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Background: Stage IV gastric cancer is a highly heterogeneous and lethal tumor with few therapeutic strategies. The combination of programmed cell death protein 1 inhibitors and chemotherapy is currently the standard frontline treatment regimen for advanced gastric cancer. Nevertheless, it remains a great challenge to screen the beneficiaries of immunochemotherapy and expand indications for this treatment regimen., Methods: We conducted a pathological assessment to ascertain the importance of tertiary lymphoid structures based on the tissue samples collected from patients with stage IV gastric cancer (n=15) both prior to and following immunochemotherapy treatment. Additionally, we used spatial (n=10) and single-cell transcriptional analysis (n=97) to investigate the key regulators of tertiary lymphoid structures (TLSs). Multiplex immunofluorescence and image analysis (n=34) were performed to explore the association between tumor-infiltrating CXCL13 + CD160 + CD8 + T cells and TLSs. The relationship between CXCL13 + CD160 + CD8 + T cells and the responsiveness to immunotherapy was also evaluated by multiplex immunofluorescence and image analysis approaches (n=15). Furthermore, we explored the intrinsic characteristics of CXCL13 + CD160 + CD8 + T cells through various experimental techniques, including quantitative reverse transcription-PCR, western blot, and flow cytometry., Results: We found that responders exhibited higher levels of TLSs and CXCL13 + CD160 + CD8 + T cells in biopsy tissues prior to immunochemotherapy compared with non-responders. Following conversion therapy, responders also had a higher percentage of mature TLSs and a higher number of CXCL13 + CD160 + CD8 + T cells in surgical resections. Moreover, we discovered that vitamin B 6 in CD160 + CD8 + T cells could reduce the ubiquitination modification of HIF-1α by MDM2, thereby attenuating the degradation of HIF-1α. Consequently, this led to the transcriptional upregulation of CXCL13 expression, facilitating the recruitment of CXCR5 + B cells and the formation of TLSs., Conclusion: The number and maturity of TLSs, along with the extent of CXCL13 + CD160 + CD8 + T-cell infiltration, might function as potential indicators for assessing the effectiveness of immunotherapy in treating gastric malignancies. Furthermore, our research suggests that vitamin B 6 could enhance the secretion of CXCL13 by CD160 + CD8 + T cells by reducing the degradation of HIF-1α. Additionally, we demonstrate that vitamin B 6 supplementation or targeting pyridoxal kinase could substantially improve the efficacy of immunotherapies for gastric cancer., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Ripretinib, a broad-spectrum inhibitor of the KIT and PDGFRA receptor tyrosine kinases, is designated as a fourth-line treatment for gastrointestinal stromal tumor (GIST). It is tailored for patients resistant to imatinib, sunitinib, and regorafenib. As its increasing use, instances of resistance to ripretinib are becoming more frequent. Unfortunately, there are currently no scientifically mature treatment options available for patients resistant to ripretinib. Posttranslational modifications (PTMs) such as ubiquitination, in conjunction with its interplay with other modifications, play a collective role in regulating tumor initiation and progression. However, the specific association between ubiquitination and ripretinib resistance is not reported. Through proteome-ubiquitinome sequencing, increased levels of the USP5 protein and decreased ubiquitination in ripretinib-resistant GISTs are detected. Subsequent examination of the mass spectrometry findings validated the interaction through which TRIM21 governs USP5 expression via ubiquitination, and USP5 regulates MDH2 expression through deubiquitination, consequently fostering ripretinib resistance in GIST. Moreover, ZDHHC18 can palmitoylate MDH2, preventing its ubiquitination and further increasing its protein stability. The research underscores the correlation between posttranslational modifications, specifically ubiquitination, and drug resistance, emphasizing the potential of targeting the USP5-MDH2 axis to counteract ripretinib resistance in GIST., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Risk prediction tools for colorectal cancer (CRC) have potential to improve the efficiency of population-based screening by facilitating risk-adapted strategies. However, such an applicable tool has yet to be established in the Chinese population. In this study, a risk score was created using data from the China Kadoorie Biobank (CKB), a nationwide cohort study of 409,854 eligible participants. Diagnostic performance of the risk score was evaluated in an independent CRC screening programme, which included 91,575 participants who accepted colonoscopy at designed hospitals in Zhejiang Province, China. Over a median follow-up of 11.1 years, 3136 CRC cases were documented in the CKB. A risk score was created based on nine questionnaire-derived variables, showing moderate discrimination for 10-year CRC risk (C-statistic = 0.68, 95 % CI: 0.67-0.69). In the CRC screening programme, the detection rates of CRC were 0.25 %, 0.82 %, and 1.93 % in low-risk (score <6), intermediate-risk (score: 6-19), and high-risk (score >19) groups, respectively. The newly developed score exhibited a C-statistic of 0.65 (95 % CI: 0.63-0.66), surpassing the widely adopted tools such as the Asia-Pacific Colorectal Screening (APCS), modified APCS, and Korean Colorectal Screening scores (all C-statistics = 0.60). In conclusion, we developed a novel risk prediction tool that is useful to identify individuals at high risk of CRC. A user-friendly online calculator was also constructed to encourage broader adoption of the tool., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Lymph node metastasis (LNM) is the primary mode of metastasis in gastric cancer (GC). However, the precise mechanisms underlying this process remain elusive. Tumor cells necessitate lipid metabolic reprogramming to facilitate metastasis, yet the role of lipoprotein lipase (LPL), a pivotal enzyme involved in exogenous lipid uptake, remains uncertain in tumor metastasis. Therefore, the aim of this study was to investigate the presence of lipid metabolic reprogramming during LNM of GC as well as the role of LPL in this process., Methods: Intracellular lipid levels were quantified using oil red O staining, BODIPY 493/503 staining, and flow cytometry. Lipidomics analysis was employed to identify alterations in intracellular lipid composition following LPL knockdown. Protein expression levels were assessed through immunohistochemistry, Western blotting, and enzyme-linked immunosorbent assays. The mouse popliteal LNM model was utilized to investigate differences in LNM. Immunoprecipitation and mass spectrometry were employed to examine protein associations. In vitro phosphorylation assays and Phos-tag sodium dodecyl-sulfate polyacrylamide gel electrophoresis assays were conducted to detect angiopoietin-like protein 4 (ANGPTL4) phosphorylation., Results: We identified that an elevated intracellular lipid level represents a crucial characteristic of node-positive (N+) GC and further demonstrated that a high-fat diet can expedite LNM. LPL was found to be significantly overexpressed in N+ GC tissues and shown to facilitate LNM by mediating dietary lipid uptake within GC cells. Leptin, an obesity-related hormone, intercepted the effect exerted by ANGPTL4/Furin on LPL cleavage. Circulating leptin binding to the leptin receptor could induce the activation of inositol-requiring enzyme-1 (IRE1) kinase, leading to the phosphorylation of ANGPTL4 at the serine 30 residue and subsequently reducing its binding affinity with LPL. Moreover, our research revealed that LPL disrupted lipid homeostasis by elevating intracellular levels of arachidonic acid, which then triggered the cyclooxygenase-2/prostaglandin E2 (PGE2) pathway, thereby promoting tumor lymphangiogenesis., Conclusions: Leptin-induced phosphorylation of ANGPTL4 facilitates LPL-mediated lipid uptake and consequently stimulates the production of PGE2, ultimately facilitating LNM in GC., (© 2024 The Author(s). Cancer Communications published by John Wiley & Sons Australia, Ltd on behalf of Sun Yat‐sen University Cancer Center.)

Background: The short-term and long-term outcomes of laparoscopic-assisted distal gastrectomy (LADG) and totally laparoscopic distal gastrectomy (TLDG) have been subject to controversy with various reconstruction techniques of Billroth-I, Billroth-II, Roux-en-Y, and Uncut. This study aims to compare the short-term and long-term outcomes of LADG and TLDG as well as the outcomes of different anastomoses. Methods: This study enrolled patients with gastric cancer at the First Affiliated Hospital of Nanjing Medical University (NMUH) between 2017 and 2021. Postoperative complications were classified according to the Clavien-Dindo grade. Exclusion criteria included metachronous and synchronous malignancy and palliative surgery. The Kaplan-Meier analysis was applied to assess 5-year prognosis between two groups. Results : This study included 1221 cases with an overall complication rate of 17.37% for LADG, which was significantly higher than TLDG's 10.72%. The incidence of anastomosis-related complications was 4.79% for LADG and 1.13% lower for TLDG. LADG and TLDG did not show significant difference for Grade III-V complications and resected lymph nodes. The postoperative stay was shorter for TLDG than LADG, and R-Y had a longer postoperative stay than B-II and Uncut after combining LADG and TLDG. The operation time was shorter in TLDG cases than that in LADG cases. The 5-year OS of the TLDG group was not significantly better than that of the LADG group. Conclusion : TLDG is superior in overall complication rate, anastomosis-related complication rate, postoperative stay and operation time to LADG. No difference of OS was observed between LADG and TLDG. Four anastomoses had no convincing evidence of being superior in complications rates, post-op stay, and harvested lymph nodes to each other., Competing Interests: Competing Interests: The authors have declared that no competing interests exist., (© The author(s).)

