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The influences of TRIM28 on the gastric tumorigenesis together with potential molecular mechanisms remain to be studied. We aimed at exploring the important effects of TRIM28 on gastric cancer (GC) and uncovering underling molecular mechanisms. Through immunohistochemistry analysis of 20 pairs of GC and the peritumoral tissues, the expression level of TRIM28 was determined. A variety of assays were applied to explore the important roles of TRIM28 in GC. Western blotting and qRT-PCR analyses were used to analyze the association between TRIM28 and the Wnt/β-catenin signaling pathway. TRIM28 was highly expressed in GC tissues than peritumoral tissues. And high expression level of TRIM28 in GC was associated with good prognostic effects. In vitro functional assays suggested TRIM28 knockdown enhanced the proliferation and clone formation of GC cell. Moreover, TRIM28 knockdown enhanced the expression level of stemness markers, strengthened sphere-forming and drug-resistance properties of GC cells, suggesting important effect on GC cell stemness. Besides, our analysis showed that the Wnt/β-catenin signaling was involved in the effect of TRIM28 on GC cell stemness property, and blocking Wnt/β-catenin signaling pathway obviously rescued the promotion influence of TRIM28 knockdown. Overall, TRIM28 has an important influence on regulating the stem-like property of GC cell via Wnt/β-catenin signaling, suggesting TRIM28 a promising drug target and a potential predictor of prognosis., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Early diagnosis is crucial for optimal prognosis of gastric cancer (GC). Hereby, we aimed to identify novel serum autoantibody-based biomarkers for precancerous lesion (PL) and early GC., Methods: We performed serological proteome analysis (SERPA) combined with nanoliter-liquid chromatography combined with quadrupole time of flight tandem mass spectrometry (Nano-LC-Q-TOF-MS/MS) to screen for GC-associated autoantibodies. The identified autoantibodies were analyzed for potential detection value for PL and GC by enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristic (ROC) curves analysis was conducted to evaluate the accuracy of the biomarkers., Results: We identified seven candidates, such as mRNA export factor (RAE1), Nucleophosmin 1 (NPM1), phosphoglycerate kinase 1 (PGK1), and ADP-ribosylation factor 4 (ARF4). Antibodies against all seven proteins were present at higher levels in sera from 242 patients (51 PL, 78 early GC, 113 advanced GC) compared with sera from 122 healthy individuals. RAE1-specific autoantibody discriminated best between patients at different GC stages, with area under the curve (AUC) values of 0.710, 0.745, and 0.804 for PL, early GC, and advanced GC, respectively. Two predictive models composed of gender, RAE1, PGK1, NPM1, and ARF4 autoantibodies (Model 2 for PL) and of age, gender, RAE1, PGK1, and NPM1 autoantibodies (Model 3 for early GC) had improved diagnostic efficiencies, with AUCs of 0.803 and 0.857, sensitivities of 66.7% and 75.6%, and specificities of 78.7% and 87.7%, respectively., Conclusion: The identified serum tumor-associated autoantibodies (TAAbs) may have good potential for early detection of GC and PL., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Helicobacter pylori infection is a leading cause of gastric cancer (GC). However, the underlying mechanisms have not yet been fully elucidated. We aimed to identify microRNAs (miRNAs) regulated by H. pylori infection and their underlying mechanisms in gastric carcinogenesis. Using a mouse model, it was established that H. pylori infection inhibited autophagy in the gastric mucosa. Importantly, H. pylori infection decreased miR-1298-5p levels in human and mouse gastric tissues and human gastric cell lines. Furthermore, the downregulation of miR-1298-5p levels remarkably inhibited autophagy, ultimately increasing the intracellular H. pylori load, which was detected using a gentamicin protection assay. A series of in vitro assays showed that the downregulation of miR-1298-5p expression promoted GC cell proliferation, migration, and invasion. Mechanistically, using bioinformatics prediction, miRNA pull-down assays, and luciferase reporter assays, mitogen-activated protein kinase kinase 6 (MAP2K6) was found to be the direct target of miR-1298-5p, through which miR-1298-5p regulated autophagy and GC cell viability and motility. Moreover, MAP2K6/p38 mitogen-activated protein kinase (MAPK) axis was determined to be the downstream pathway of miR-1298-5p. These findings revealed that H. pylori infection was found to inhibit autophagy and promote tumor growth by regulating miR-1298-5p expression and the miR-1298-5p/MAP2K6/p38 MAPK axis might be a new avenue for the clinical management of H. pylori infection and H. pylori-associated GC., (Copyright © 2022. Published by Elsevier Inc.)

