells and T cells, promoting the G1/S phase transition of the cell cycle in GC cells while inhibiting the activation of the T cell receptor signalling pathway in T cells to decrease antitumour activity. Mechanistically, circMAN1A2 competed with FBXW11 for binding to SFPQ, preventing FBXW11-mediated k48-linked ubiquitination and SFPQ protein degradation, thereby stabilizing SFPQ expression. Conclusions Our work confirms the critical role of exosomal circMAN1A2 in the progression and immunosuppression of GC. This novel axis of circMAN1A2-SFPQ provides new insights into exosomal circRNA-based GC diagnostic and therapeutic strategies.

BackgroundCholesterol metabolism plays a crucial role in tumor progression and immune response modulation. However, the precise connection between cholesterol metabolism-related genes (CMRGs) and their implications for clinical prognosis, the tumor microenvironment (TME), and the outcomes of immunotherapy in gastric cancer remains to be fully elucidated.MethodsTranscriptome data and related clinical information from 675 gastric cancer patients were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. A total of 50 cholesterol metabolism-related genes (CMRGs) were identified from the Kyoto Encyclopedia of Genes and Genomes (KEGG, hsa04979). Consensus clustering analysis was used to classify patients into distinct molecular subgroups, while principal component analysis (PCA) was applied to develop a prognostic scoring system for predicting survival and immunotherapy response. The scoring system was validated using three independent cohorts of gastric cancer patients.ResultsBased on 49 CMRGs, 675 gastric cancer patients were categorized into three distinct subgroups with varying prognoses, tumor microenvironment features, and clinical characteristics. Further differential gene analysis and consensus clustering identified two additional subgroups. The prognostic scoring system developed through PCA demonstrated that the high-score subgroup had significantly improved survival, higher tumor mutational burden (TMB), and microsatellite instability (MSI), as well as a greater number of mutated genes, indicating greater sensitivity to immunotherapy. This system was validated in a real-world cohort undergoing immunotherapy. Additionally, the correlation between GPC3 expression and cholesterol levels was confirmed, highlighting GPC3’s potential biological role.ConclusionThis study highlights the importance of CMRGs in gastric cancer, deepens our understanding of the tumor immune microenvironment, and guides individualized immunotherapy.

Background The prognostic significance of neural invasion (NI) in gastric cancer (GC) has not been established. This study is to investigate the characteristic and prognostic value of NI in GC. Methods 592 patients who had undergone gastrectomy for GC were retrospectively analyzed. NI was defined when cancer cells infiltrated into the perineurium or neural fascicles by hematoxylin and eosin staining of surgical specimens. NI and the other clinical factors were analyzed. Results NI was detected in 270 of the 592 patients. NI was associated with tumor size, site, depth of invasion, lymph node metastasis, TNM stage, D dissection, tumor differentiation, Lauren classification, and blood vessel invasion. NI was associated with the overall survival. Multivariate analysis indicated that NI was not an independent prognostic factor for total patients, while NI independently predicted prognosis for age < 60 and lymph node metastasis negative patients by subgroup analysis. Concomitant existence of NI with tumor size ≥3cm, TNM stage III, or diffused Lauren classification independently predicted prognosis. Conclusions The frequency of NI is high in GC patients and increases with disease progression. NI is related to poor survival in GC patients who underwent curative gastrectomy and provides independent prognostic value for young and lymph node metastasis negative patients.

Abstract Neural invasion (NI) is a vital pathological characteristic of gastric cancer (GC), which correlates with tumor recurrence and a worse prognosis. Long noncoding RNAs (lncRNAs) play critical roles in various biological processes. However, the involvement of lncRNAs in NI of GC (GC-NI) remains unclear. DIAPH2-AS1 was upregulated in NI-positive GC tissues, which was confirmed by qRT-PCR. The higher expression of DIAPH2-AS1 predicted NI and worse survival for GC patients. Both in vitro and in vivo experiments, including wound-healing assay, Transwell assay, DRG-GC cells co-culture model, the mouse sciatic nerve model, and the lung metastasis model, indicated that DIAPH2-AS1 promoted the migration, invasion, and NI potential of GC cells. Mechanistically, pulldown assay and RNA immunoprecipitation assay revealed that DIAPH2-AS1 interacted with NSUN2. Subsequent experiments indicated that DIAPH2-AS1 stabilized NSUN2 from ubiquitin-proteasomal degradation via masking the K577 and K579 of NSUN2. The protection of DIAPH2-AS1 on NSUN2 improved the stability of NTN1 mRNA via m5C modification, which finally induced GC-NI. Our work uncovered DIAPH2-AS1 as a novel oncogenic lncRNA in GC-NI and validated the DIAPH2-AS1-NSUN2-NTN1 axis as a potential therapeutic target for NI-positive GC.