Cholesterol and Helicobacter pylori ( H. pylori ) are both risk factors for gastric cancer (GC). However, the relationship between cholesterol and H. pylori and their function in the progression of GC are controversial. In this study, we addressed that H. pylori could induce mitochondrial cholesterol accumulation and promote GC proliferation and protect GC cells against apoptosis via cholesterol. Metabolomic and transcriptomic sequencing were used to identify CYP11A1 responsible for H. pylori -induced cholesterol accumulation. In vitro and in vivo function experiments revealed that cholesterol could promote the proliferation of GC and inhibit apoptosis. Mechanically, the interaction of Cytotoxin-associated gene A (CagA) and CYP11A1 redistributed mitochondrial CYP11A1 outside the mitochondria and subsequently caused mitochondrial cholesterol accumulation. The CYP11A1-knockdown upregulated cholesterol accumulation and reproduced the effect of cholesterol on GC in a cholesterol-dependent manner. Moreover, CYP11A1-knockdown or H. pylori infection inhibited mitophagy and maintained the mitochondria homeostasis. H. pylori could contribute to the progression of GC through the CagA/CYP11A1-mitoCHO axis. This study demonstrates that H. pylori can contribute to the progression of GC via cholesterol, and eradicating H. pylori is still prognostically beneficial to GC patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Ubiquitination plays a pivotal regulatory role in tumor progression. Among the components of the ubiquitin-proteasome system (UPS), ubiquitin-protein ligase E3 has emerged as a key molecule. Nevertheless, the biological functions of E3 ubiquitin ligases and their potential mechanisms orchestrating glycolysis in gastric cancer (GC) remain to be elucidated. In this study, we conducted a comprehensive transcriptomic analysis to identify the core E3 ubiquitin ligases in GC, followed by extensive validation of the expression patterns and clinical significance of Tripartite motif-containing 50 (TRIM50) both in vitro and in vivo . Remarkably, we found that TRIM50 was downregulated in GC tissues, associated with malignant progression and poor patient survival. Functionally, overexpression of TRIM50 suppressed GC cell proliferation and indirectly mitigated the invasion and migration of GC cells by inhibiting the M2 polarization of tumor-associated macrophages (TAMs). Mechanistically, TRIM50 inhibited the glycolytic pathway by ubiquitinating Phosphoglycerate Kinase 1 (PGK1), thereby directly suppressing GC cell proliferation. Simultaneously, the reduction in lactate led to diminished M2 polarization of TAMs, indirectly inhibiting the invasion and migration of GC cells. Notably, the downregulation of TRIM50 in GC was mediated by the METTL3/YTHDF2 axis in an m6A-dependent manner. In our study, we definitively identified TRIM50 as a tumor suppressor gene (TSG) that effectively inhibits glycolysis and the malignant progression of GC by ubiquitinating PGK1, thus offering novel insights and promising targets for the diagnosis and treatment of GC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Gastric cancer (GC) is one of the most common cancer worldwide. Neural invasion (NI) is considered as the symbiotic interaction between nerves and cancers, which strongly affects the prognosis of GC patients. Small extracellular vesicles (sEVs) play a key role in intercellular communication. However, whether sEVs mediate GC-NI remains unexplored. In this study, sEVs release inhibitor reduces the NI potential of GC cells. Muscarinic receptor M3 on GC-derived sEVs regulates their absorption by neuronal cells. The enrichment of sEV-circVAPA in NI-positive patients' serum is validated by serum high throughput sEV-circRNA sequencing and clinical samples. sEV-circVAPA promotes GC-NI in vitro and in vivo. Mechanistically, sEV-circVAPA decreases SLIT2 transcription by miR-548p/TGIF2 and inhibits SLIT2 translation via binding to eIF4G1, thereby downregulates SLIT2 expression in neuronal cells and finally induces GC-NI. Together, this work identifies the preferential absorption mechanism of GC-derived sEVs by neuronal cells and demonstrates a previously undefined role of GC-derived sEV-circRNA in GC-NI, which provides new insight into sEV-circRNA based diagnostic and therapeutic strategies for NI-positive GC patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Single nuclear polymorphisms (SNPs) have been published to be correlated with multiple diseases. Transcription Factor 21 (TCF21) is a critical transcription factor involved in various types of cancers. However, the association of TCF21 genetic polymorphisms with gastric cancer (GC) susceptibility and prognosis remains unclear., Methods: A case-control study comprising 890 patients diagnosed with GC and an equal number of cancer-free controls was conducted. After rigorous statistical analysis, molecular experiments were carried out to elucidate the functional significance of the SNPs in the context of GC., Results: TCF21 rs2327430 (OR = 0.78, P = 0.026) provides protection against GC, while rs4896011 (OR = 1.39, P = 0.005) exhibit significant associations with GC risk. Furthermore, patients with the (TC + CC) genotype of rs2327430 demonstrate a relatively favorable prognosis (OR = 0.47, P = 0.012). Mechanistically, chromatin immunoprecipitation assay and luciferase reporter assay revealed that the C allele of rs2327430 disrupts the binding of Transcription Factor AP-2 Alpha (TFAP2A) to the promoter region of TCF21, resulting in increased expression of TCF21 and inhibition of malignant behaviors in GC cells., Conclusion: Our findings highlight the significant role of TCF21 SNPs in both the risk and prognosis of GC and provide valuable insights into the underlying molecular mechanisms. Specifically, the disruptive effect of rs2327430 on TCF21 expression and its ability to modulate malignant cell behaviors suggest that rs2327430 may serve as a potential predictive marker for GC risk and prognosis., (© 2024. The Author(s).)

Background: Gastric cancer (GC) continues to be one of the leading causes of cancer-related deaths globally. Diet significantly influences the incidence and progression of GC. However, the relationship between dietary intake and GC is inconsistent. Methods: A study was conducted with adults who participated in the National Health and Nutrition Examination Survey (NHANES) from 2003 to 2016 to investigate possible associations between 32 dietary factors and GC. To further detect potential causal relationships between these dietary factors and the risk of GC, a two-sample Mendelian randomization (MR) analysis was conducted. The primary method employed was the inverse variance weighted (IVW) analysis, and its results were further validated by four other methods. Results: Of the 35,098 participants surveyed, 20 had a history of GC. Based on the results of weighted logistic multivariate analysis, it was observed that there was a positive correlation between total fat intake [odds ratio (OR) = 1.09, 95% confidence interval (CI): (1.01-1.17), p = 0.03] and GC as well as negative association of dietary monounsaturated fatty acids (MUFAs) intake [OR = 0.83, 95% CI: (0.76-0.92), p < 0.001]. Further evaluations of the odds of GC across the quartiles of dietary MUFAs showed that the top quartile of total MUFA intake was associated with a lower likelihood of GC in three different models [model1: OR = 0.03, 95% CI: (0.00-0.25), p < 0.01; model2: OR = 0.04, 95% CI: (0.00-0.38), p = 0.01; model3: OR = 0.04, 95% CI: (0.00-0.40), p = 0.01]. For the MR analyses, genetic instruments were selected from the IEU Open GWAS project; IVW analysis showed that GC risk was not associated with MUFAs [OR = 0.82, 95% CI: (0.59-1.14), p = 0.23] or the ratio of MUFAs to total fatty acids [OR = 1.00, 95% CI: (0.75-1.35), p = 0.98]. Similar results were observed when using the other MR methods. Conclusion: The NHANES study revealed that consuming MUFAs was linked to a lower risk of GC, although the results of MR analyses do not provide evidence of a causal relationship. Additional research is therefore necessary to clarify these findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Wang, Li, Liu, Xuan, Li, Li, Xia, Jiang, Xu, Fang, Wang, Zhang, Xu, Yang and Xu.)