Asporin (ASPN) presents in the tumor microenvironment and exhibits a cancer-promoting effect as a stroma protein. Even though ASPN has already been observed inside cancer cells, the functions of intracellular ASPN and its underlying mechanisms remain unknown. Here we reported that ASPN was upregulated in different stages of gastric cancer (GC), and associated with a poor prognosis. Moreover, we found that ASPN markedly inhibited GC cell apoptosis and promoted cell growth in vitro and in vivo. Further mechanism investigations revealed that ASPN directly binding to lymphoid enhancer-binding factor 1 (LEF1) and promoted LEF1-mediated gene transcription independent of β-catenin, the classic co-factor in the Wnt/LEF1 pathway. We also demonstrated that ASPN selectively facilitated LEF1 binding to and activating the promoters of PTGS2, IL6, and WISP1 to promote their transcription. The suppression of cell apoptosis by ASPN overexpression could be attenuated by LEF1 knockdown or 100 µM aspirin (PTGS2 inhibitor), and siASPN mediated apoptosis could be rescued by LEF1 ectopic expression or adding recombinant IL6. Therefore, we concluded that ASPN repressed GC cell apoptosis via activating LEF1-mediated gene transcription independent of β-catenin, which could serve as a potential prognostic biomarker in GC patients.

Gastric cancer (GC) is one of the most common malignancies in the world. Exosomes, a subset of extracellular vesicles with an average diameter of 100 nm, contain and transfer a variety of functional macromolecules such as proteins, lipids, and nucleic acids. A large number of studies indicated that exosomes can play a significant role in the initiation and development of GC via facilitating intercellular communication between gastric cancer cells and microenvironment. Exosomal RNAs, one of the key functional cargos, are involved in the pathogenesis, development, and metastasis of GC. In addition, recent studies elucidated that exosomal RNAs may serve as diagnostic and prognostic biomarkers or therapeutic targets for GC. In this review, we summarized the function of exosomal RNA in the tumorigenesis, progression, diagnosis, and treatment of GC, which may further unveil the functions of exosome and promote the potentially diagnostic and therapeutic application of exosomes in GC.

Matrix Gla protein (MGP) has been widely reported as an extracellular matrix protein with abnormal expression in various types of cancer. However, the function of intracellular MGP in gastric cancer (GC) cells remains largely unknown. Here, we demonstrated aberrantly high expression of intracellular MGP in GC as compared to adjacent normal tissues by immunohistochemistry. Moreover, The Cancer Genome Atlas (TCGA) dataset analysis suggested a positive correlation between MGP overexpression and unfavorable prognosis. MGP silencing reduced cell proliferation, migration, invasion, and survival in GC cell lines. Gene set enrichment analysis of TCGA dataset indicated significant enrichment of the IL2-STAT5 signaling in MGP-high GC patients. Immunofluorescence staining and immunoprecipitation showed that MGP binds to p-STAT5 in the nuclei of GC cells. Furthermore, ChIP-qPCR and luciferase reporter assays indicated that MGP acts as a transcriptional co-activator through the enhancement of STAT5 binding to target gene promoters. Use of STAT5 inhibitor revealed that the oncogenic functions of intracellular MGP mainly depend on the JAK2/STAT5 signaling pathway. Taken together, our results indicate that intracellular MGP promotes proliferation and survival of GC cells by acting as a transcriptional co-activator of STAT5. The detected aberrant, high MGP expression in GC tissues highlights MGP as a potential new prognostic biomarker in patients with GC., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