Background: Telomere maintenance takes part in the regulation of gastric cancer (GC) pathogenesis and is essential for patients' clinical features. Though the correlation between a single telomere maintenance-related gene and GC has previously been published, comprehensive exploration and systematic analysis remain to be studied. Our study is aimed at determining telomere maintenance-related molecular subtypes and examining their role in GC. Methods: By analyzing the transcriptome data, we identified three telomere maintenance-associated clusters (TMCs) with heterogeneity in clinical features and tumor microenvironment (TME). Then, we screened five prognostic telomere maintenance-related genes and established corresponding TM scores. Additionally, the expression level and biological function of tubulin beta 6 class V (TUBB6) were validated in GC tissues and cells. Results: TMC1 was correlated with EMT and TGF-beta pathway and predicted low tumor mutation burden (TMB) as well as bad prognostic outcomes. TMC3 was associated with cell cycle and DNA repair. In terms of TMB and overall survival, TMC3 exhibited opposite results against TMC1. Significant heterogeneity was observed between TMCs. TUBB6 was upregulated and could promote GC proliferation, migration, and invasion. Conclusion: Altogether, combining bioinformatics and functional experiments, we identified three molecular subtypes based on telomere maintenance-associated genes in GC, which could bring new ideas and novel biomarkers to the clinic., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Peritoneal metastasis (PM), one of the most typical forms of metastasis in advanced gastric cancer (GC), indicates a poor prognosis. Exploring the potential molecular mechanism of PM is urgently necessary, as it has not been well studied. E3 ubiquitin ligase has been widely established to exert a biological function in various cancers, but its mechanism of action in GC with PM remains unknown., Methods: The effect of MIB1 on PM of GC was confirmed in vitro and in vivo. Co-immunoprecipitation (Co-IP) and mass spectrometry demonstrated the association between MIB1 and DDX3X. Western blot, flow cytometry and immunofluorescence determined that DDX3X was ubiquitylated by MIB1 and promoted stemness. We further confirmed that METTL3 promoted the up-regulation of MIB1 by RNA immunoprecipitation (RIP), luciferase reporter assay and other experiments., Results: We observed that the E3 ubiquitin ligase Mind bomb 1 (MIB1) was highly expressed in PMs, and patients with PM with high MIB1 expression showed a worse prognosis than those with low MIB1 expression. Mechanistically, our study demonstrated that the E3 ubiquitin ligase MIB1 promoted epithelial-mesenchymal transition (EMT) progression and stemness in GC cells by degrading DDX3X. In addition, METTL3 mediated m6A modification to stabilize MIB1, which required the m6A reader IGF2BP2., Conclusions: Our study elucidated the specific molecular mechanism by which MIB1 promotes PM of GC, and suggested that targeting the METTL3-MIB1-DDX3X axis may be a promising therapeutic strategy for GC with PM., (© 2024. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Background: Imatinib has become an exceptionally effective targeted drug for treating gastrointestinal stromal tumors (GISTs). Despite its efficacy, the resistance to imatinib is common in GIST patients, posing a significant challenge to the effective treatment., Methods: The expression profiling of TRIM21, USP15, and ACSL4 in GIST patients was evaluated using Western blot and immunohistochemistry. To silence gene expression, shRNA was utilized. Biological function of TRIM21, USP15, and ACSL4 was examined through various methods, including resistance index calculation, colony formation, shRNA interference, and xenograft mouse model. The molecular mechanism of TRIM21 and USP15 in GIST was determined by conducting Western blot, co-immunoprecipitation, and quantitative real-time PCR (qPCR) analyses., Results: Here we demonstrated that downregulation of ACSL4 is associated with imatinib (IM) resistance in GIST. Moreover, clinical data showed that higher levels of ACSL4 expression are positively correlated with favorable clinical outcomes. Mechanistic investigations further indicated that the reduced expression of ACSL4 in GIST is attributed to excessive protein degradation mediated by the E3 ligase TRIM21 and the deubiquitinase USP15., Conclusion: These findings demonstrate that the TRIM21 and USP15 control ACSL4 stability to maintain the IM sensitive/resistant status of GIST., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Lymph node metastasis (LNM) is a significant barrier to the prognosis of patients with gastric cancer (GC). Helicobacter pylori (H. pylori)-positive GC patients experience a higher rate of LNM than H. pylori-negative GC patients. However, the underlying mechanism remains unclear. Based on the findings of this study, H. pylori-positive GC patients have greater lymphangiogenesis and lymph node immunosuppression than H. pylori-negative GC patients. In addition, miR-1246 is overexpressed in the plasma small extracellular vesicles (sEVs) of H. pylori-positive GC patients, indicating a poor prognosis. Functionally, sEVs derived from GC cells infected with H. pylori deliver miR-1246 to lymphatic endothelial cells (LECs) and promote lymphangiogenesis and lymphatic remodeling. Mechanistically, miR-1246 suppresses GSK3β expression and promotes β-Catenin and downstream MMP7 expression in LECs. miR-1246 also stabilizes programmed death ligand-1 (PD-L1) by suppressing GSK3β and induces the apoptosis of CD8 + T cells. Overall, miR-1246 in plasma sEVs may be a novel biomarker and therapeutic target in GC-LNM., (© 2023 Wiley‐VCH GmbH.)

Competing Interests: Conflict of interest The authors declare that they have no conflict of interest.

Helicobacter pylori (H. pylori) is the leading risk factor for gastric carcinogenesis. Fibroblast growth factor receptor 4 (FGFR4) is a member of transmembrane tyrosine kinase receptors that are activated in cancer. We investigated the role of FGFR4 in regulating the cellular response to H. pylori infection in gastric cancer. High levels of oxidative stress signature and FGFR4 expression were detected in gastric cancer samples. Gene set enrichment analysis (GSEA) demonstrated enrichment of NRF2 signature in samples with high FGFR4 levels. H. pylori infection induced reactive oxygen species (ROS) with a cellular response manifested by an increase in FGFR4 with accumulation and nuclear localization NRF2. Knocking down FGFR4 significantly reduced NRF2 protein and transcription activity levels, leading to higher levels of ROS and DNA damage following H. pylori infection. We confirmed the induction of FGFR4 and NRF2 levels using mouse models following infection with a mouse-adapted H. pyloristrain. Pharmacologic inhibition of FGFR4 using H3B-6527, or its knockdown, remarkably reduced the level of NRF2 with a reduction in the size and number of gastric cancer spheroids. Mechanistically, we detected binding between FGFR4 and P62 proteins, competing with NRF2-KEAP1 interaction, allowing NRF2 to escape KEAP1-dependent degradation with subsequent accumulation and translocation to the nucleus. These findings demonstrate a novel functional role of FGFR4 in cellular homeostasis via regulating the NRF2 levels in response to H. pylori infection in gastric carcinogenesis, calling for testing the therapeutic efficacy of FGFR4 inhibitors in gastric cancer models., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Published by Elsevier B.V.)

Tripartite motif-containing protein 29 (TRIM29) is a member of TRIM family protein which has been reported to play a role in the progress of inflammatory and cancer diseases. However, its specific role in gastric cancer (GC) has yet to be fully understood. Here, we investigated the expression of TRIM29 in gastric cancer and its functions in the antitumor immunity. TRIM29 expression was lower in tumor tissues than that in paired normal tissues. Lower expression of TRIM29 was related to aberrant hypermethylation of CpG islands in TRIM29 gene. Comprehensive proteomics and immunoprecipitation analyses identified IGF2BP1 as TRIM29 interactors. TRIM29 interacted with IGF2BP1 and induced its ubiquitination at Lys440 and Lys450 site by K48-mediated linkage for protein degradation. IGF2BP1 promoted PD-L1 mRNA stability and expression in a 3'UTR and m 6 A-dependent manner. Functionally, TRIM29 enhanced antitumor T-cell immunity in gastric cancer dependent on the IGF2BP1/PD-L1 axis in vivo and in vitro. Clinical correlation analysis revealed that TRIM29 expression in patient samples was associated with CD8 + immune cell infiltration in the GC microenvironment and the overall survival rates of GC patients. Our findings revealed a crucial role of TRIM29 in regulating the antitumor T-cell immunity in GC. We also suggested that the TRIM29/IGF2BP1/PD-L1 axis could be used as a diagnostic and prognostic marker of gastric cancer and a promising target for GC immunotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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.

Background: Liver metastasis (LM) is one of the most common distant metastases of gastric cancer (GC). However, the mechanisms underlying the LM of GC (GC-LM) remain poorly understood. This study aimed to identify the tumour-secreted protein associated with GC-LM and to investigate the mechanisms by which this secreted protein remodels the liver microenvironment to promote GC-LM., Methods: Data-independent acquisition mass spectrometry (DIA-MS), mRNA expression microarray, quantitative real-time PCR, enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) were performed to identify and validate the GC-secreted proteins associated with GC-LM. A modified intrasplenic injection mouse model of LM was used to evaluate the progression and tumour burden of LM in vivo. Flow cytometry, immunofluorescence (IF), western blots (WB) and IHC were performed to validate the pre-metastatic niche (PMN) formation in the pre-modelling mouse models. mRNA sequencing of PMA-treated THP-1 cells with or without lipopolysaccharide binding protein (LBP) treatment was used to identify the functional target genes of LBP in macrophages. Co-immunoprecipitation (Co-IP), WB, ELISA, IF and Transwell assays were performed to explore the underlying mechanism of LBP in inducing intrahepatic PMN formation., Results: LBP was identified as a critical secreted protein associated with GC-LM and correlated with a worse prognosis in patients with GC. LBP activated the TLR4/NF-κB pathway to promote TGF-β1 secretion in intrahepatic macrophages, which, in turn, activated hepatic satellite cells (HSCs) to direct intrahepatic fibrotic PMN formation. Additionally, TGF-β1 enhanced the migration and invasion of incoming metastatic GC cells in the liver. Consequently, selective targeting of the TGF-β/Smad signaling pathway with galunisertib demonstrated its efficacy in effectively preventing GC-LM in vivo., Conclusions: The results of this study provide compelling evidence that serological LBP can serve as a valuable diagnostic biomarker for the early detection of GC-LM. Mechanistically, GC-derived LBP mediates the crosstalk between primary GC cells and the intrahepatic microenvironment by promoting TGF-β1 secretion in intrahepatic macrophages, which induces intrahepatic fibrotic PMN formation to promote GC-LM. Importantly, selectively targeting the TGF-β/Smad signaling pathway with galunisertib represents a promising preventive and therapeutic strategy for GC-LM., (© 2023. Italian National Cancer Institute ‘Regina Elena’.)