RB Binding Protein 8 (RBBP8) was previously reported being involved in DNA double-strand break (DSB) repair in cancers. However, there is no systematic study about the specific functions and related mechanisms of RBBP8 in gastric carcinogenesis. Through immunohistochemistry staining of paired gastric cancer (GC) tissues, adjacent high-grade intraepithelial neoplasia (HGIEN) tissues, and non-cancerous tissues, we found RBBP8 expression was upregulated in both HGIEN and GC tissues. Functional experiments showed the knockdown of RBBP8 inhibited cell proliferation and colony formation ability. This is mainly achieved through the role of RBBP8 in facilitating G1/S transition and promoting Cyclin D1 and CDK4 level. Then the interaction between RBBP8, BRCA1, and CtBP was revealed by co-immunoprecipitation (co-IP) and immunofluorescence confocal imaging. Moreover, we found RBBP8 acted as an adapter in this complex and RBBP8 overexpression enhanced the nucleus location of BRCA1. RBBP8 overexpression could inhibit P21 expression and HDAC (histone deacetylase) inhibitor Trichostatin A (TSA) eliminated this effect. The HDAC activity of CtBP-RBBP8-BRCA1 complex was also further verified by HDAC activity assay. Through Chromatin immunoprecipitation (ChIP), we found RBBP8 could induce P21 promoter histone deacetylation and inhibit P21 transcription. In conclusion, we found RBBP8 could promote the G1/S transition of GC cells by inhibiting P21 level. Moreover, we revealed the chromatin modification role of RBBP8, which could suppress the histone acetylation level of P21 promoter by recruiting CtBP co-repressor complex to BRCA1 binding site.

Background and aims: The aim of this study was to compare and analyze the feasibility and safety of two methods of endoscopic full-thickness resection (EFTR) for the management of challenging epithelial and subepithelial neoplasms that are not amenable to resection techniques. Material and methods: This was a retrospective case series study of patients who underwent one of two methods of EFTR, resection using ESD knives and post-resection closure with OTSC (Group 1), or closure with OTSC and secondary EFTR with snare (Group 2). Results: Of 11 patients, six were in Group 1 and five in Group 2. The mean time of the EFTR procedure was 76.83 ± 34.97 min in Group 1 which is significantly longer than that of Group 2 ( p  = .0128). The mean time of OSTC closure and length of hospital stay of Group 1 were also longer compared to Group 2, but the difference was not significant. Complete resection (R0) and technical success rates of Group 1 and Group 2 were 83.3% and 100% ( p  = .338), respectively. VAS scores of Group 1 immediately after the operation and after 24 h are significantly higher than those of Group 2 ( p  = .047 and p  = .009, respectively). In Group 1, one patient had delayed perforation which led to fever and pneumoperitoneum, and one patient developed abdominal pain. No complications associated with the endoscopic procedure were observed in Group 2. Conclusion: EFTR of pre-resection closure are potentially faster compared with the concept of applying closure after EFTR. Larger prospective controlled studies comparing these two techniques are warranted in the future.

Asporin (ASPN), a member of small leucine-rich repeat proteoglycan (SLRP) family of proteins, serves important roles in diverse biological responses and disease conditions. We tested the hypothesis that ASPN regulated proliferation of gastric cancer (GC) cells and identified its down-stream regulators. ASPN promoted the proliferation of GC cells. We identified the effector of this effect as proteasome 26S subunit non-ATPase 2 (PSMD2) which is known to regulate proliferation through suppression of DUSP7, WIP1 and PTEN and then inducing the phosphorylation of ERK, P38 and AKT. PSMD2 co-immunoprecipitated with ASPN from GC cell lysates and co-localized with PSMD2 inside GC cells. Moreover, knockdown of ASPN significantly increased the expression of DUSP7, WIP1 and PTEN and led to a repression in the phosphorylation of ERK, P38 and AKT. These changes were counteracted by knockdown of PSMD2. In conclusion, ASPN promotes cell proliferation by interacting with PSMD2, and down-regulation of its effectors and serves as a potential therapeutic target in GC.