Background: The aim of this retrospective matched-paired cohort study was to clarify the effectiveness of preserving the vagus nerve in totally laparoscopic radical distal gastrectomy (TLDG)., Methods: One hundred eighty-three patients with gastric cancer who underwent TLDG between February 2020 and March 2022 were included and followed up. Sixty-one patients with preservation of the vagal nerve (VPG) in the same period were matched (1:2) to conventional sacrificed (CG) cases for demographics, tumor characteristics, and tumor node metastasis stage. The evaluated variables included intraoperative and postoperative indices, symptoms, nutritional status, and gallstone formation at 1 year after gastrectomy between the two groups., Results: Although the operation time was significantly increased in the VPG compared with the CG (198.0 ± 35.2 vs. 176.2 ± 35.2 min, P < 0.001), the mean time of gas passage in the VPG was significantly lower than that in the CG (68.1 ± 21.7 h vs. 75.4 ± 22.6 h, P = 0.038). The overall postoperative complication rate was similar between the two groups (P = 0.794). There was no statistically significant difference between the two groups hospital stay, total number of harvested lymph nodes, and mean number of examined lymph nodes at each station. During follow-up, the morbidity of gallstones or cholecystitis (8.2% vs. 20.5%, P = 0.036), chronic diarrhea (3.3% vs. 14.8%, P = 0.022), and constipation (4.9% vs. 16.4%, P = 0.032) were significantly lower in the VPG than in the CG in this study. Moreover, injury to the vagus nerve was found to be an independent risk factor for gallstone formation or cholecystitis and chronic diarrhea in univariate analysis and multivariate analysis., Conclusion: The vagus nerve plays an imperative role in gastrointestinal motility, and hepatic and celiac branch preservation mainly exerts efficacy and safety in patients who undergo TLDG., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background. Although tumor size is regarded as the "T" stage of the tumor-node-metastasis (TNM) staging system for many solid tumors, its prognostic impact in gastric cancer remains uncertain and conflicting. Methods. We enrolled 6960 eligible patients from the Surveillance, Epidemiology, and End Results (SEER) database. The X-tile program was used to select the best cut-off value of tumor size. Then, the Kaplan-Meier method and the Cox proportional hazards model were applied to examine the efficacy of tumor size on prognostic prediction for overall survival (OS) and gastric cancer-specific survival (GCSS). The presence of nonlinear association was determined by the restricted cubic spline (RCS) model. Results. Tumor size was divided into 3 groups: small size (≤2.5 cm), medium size (2.6-5.2 cm), and large size (≥5.3 cm). After adjusting by covariates such as depth of tumor infiltration, the large and medium groups showed a worse prognosis than the small group; however, no survival difference in OS was suggested between the medium and large groups. Similarly, although there was a nonlinear relationship between tumor size and survival, increasing tumor size did not show an independent negative effect on prognosis in the RCS analysis. However, the stratified analyses proposed this 3-way cut of tumor size in prognostic prediction for patients with both inadequate lymphadenectomy and negative nodal metastasis. Conclusions. Tumor size as a prognostic predictor may not have good clinical applicability in gastric cancer. Otherwise, it was recommended for patients with both insufficient examinations of lymph nodes and stage N0 disease., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Mounting evidence indicates the potential involvement of ATP-citrate lyase (ACLY) in the modulation of various cancer types. Nevertheless, the precise biological significance of ACLY in gastric cancer (GC) remains elusive. This study sought to elucidate the biological function of ACLY and uncover its influence on peritoneal metastasis in GC. The expression of ACLY was assessed using both real-time quantitative PCR and western blot techniques. To investigate the impact of ACLY on the proliferation of gastric cancer (GC) cells, colony formation and 5-ethynyl-2'-deoxyuridine (EdU) assays were performed. The migratory and invasive abilities of GC were evaluated using wound healing and transwell assays. Additionally, a bioinformatics analysis was employed to predict the correlation between ACLY and HIF-1A. This interaction was subsequently confirmed through a chromatin immunoprecipitation (ChIP) assay. ACLY exhibited upregulation in gastric cancer (GC) as well as in peritoneal metastasis. Its overexpression was found to facilitate the proliferation and metastasis of GC cells in both in vitro and in vivo experiments. Moreover, ACLY was observed to play a role in promoting angiogenesis and epithelial-mesenchymal transition (EMT). Notably, under hypoxic conditions, HIF-1A levels were elevated, thereby acting as a transcription factor to upregulate ACLY expression. Under the regulatory influence of HIF-1A, ACLY exerts a significant impact on the progression of gastric cancer, thereby facilitating peritoneal metastasis.

Background: Sec23 homolog A (SEC23A), a core component of coat protein complex II (COPII), has been reported to be involved in several cancers. However, the role of SEC23A in gastric cancer remains unclear., Methods: The expression of SEC23A in gastric cancer was analyzed by using qRT-PCR, western blotting and IHC staining. The role of SEC23A in ER stress resistance was explored by functional experiments in vitro and vivo. The occupation of STAT3 on the SEC23A promoter region was verified by luciferase reporter plasmids and CHIP assay. The interaction between SEC23A and ANXA2 was identified by Co-IP and mass spectrometry analysis., Results: We demonstrated that SEC23A was upregulated in gastric cancer and predicted poor prognosis in patients with gastric cancer. Mechanistically, SEC23A was transcriptional upregulated by ER stress-induced pY705-STAT3. Highly expressed SEC23A promoted autophagy by regulating the cellular localization of ANXA2. The SEC23A-ANXA2-autophay axis, in turn, protected gastric cancer cells from ER stress-induced apoptosis. Furthermore, we identified SEC23A attenuated 5-FU therapeutic effectiveness in gastric cancer cells through autophagy-mediated ER stress relief., Conclusion: We reveal an ER stress-SEC23A-autophagy negative feedback loop that enhances the ability of gastric cancer cells to resist the adverse survival environments. These results identify SEC23A as a promising molecular target for potential therapeutic intervention and prognostic prediction in patients with gastric cancer., (© 2023. Italian National Cancer Institute ‘Regina Elena’.)

Abnormal 5-methylcytosine (m5C) methylation has been proved to be closely related to gastric carcinogenesis, progression, and prognosis. Dysregulated long noncoding RNAs (lncRNAs) participate in a variety of biological processes in cancer. However, to date, m5C-methylated lncRNAs are rarely researched in gastric cancer (GC). Here, we found that RNA cytosine-C(5)-methyltransferase (NSUN2) was upregulated in GC and high NSUN2 expression was associated with poor prognosis. NR&#95;033928 was identified as an NSUN2-methylated and upregulated lncRNA in GC. Functionally, NR&#95;033928 upregulated the expression of glutaminase (GLS) by interacting with IGF2BP3/HUR complex to promote GLS mRNA stability. Increased glutamine metabolite, α-KG, upregulated NR&#95;033928 expression by enhancing its promoter 5-hydroxymethylcytosine (hm5C) demethylation. In conclusion, our results revealed that NSUN2-methylated NR&#95;033928 promoted GC progression and might be a potential prognostic and therapeutic target for GC., (© 2023. The Author(s).)

Context: Calcium plays a critical role in various physiological activities. However, the association between circulating calcium concentrations and mortality in a general healthy population remains undetermined., Objective: To examine the association of serum calcium concentrations with all-cause and cause-specific mortality., Methods: Leveraging data from the UK Biobank (n = 361 662) and the US National Health and Nutrition Examination Survey (NHANES, n = 36 985), we prospectively examined the association of serum calcium concentrations with all-cause and cause-specific mortality using Cox proportional hazard and restricted cubic spline models., Results: During a median follow-up of 12.0 years, UK Biobank documented 18 327 deaths, including 3119 (17.0%) from cardiovascular disease (CVD) and 9599 (52.4%) from cancer. We found a U-shaped relationship of albumin-adjusted calcium concentrations with all-cause and CVD mortality. Compared with participants with moderate calcium levels (the third quintile, Q3), those with low and high levels had an increased risk of all-cause (hazard ratio [HR] 1.02 for Q1 vs Q3; 1.10 for Q5 vs Q3) and CVD mortality (HR 1.11 for Q1 vs Q3; 1.25 for Q5 vs Q3). In contrast, there was a linear positive relationship with cancer mortality (HR 1.09 for Q5 vs Q1). Similar results for all-cause, CVD, and cancer mortality were observed in US NHANES., Conclusion: Our findings provide novel insights into the association between serum calcium concentrations and mortality in the general healthy population., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cisplatin (CDDP)-based chemotherapy is the preferred treatment strategy for advanced stage gastric cancer (GC) patients. Despite the efficacy of chemotherapy, the development of chemoresistance negatively affects the prognosis of GC and the underlying mechanism remains poorly understood. Accumulated evidence suggests that mesenchymal stem cells (MSCs) play important roles in drug resistance. The chemoresistance and stemness of GC cells were observed by colony formation, CCK-8, sphere formation and flow cytometry assays. Cell lines and animal models were utilized to investigate related functions. Western blot, quantitative real-time PCR (qRT-PCR) and co-immunoprecipitation were used to explore related pathways. The results showed that MSCs improved the stemness and chemoresistance of GC cells and accounted for the poor prognosis of GC. Natriuretic peptide receptor A (NPRA) was upregulated in GC cells cocultured with MSCs and knockdown of NPRA reversed the MSC-induced stemness and chemoresistance. At the same time, MSCs could be recruited to GC by NPRA, which formed a loop. In addition, NPRA facilitated stemness and chemoresistance through fatty acid oxidation (FAO). Mechanistically, NPRA protected Mfn2 against protein degradation and promoted its mitochondrial localization, which consequently improved FAO. Furthermore, inhibition of FAO with etomoxir (ETX) attenuated MSC-induced CDDP resistance in vivo. In conclusion, MSC-induced NPRA promoted stemness and chemoresistance by upregulating Mfn2 and improving FAO. These findings help us understand the role of NPRA in the prognosis and chemotherapy of GC. NPRA may be a promising target to overcome chemoresistance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Recently, several studies have indicated the great potential of gene expression signature of the primary tumor in predicting lymph node metastasis; however, few current gene biomarkers can predict lymph node status and prognosis in gastric cancer (GC). Thus, we used the RNA-seq data from The Cancer Genome Atlas (TCGA) to identify differentially expressed genes between pathological lymph node-negative (pN0) and positive (pN+) patients and to establish a gene signature that could predict lymph node metastasis. Meanwhile, the robustness of identified gene signatures was validated in an independent dataset Asian Cancer Research Group (n = 300). In this study, our thirty-three gene-based signature was highly correlated with lymph node metastasis and could successfully discriminate pN + patients in the training set (Area under the receiver operating characteristic curve = 0.951). Moreover, Disease-free survival ( P  = 0.0029) and overall survival ( P  = 0.026) were significantly worse in high-risk compared with low-risk patients overall and when confined to pN0 patients only ( P  < 0.0001). Of note, this gene signature also proved useful in predicting lymph node status and survival in the validation cohort. The present study suggests a thirty-three gene-based signature that could effectively predict lymph node metastasis and prognosis in GC., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Lymph node metastasis, a crucial factor in the spread of gastric cancer (GC), is strongly associated with a negative prognosis for patients. This study aimed to investigate the association of the mesothelin (MSLN) gene polymorphisms (rs3764247, rs3764246, rs12597489, rs1057147, and rs3765319) with the risk of lymph node metastasis of GC patients in a Chinese Han population. The PCR-LDR genotyping was used to detect the genotypes of MSLN polymorphisms in GC patients with lymph node metastasis (n = 610) or without (n = 356). Our research indicates that certain genetic markers, specifically rs3764247, rs3764246, rs12597489, and rs3765319, do not appear to be linked with an increased risk of lymph node metastasis in GC. However, we did observe that patients with the rs1057147 GA genotype exhibited a higher likelihood of lymph node metastasis in GC when compared to those with the GG genotype (OR = 1.33, 95% CI = 1.01 - 1.76, P = 0.045). Patients with rs1057147 GA + AA genotype were found to have a higher likelihood of lymph node involvement (OR = 1.35, 95% CI = 1.03 - 1.77, P = 0.029) when compared to those with GG genotype in the dominant model. The allelic model revealed that the A allele of rs1057147 exhibited a stronger correlation with lymph node metastasis compared to the G allele (OR = 1.28, 95% CI = 1.02 - 1.60, P = 0.031). In addition, we found that rs1057147 polymorphism revealed a poor prognosis for GC patients with lymph node metastasis. Further stratified analysis revealed that the prognostic effect of rs1057147 was more pronounced in patients with GC who had lymph node metastasis and had a tumor size of 4 cm or greater, as well as more than 2 lymph node metastases. Bioinformatics studies showed that the binding mode of miR-3144-5p or miR-3619-3p to MSLN was altered by the mutation of rs1057147. Our study confirmed the important role of MSLN rs1057147 polymorphism locus in GC lymph node metastases and suggested a potential prognostic factor during GC progression. KEY POINTS: • Rs1057147 GA genotype had an increased risk of lymph node metastasis in gastric cancer. • The A allele of rs1057147 had a stronger association with lymph node metastasis than the G allele. • The binding mode of miR-3144-5p or miR-3619-3p to MSLN was altered by the mutation of rs1057147., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: N6-methyladenosine (m 6 A) modification is the most common modification that occurs in eukaryotes. Although substantial effort has been made in the prevention and treatment of gastric cancer (GC) in recent years, the prognosis of GC patients remains unsatisfactory. The regulatory mechanism between m 6 A modification and GC development needs to be elucidated. In this study, we examined m 6 A modification and the downstream mechanism in GC., Methods: Dot blotting assays, The Cancer Genome Atlas analysis, and quantitative real-time PCR (qRT-PCR) were used to measure the m 6 A levels in GC tissues. Methylated RNA-immunoprecipitation sequencing and RNA sequencing were performed to identify the targets of m 6 A modification. Western blotting, Transwell, wound healing, and angiogenesis assays were conducted to examine the role of centromere protein F (CENPF) in GC in vitro. Xenograft, immunohistochemistry, and in vivo metastasis experiments were conducted to examine the role of CENPF in GC in vivo. Methylated RNA-immunoprecipitation-qPCR, RNA immunoprecipitation-qPCR and RNA pulldown assays were used to verify the m 6 A modification sites of CENPF. Gain/loss-of-function and rescue experiments were conducted to determine the relationship between CENPF and the mitogen-activated protein kinase (MAPK) signaling pathway in GC cells. Coimmunoprecipitation, mass spectrometry, qRT-PCR, and immunofluorescence assays were performed to explore the proteins that interact with CENPF and elucidate the regulatory mechanisms between them., Results: CENPF was upregulated in GC and facilitated the metastasis of GC both in vitro and in vivo. Mechanistically, increased m 6 A modification of CENPF was mediated by methyltransferase 3, and this modified molecule could be recognized by heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1), thereby promoting its mRNA stability. In addition, the metastatic phenotype of CENPF was dependent on the MAPK signaling pathway. Furthermore, CENPF could bind to FAK and promote its localization in the cytoplasm. Moreover, we discovered that high expression of CENPF was related to lymphatic invasion and overall survival in GC patients., Conclusions: Our findings revealed that increased m 6 A modification of CENPF facilitates the metastasis and angiogenesis of GC through the CENPF/FAK/MAPK and epithelial-mesenchymal transition axis. CENPF expression was correlated with the clinical features of GC patients; therefore, CENPF may serve as a prognostic marker of GC., (© 2023 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.)

Background: Great progress has been made in studying the function of long non-coding RNA (lncRNA) in various tumors, including gastric cancer (GC). However, there are still numerous lncRNAs that have not yet been studied and explored for their roles in GC, and their important functions need to be further revealed., Methods: Through analyzing The Cancer Genome Atlas (TCGA) database combined with bioinformatics survival tools, a novel GC-related lncRNA LGALS8-AS1 was identified. A quantitative real-time polymerase chain reaction and a series of in vitro or in vivo cell functional experiments were performed to determine the expression and the role of LGALS8-AS1/miR-138-5p/PLAGL2 in GC., Results: LGALS8-AS1 was remarkably upregulated and correlated with the unfavorable prognosis in GC. Higher expression of LGALS8-AS1 was positively associated with higher lymph node metastasis rate, as well as larger tumor size. In addition, a series of cell functional experiments revealed that LGALS8-AS1 could facilitate GC cell proliferation, migration and metastasis in vitro or in vivo. A deeper mechanism exploration revealed that LGALS8-AS1 could function as the miR-138-5p molecular sponge and upregulate the PLAGL2 expression, thereby promoting the cell proliferation, migration and metastasis in GC., Conclusions: In brief, we revealed the tumor promoting role of the LGALS8-AS1/miR-138-5p/PLAGL2 molecular signaling axis in GC, and our findings provide enlightenment for further understanding of the mechanism of tumorigenesis and development of GC, making LGALS8-AS1 a possible new diagnostic or therapeutic target for GC., (© 2023 John Wiley & Sons Ltd.)

Peritoneal metastasis (PM) is an important metastatic modality of gastric cancer (GC).It is associated with poor prognosis. The underlying molecular mechanism of PM remains elusive. 5-Methylcytosine (m 5 C), a posttranscriptional RNA modification, involves in the progression of many tumors. However, its role in GC peritoneal metastasis remains unclear. In our study, transcriptome results suggested that NSUN2 expression was significantly upregulated in PM. And patients with high NSUN2 expression of PM predicted a worse prognosis. Mechanistically, NSUN2 regulates ORAI2 mRNA stability by m5C modification, thereby promoting ORAI2 expression and further promoting peritoneal metastasis and colonization of GC. YBX1 acts as a "reader" by binding to the ORAI2 m5C modification site. Following the uptake of fatty acids from omental adipocytes by GC cells, the transcription factor E2F1 was upregulated, which further promoted the expression of NSUN2 through cis-element. Briefly, these results revealed that peritoneal adipocytes provide fatty acid for GC cells, thus contributing to the elevation of E2F1 and NSUN2 through AMPK pathway, and upregulated NSUN2 activates the key gene ORAI2 through m5C modification, thereby promoting peritoneal metastasis and colonization of gastric cancer., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Lipoprotein lipase (LPL), a crucial gene in lipid metabolism, has a significant role in the progression of malignant tumors. The purpose of this research was to investigate the impact of rs15285 found in the LPL gene's 3'UTR region on the risk, biological behavior, and gastric cancer (GC) prognosis as well as to examine its potential function. Genotyping of rs15285 in 888 GC cases and 874 controls was conducted by SNaPshot technology. We used bioinformatics analysis and in vitro experiments to study the role of rs15285. First, this study revealed for the first time that polymorphism rs15285 increases the risk of GC (OR = 1.48, 95%CI = 1.16-1.89, P = 0.002). Although no relationship was found between rs12585 and the pathological features of GC, the prognosis of individuals with the rs12585 TT genotype was poorer than that of patients with the CC or CC+CT genotype (HR = 2.39 for TT vs. CC, P = 0.025; HR = 2.38 for TT vs. CC+CT, P = 0.025). In addition, bioinformatics analysis showed rs12585 may affect the binding of miRNAs to LPL, resulting in an increase of LPL expression to promote cancer progression. Ultimately, in vitro tests revealed that the rs15285 T allele increased LPL expression on the mRNA as well as the protein levels, promoting GC cell proliferation, invasion, and metastasis. The LPL rs12528 TT genotype increased the risk of GC and predicted a poor prognosis. Mechanistically, the rs15285 T allele could improve the expression of LPL, and thus promotes the malignant phenotype of GC. Therefore, our study may provide new biological predictors and a theoretical basis for the prognosis and customized therapy of stomach cancer patients. KEY POINTS: • Rs15285 polymorphism is a risk factor for GC. • Rs12585 TT genotype predicts a bad outcome in GC individuals. • Rs15285 T allele enhances GC cells malignant biological behavior., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: For gastric cancer (GC) patients with pylorus outlet obstruction (POO), whether laparoscopic surgery has advantages over open surgery remains unclear. This study aims to investigate the differences between patients with and without POO in open and laparoscopic groups and to determine the differences between laparoscopic distal gastrectomy (LDG) and open distal gastrectomy (ODG) in GC patients with POO., Methods: A total of 241 GC patients with POO who underwent distal gastrectomy at the Department of Gastric Surgery of the First Affiliated Hospital of Nanjing Medical University between 2016 and 2021 were included in this study. A total of 1,121 non-POO patients who underwent laparoscopic surgery and 948 non-POO patients who underwent open surgery from 2016 to 2021 were also enrolled in the study. We compared complication rates and hospital stays between open and laparoscopic groups., Results: There was no significant difference for LDG between GC patients with and without POO regarding the overall complication rates (P = 0.063), the Grade III-V complication rate (P = 0.673), and the anastomotic complication rate (P = 0.497) from 2016 to 2021. The patients with POO had longer preoperative hospital stay (P = 0.001) and postoperative hospital stay (P=0.007) compared to patients without POO. No significant difference was observed for open patients between POO and non-POO patients regarding the overall complication rate (P = 0.357), grade III-V complication rate (P = 1.000), and anastomosis-related complication rate (P = 0.766). Compared with open surgery in GC patients with POO (n = 111), the total complication rate of the LDG group was 16.2%, which was significantly lower than that of the open group (26.1%, P = 0.041). No significant differences in the Grade III-V complication rate (P = 0.574) and anastomotic complication rate (P = 0.587) were observed between laparoscopic and open groups. Patients receiving laparoscopic surgery had shorter postoperative hospital stay than open surgery (P = 0.001). More resected lymph nodes (LNs) were also observed in the laparoscopic group (P = 0.0145)., Conclusion: The comorbidity of GC with POO does not increase the complication rate after laparoscopic or open distal gastrectomy. In GC patients with POO, laparoscopic surgery shows advantages over open surgery with a lower overall complication rate, shorter postoperative hospital stay, and more harvested lymph nodes. Laparoscopic surgery is a safe, feasible, and effective treatment for GC with POO., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Zhang, Chen, Li, Li, Li, Liu, Xuan, Xia, Xu, Fang, Wang, Zhang, Xu, Yang and Xu.)

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., (© 2023. The Author(s).)

Despite many advances in treatment over the past few years, the poor 5-year survival rate and high recurrence rate of gastric cancer (GC) remain unsatisfactory. As the most abundant epigenetic modification in the eukaryotic mRNA, N6-methyladenosine (m 6 A) methylation participates in tumor progression and tissue development. During tumor progression, DNA damage repair mechanisms can be reprogrammed to give new growth advantages on tumor clones whose genomic integrity is disturbed. Here we detected the elevated SUV39H2 expression in GC tissues and cell lines. Functionally, SUV39H2 promoted GC proliferation and inhibited apoptosis in vitro and in vivo. Mechanistically, METTL3-mediated m 6 A modification promotes mRNA stability of SUV39H2 in an IGF2BP2 dependent manner, resulting in upregulated mRNA expression of SUV39H2. As a histone methyltransferase, SUV39H2 was verified to increase the phosphorylation level of ATM through transcriptional repression of DUSP6, thereby promoting HRR and ultimately inhibiting GC chemosensitivity to cisplatin. Collectively, these results indicate the specific mechanism of m 6 A-modified SUV39H2 as a histone methyltransferase promoting HRR to inhibit the chemosensitivity of GC. SUV39H2 is expected to become a key target in the precision targeted therapy of GC., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Anastomotic leakage (AL) after gastrectomy is one of the severest postoperative complications and is related to increasing mortality. In addition, no consensus guidelines about strategies of AL treatment have been established. This large cohort study aimed to inspect the risk factors and efficacy of the conservative treatment for AL in patients with gastric cancer., Methods: We reviewed the clinicopathological data of 3,926 gastric cancer patients undergoing gastrectomy between 2014 and 2021. Results contained the rate, risk factors, and conservative therapy outcomes of AL., Results: In total, 80 patients (2.03%, 80/3,926) were diagnosed with AL, and esophagojejunostomy was the most frequent AL site (73.8%, 59/80). Among them, one patient (2.5%, 1/80) died. Multivariate analysis indicated that low albumin concentration ( P = 0.001), presence of diabetes ( P = 0.025), laparoscopic method ( P < 0.001), total gastrectomy ( P = 0.003), and proximal gastrectomy ( P = 0.002) were predicting factors for AL. The closure rate for the conservative treatment of AL in the first month after AL diagnosis was 83.54% (66/79), and the median time from leakage diagnosis to the closure of leakage was 17 days (interquartile range 11-26 days). Low level of plasma albumin ( P = 0.004) was associated with late leakage closures. In terms of 5-year overall survival, no significant difference was observed between patients with and without AL., Conclusion: The incidence of AL after gastrectomy is associated with low albumin concentration, diabetes, the laparoscopic method, and extent of resection. The conservative treatment is relatively safe and effective for the AL management in patients after gastric cancer surgery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 He, Liu, Zhou, Li, Wang, Zhang, Xu and Xu.)

Imatinib is a tyrosine kinase inhibitor that is widely used to combat gastrointestinal stromal tumours (GISTs). However, secondary resistance to imatinib is an important challenge in GIST treatment. Recent studies have demonstrated that cancer-derived nanosized exosomes play a key role in intercellular communication, but little is known about the roles of exosomes in imatinib-resistant GISTs. Here, we reveal that exosomes released from imatinib-resistant GISTs transmit drug resistance to imatinib-sensitive tumours. By using iTRAQ technology, we demonstrate that Ras-related protein Rab-35 (Rab35) is upregulated differentially in imatinib-resistant GISTs. Loss of Rab35 decreases exosome secretion, thereby hampering the transmission of imatinib resistance to sensitive tumours. Mechanistically, we showed that the ubiquitin‒proteasome system is involved in elevated Rab35 expression and that ubiquitin-specific protease 32 (USP32), a deubiquitylating enzyme, is bound to Rab35. Further experiments demonstrate that this protease protects Rab35 from proteasomal degradation by reducing Lys48 (K48)-ubiquitination. Additionally, we found that the transcription factor ETV1, which is a lineage survival factor in GISTs, promotes USP32 expression. Collectively, our results reveal that exosomes transmit imatinib resistance in GISTs and that deubiquitylation plays a key role in regulating the transmission process. The USP32-Rab35 axis provides a potential target for interventions to reduce the occurrence of imatinib resistance in GISTs., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Obesity is a leading contributor to colorectal cancer (CRC) risk, but the metabolic mechanisms linking obesity to CRC are not fully understood. We leveraged untargeted metabolomics data from two 1:1 matched, nested case-control studies for CRC, including 223 pairs from the US Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and 190 pairs from a prospective Chinese cohort. We explored serum metabolites related to body mass index (BMI), constructed a metabolomic signature of obesity, and examined the association between the signature and CRC risk. In total, 72 of 278 named metabolites were correlated with BMI after multiple testing corrections ( p FDR < 0.05). The metabolomic signature was calculated by including 39 metabolites that were independently associated with BMI. There was a linear positive association between the signature and CRC risk in both cohorts ( p for linear < 0.05). Per 1-SD increment of the signature was associated with 38% (95% CI: 9-75%) and 28% (95% CI: 2-62%) higher risks of CRC in the US and Chinese cohorts, respectively. In conclusion, we identified a metabolomic signature for obesity and demonstrated the association between the signature and CRC risk. The findings offer new insights into the underlying mechanisms of CRC, which is critical for improved CRC prevention.

Secondary resistance to imatinib (IM) represents a major challenge for therapy of gastrointestinal stromal tumors (GISTs). Aberrations in oncogenic pathways, including autophagy, correlate with IM resistance. Regulation of autophagy-related protein 5 (ATG5) by the ubiquitin-proteasome system is critical for autophagic activity, although the molecular mechanisms that underpin reversible deubiquitination of ATG5 have not been deciphered fully. Here, we identified USP13 as an essential deubiquitinase that stabilizes ATG5 in a process that depends on the PAK1 serine/threonine-protein kinase and which enhances autophagy and promotes IM resistance in GIST cells. USP13 preferentially is induced in GIST cells by IM and interacts with ATG5, which leads to stabilization of ATG5 through deubiquitination. Activation of PAK1 promoted phosphorylation of ATG5 thereby enhancing the interaction of ATG5 with USP13. Furthermore, N 6 -methyladenosine methyltransferase-like 3 (METTL3) mediated stabilization of USP13 mRNA that required the m 6 A reader IGF2BP2. Moreover, an inhibitor of USP13 caused ATG5 decay and co-administration of this inhibitor with 3-methyladenine boosted treatment efficacy of IM in murine xenograft models derived from GIST cells. Our findings highlight USP13 as an essential regulator of autophagy and IM resistance in GIST cells and reveal USP13 as a novel potential therapeutic target for GIST treatment., (© 2022. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

Background: Previous studies have revealed the critical role of transglutaminase 2 (TGM2) as a potential therapeutic target in cancers, but the oncogenic roles and underlying mechanisms of TGM2 in gastric cancer (GC) are not fully understood. In this study, we examined the role and potential mechanism of TGM2 in GC., Methods: Western blotting, immunohistochemistry, CCK8, colony formation and transwell assays were used to measure TGM2 expression in the GC cells and tissues and to examine the in vitro role of TGM2 in GC. Xenograft and in vivo metastasis experiments were performed to examine the in vivo role of TGM2 in GC. Gene set enrichment analysis, quantitative PCR and western blotting were conducted to screen for potential TGM2 targets involved in GC. Gain/loss-of-function and rescue experiments were conducted to detect the biological roles of STAT1 in GC cells in the context of TGM2. Co-immunoprecipitation, mass spectrometry, quantitative PCR and western blotting were conducted to identify STAT1-interacting proteins and elucidate their regulatory mechanisms. Mutations in TGM2 and two molecules (ZM39923 and A23187) were used to identify the enzymatic activity of TGM2 involved in the malignant progression of GC and elucidate the underlying mechanism., Results: In this study, we demonstrated elevated TGM2 expression in the GC tissues, which closely related to pathological grade, and predicted poor survival in patients with GC. TGM2 overexpression or knockdown promoted (and inhibited) cell proliferation, migration, and invasion, which were reversed by STAT1 knockdown or overexpression. Further studies showed that TGM2 promoted GC progression by inhibiting STAT1 ubiquitination/degradation. Then, tripartite motif-containing protein 21 (TRIM21) was identified as a ubiquitin E3 ligase of STAT1 in GC. TGM2 maintained STAT1 stability by facilitating the dissociation of TRIM21 and STAT1 with GTP-binding enzymatic activity. A23187 abolished the role of TGM2 in STAT1 and reversed the pro-tumor role of TGM2 in vitro and in vivo., Conclusions: This study revealed a critical role and regulatory mechanism of TGM2 on STAT1 in GC and highlighted the potential of TGM2 as a therapeutic target, which elucidates the development of medicine or strategies by regulating the GTP-binding activity of TGM2 in GC., (© 2022 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.)

Background: The connection between obesity, lipid accumulation, and lymph node metastasis (LNM) in gastric cancer (GC) is unclear., Methods: The association of body mass index (BMI) and serum lipid levels with LNM was measured by calculating the odds ratio (OR) and 95% confidence interval (CI) in 1,058 eligible GC patients with a mean age of 61.4 years. Meanwhile, differentially expressed genes (DEGs) were identified between lymph node metastasis-positive (N +) and -negative (N0) groups using public RNA-seq data. Neutral lipids in human GC samples were detected by Oil red O staining. The expression of cluster of differentiation 36 (CD36), fatty acid synthase (FASN), and lipoprotein lipase (LPL) was detected by immunohistochemistry (IHC) and quantitative real-time PCR., Results: Compared with normal-weight patients, overweight (OR = 2.02, 95% CI = 1.26-3.23) and obese (OR = 1.83, 95% CI = 1.15-2.91) patients showed increased ORs for LNM. However, no significant results were obtained for serum lipids in the multivariable-adjusted model (P > 0.05). Subgroup analysis suggested that increased low-density lipoprotein cholesterol was a risk factor in females (OR = 1.27, 95% CI = 1.02-1.59). Functional enrichment analysis of DEGs revealed a connection between lipid metabolism and LNM. Meanwhile, lipid staining showed a mass of lipids in obese N + tumor samples, and IHC analysis indicated an increase in LPL and CD36 expression in N + cases, implying a crucial role for exogenous lipid supply in LNM., Conclusions: High BMI significantly increases the risk of LNM in GC and promotes lipid accumulation in GC cells in LNM., (© 2022. The Author(s).)

Recent studies have identified cuproptosis, a new mechanism of regulating cell death. Accumulating evidence suggests that copper homeostasis is associated with tumorigenesis and tumor progression, however, the clinical significance of cuproptosis in gastric cancer (GC) is unclear. In this study, we obtained 26 prognostic cuproptosis-related lncRNAs (CRLs) based on 19 cuproptosis-related genes (CRGs) via Pearson correlation analysis, differential expression analysis, and univariate Cox analysis. A risk model based on 10 CRLs was established with the least absolute shrinkage and selection operator (LASSO) Cox regression analysis and multivariate Cox proportional hazards model to predict the prognosis and immune landscape of GC patients from The Cancer Genome Atlas (TCGA). The risk model has excellent accuracy and efficiency in predicting prognosis of GC patients (Area Under Curve (AUC) = 0.742, 0.803, 0.806 at 1,3,5 years, respectively, P < 0.05 ). In addition, we found that the risk score was negatively correlated with the infiltration of natural killer (NK) cells and helper T cells, while positively correlated with the infiltration of monocytes, macrophages, mast cells, and neutrophils. Moreover, we evaluated the difference in drug sensitivity of patients with different risk patterns. Furthermore, low-risk patients showed higher tumor mutation burden (TMB) and better immunotherapy response than high-risk patients. In the end, we confirmed the oncogenic role of AL121748.1 which exhibited the highest Hazard Ratio (HR) value among 10 CRLs in GC via cellular functional experiments. In conclusion, our risk model shows a significant role in tumor immunity and could be applied to predict the prognosis of GC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Liu, Shen, Xiao, Zhou, Cheng, Hu, Fan, Ni, Xu, Zhang and Yang.)

Background: Liver metastasis (LM) is a major obstacle to the prognosis of gastric cancer (GC) patients, but the molecular mechanism underlying gastric cancer liver metastasis (GC-LM) remains unknown. Exosomes have been identified as an important mediator of communication between tumor cells and the microenvironment. Therefore, we sought to investigate the effects of primary GC cells on the liver microenvironment and the role of exosomal microRNAs (exo-miRNA) in GC-LM., Methods: Sequential differential centrifugation, transmission electron microscopy and NanoSight analysis were used to extract and characterize exosomes. MicroRNA sequencing in GC-derived exosomes and mRNA sequencing in PMA-treated THP-1 cells were used to identify differentially expressed miRNAs in exosomes and the functional targets of exosomal miR-519a-3p (exo-miR-519a-3p) in macrophages, respectively. Tracing and internalization of exosomes and transfer of exo-miR-519a-3p were observed by immunofluorescence. Tubule formation assays, aortic ring assays, and exosome-educated GC-LM model were used to investigate the roles of GC-derived exosomes and exo-miR-519a-3p in angiogenesis and GC-LM. Luciferase reporter assay, qRT-PCR, Western blot, ELISA, flow cytometry and immunofluorescence were used to investigate the regulatory mechanism of exo-miR-519a-3p at GC-LM., Results: The expression level of miR-519a-3p in serum exosomes was significantly higher in GC-LM patients than in patients without LM, and high expression of exo-miR-519a-3p indicates a worse prognosis. GC-derived exosomes are mainly accumulated in the liver and internalized by intrahepatic macrophages. Mechanistically, exo-miR-519a-3p activates the MAPK/ERK pathway by targeting DUSP2, thereby causing M2-like polarization of macrophages. M2-like polarized macrophages accelerate GC-LM by inducing angiogenesis and promoting intrahepatic premetastatic niche formation., Conclusions: Our results indicate that exo-miR-519a-3p plays a critical role in mediating crosstalk between primary GC cells and intrahepatic macrophages and is a potential therapeutic target for GC-LM., (© 2022. The Author(s).)

The host microbiota is closely associated with tumor initiation and progression in multiple solid tumors including gastric cancer. The aim of this study was to investigate in patients with gastric cancer whether there are alterations in gastric microbiota and any potential association these may have with immune dysregulation. 16S rRNA gene sequencing was used to analyze tumor microbiota of 53 patients with gastric cancer and gastric mucosal tissue microbiota of 30 patients with chronic gastritis. The effect of microbiota on the tumor microenvironment (TME) was studied by single-cell sequencing, immunohistochemistry, multiplex immunofluorescence staining, and flow cytometry, as well as in a mouse model of primary gastric cancer. The gastric cancer microbiota was characterized by reduced microbial diversity and enrichment of the Oceanobacter, Methylobacterium, and Syntrophomonas genera. Intratumoral Methylobacterium was significantly associated with poor prognoses in patients with gastric cancer. It also was inversely correlated with the frequency of CD8+ tissue-resident memory T (TRM) cells in the TME. TGFβ was significantly reduced in gastric cancer samples with higher abundance of Methylobacterium. Finally, we verified that Methylobacterium can decrease TGFβ expression and CD8+ TRM cells in the tumor by establishing a mouse model of primary gastric cancer. The results suggest that tumor microbiota and exhausted CD8+ TRM cells in the TME of gastric cancer are significantly correlated, and that Methylobacterium may play a role in gastric carcinogenesis., (©2022 American Association for Cancer Research.)

Background: Early-onset gastric cancer (EOGC, ≤45 years old) is characterized with increasing incidence and more malignant phenotypes compared with late-onset gastric cancer, which exhibits remarkable immune cell infiltration and is potential immunotherapeutic population. Till now, restricted survival information of EOGC is available due to limited case numbers. This study established a novel nomogram to help evaluate cancer-specific survival (CSS) of EOGC patients who underwent gastrectomy, and may provide evidence for predicting patients' survival., Methods: We retrospectively enrolled a cohort containing 555 EOGC cases from five independent medical centers in China, among which 388 cases were randomly selected into a training set while the other 167 cases were assigned into the internal validation set. Asian or Pacific Islander (API) patients diagnosed with EOGC during 1975-2016 were retrieved from the SEER database (n=299) and utilized as the external validation cohort. Univariate and multivariate analyses were conducted to test prognostic significances of clinicopathological factors in the training set. Accordingly, two survival nomogram models were established and compared by concordance index (C-index), calibration curve, receiver operating characteristics (ROC) curves and decision curve analyses (DCA)., Results: The 5-year CSS rate of training cohort was 61.3% with a median survival time as 97.2 months. High consistency was observed on calibration curves in all three cohorts. Preferred nomogram was selected due to its better performance on ROC and DCA results. Accordingly, a novel predicative risk model was introduced to better stratify high-risk EOGC patients with low-risk patients. In brief, the 5-year CSS rates for low-risk groups were 92.9% in training set, 83.1% in internal validation set, 89.9% in combined NQSQS cohort, and 85.3% in SEER-API cohort. In contrast, the 5-year CSS rates decreased to 38.5%, 44.3%, 40.5%, and 36.9% in the high-risk groups of the four cohorts above, respectively. The significant survival difference between high-risk group (HRG) and low-risk group (LRG) indicated the precise accuracy of our risk model. Furthermore, the risk model was validated in patients with different TNM stages, respectively. Finally, an EOGC web-based survival calculator was established with public access, which can help predict prognosis., Conclusions: Our data provided a precise nomogram on predicting CSS of EOGC patients with potential clinical applicability., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Li, Zhang, Li, Zhong, Wang, Yang, Li, Wang, Li, Wang, Kong, He, Wang, Wang, Zhang, Xu, Yang, Chen, Zhou and Xu.)

Background & Aims: Helicobacter pylori (H pylori) infection is the main risk factor for gastric cancer. The role of fibroblast growth factor receptors (FGRFs) in H pylori-mediated gastric tumorigenesis remains largely unknown. This study investigated the molecular and mechanistic links between H pylori, inflammation, and FGFR4 in gastric cancer., Methods: Cell lines, human and mouse gastric tissue samples, and gastric organoids models were implemented. Infection with H pylori was performed using in vitro and in vivo models. Western blot, real-time quantitative reverse-transcription polymerase chain reaction, flow cytometry, immunofluorescence, immunohistochemistry, chromatin immunoprecipitation, and luciferase reporter assays were used for molecular, mechanistic, and functional studies., Results: Analysis of FGFR family members using The Cancer Genome Atlas data, followed by validation, indicated that FGFR4 messenger (m)RNA was the most significantly overexpressed member in human gastric cancer tissue samples (P < .001). We also detected high levels of Fgfr4 mRNA and protein in gastric dysplasia and adenocarcinoma lesions in mouse models. Infection with J166, 7.13, and PMSS1 cytotoxin-associated gene A (CagA)+ H pylori strains induced FGFR4 mRNA and protein expression in in vitro and in vivo models. This was associated with a concordant activation of signal transducer and activator of transcription 3 (STAT3). Analysis of the FGFR4 promoter suggested several putative binding sites for STAT3. Using chromatin immunoprecipitation assay and an FGFR-promoter luciferase reporter containing putative STAT3 binding sites and their mutants, we confirmed a direct functional binding of STAT3 on the FGFR4 promoter. Mechanistically, we also discovered a feedforward activation loop between FGFR4 and STAT3 where the fibroblast growth factor 19–FGFR4 axis played an essential role in activating STAT3 in a SRC proto-oncogene non-receptor tyrosine kinase dependent manner. Functionally, we found that FGFR4 protected against H pylori-induced DNA damage and cell death., Conclusions: Our findings demonstrated a link between infection, inflammation, and FGFR4 activation, where a feedforward activation loop between FGFR4 and STAT3 is established via SRC proto-oncogene non-receptor tyrosine kinase in response to H pylori infection. Given the relevance of FGFR4 to the etiology and biology of gastric cancer, we propose FGFR4 as a druggable molecular vulnerability that can be tested in patients with gastric cancer., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Mesothelin (MSLN) is a cell surface protein associated with tumor invasion and metastasis. This study aims to explore the biological function of MSLN in gastric cancer and to evaluate the association of MSLN polymorphism (rs3764247, rs3764246, rs12597489, rs1057147, rs3765319) with the risk and prognosis of gastric cancer. Small interfering RNA (siRNA) transfection and MSLN overexpression were performed in human gastric cancer cell lines, respectively. The proliferation of tumor cells was evaluated by Cell counting kit 8(CCK-8) and colony formation assay. Wound healing assay and transwell assay were used to elucidate gastric cancer cell migration and invasion rates. We conducted a case-control study involving 860 patients with gastric cancer and 870 controls. All mutation sites were genotyped by PCR-LDR sequencing. First, our study revealed the cancer-promoting role of MSLN in gastric cancer. Second, we also demonstrated that rs3764247 and rs3764246 were associated with a reduced risk of gastric cancer (OR = 0.83, p = 0.010; OR = 0.84, p = 0.011; respectively). The clinicopathological analysis further showed that rs3764247 was closely related to T stage, vascular infiltration, and HER2 expression. In addition, in the survival analysis of 392 patients with gastric cancer, patients with rs3764247 CC genotype had poorer survival than patients with AA + AC genotype after adjusting for age, sex, TNM stage, and Lauren classification (HR = 2.07, p = 0.029). Our findings indicated that MSLN could be an oncogene whose polymorphisms were closely related to the risk and prognosis of gastric cancer., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)