Lauren classification is a pathology-based gastric cancer (GC) subtyping system, which is widely used in the clinical treatment of patients with GC. However, genome-scale molecular characteristics to distinguish between diffuse (DF) and intestinal (IT) GC remain incompletely characterized, particularly at the transcriptional regulatory level. In the present study, gene regulatory networks were constructed using the Passing Attributes between Networks for Data Assimilation (PANDA) algorithm for DF, IT and mixed GC. The results indicated that >85% of transcription factor (TF)-target edges were shared among all three GC subtypes. In TF enrichment analysis, 13 TFs, including nuclear transcription factor Y subunit α (NFYA) and forkhead box L1, were activated in DF GC, whereas 8 TFs, including RELA proto-oncogene and T-cell leukemia homeobox 1 (TLX1), were activated in IT GC. Out of these identified TFs, NFYA [Hazard ratio (HR) (95% confidence interval, CI)=0.560 (0.349, 0.900), P=0.017] and sex determining region Y [HR (95% CI)=0.603 (0.375, 0.969), P=0.037] were identified as independent prognostic factors in DF GC, but not in IT GC, whereas TLX1 [HR (95% CI)=0.547 (0.321, 0.9325), P=0.027] was identified as an independent prognostic factor in IT GC, but not in DF GC. Verification at the cellular level was also performed; interference of NFYA expression using small interfering RNA in MGC803 cells (DF GC-derived cells) markedly inhibited cell growth and colony formation. Similar effects were also detected in SGC-7901 cells (IT GC-derived cells), but to a lesser extent. In conclusion, identified gene regulatory networks differed between distinct GC subtypes, in which the same TFs had different biological effects. Specifically, NFYA was identified as a DF subtype-specific independent prognostic factor in GC.

Background/aims: The function of regulatory T cells (Treg) and helper T cells 17 (Th17) related indexes, such as interleukin (IL)-6, IL-17, transforming growth factor (TGF)-β1, and forkhead box protein 3(FoxP3) in gastric adenocarcinoma tissues remains undefined. We investigated and analyzed the relevance of the proteins with the clinicopathological characteristics and the interactions among them in gastric cancer., Materials and Methods: A total 68 gastric cancer patients and 40 healthy controls were enrolled. Immunohistochemistry (IHC) as well as quantitative real-time reverse transcription- polymerase chain reaction (RT-PCR) was used to determine the expression levels of IL-6, TGF-β1, IL-17, and FoxP3 in the prepared tissues. Statistical analysis included ANOVA and chi-square test., Results: The expression levels of IL-6, IL-17, FoxP3, and TGF-β1 had significantly increased in cancer tissues compared to controls. Clinical staging of gastric cancer were correlated with the rise of IL-6, IL-17, FoxP3, and TGF-β1 levels expressed in cancer tissues. The expression level of TGF-β1 and IL-6 was positively related to that of IL-17 and FoxP3, similar to FoxP3 and IL-17 in gastric cancer tissues., Conclusion: IL-6, TGF-β1, FoxP3, and IL-17 may promote the progression of gastric cancer individually or jointly and have complex interactions.

Purpose: T cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) could weaken the Th1-mediated anti-tumor responses and accelerate the tumor cell proliferation by inhabiting the production of IL-2 or IFN-γ. This study was to assess the association between TIM-3 genetic variations and the development of gastric cancer., Patients and Methods: Five polymorphisms located in the promoter or encoding region of TIM-3 gene were genotyped in 212 gastric cancer patients and 252 controls who matched with the patients on the frequency of age, gender, smoking, and drinking. Logistic regression was used to determine whether the inherited variations within TIM-3 gene were associated with gastric cancer risk. Linkage disequilibrium and Haplotype analyses were performed by using SHEsis program., Results: By the individual genotype analysis, three polymorphisms (-574G/T, -882C/T, and -1516G/T) within TIM-3 gene were significantly associated with gastric cancer in the study population [ORs (95% CIs): 2.74 (1.21-6.20), 3.19 (1.29-7.91), and 2.03 (1.15-3.59); respectively]. Among the gastric cancer patients, the relationship between the -1516 polymorphic genotype and the distant metastasis of tumor was found (OR = 2.21, 95% CI = 1.05-4.63). Under the analysis of haplotypes, an even stronger association with haplotype TTGCT was observed in gastric cancer risk (OR = 5.57, 95% CI: 1.04-29.80, P = 0.024)., Conclusion: These results indicated that the three genetic variations within the TIM-3 gene promoter may be associated with the increased susceptibility to gastric cancer, especially among the haplotypes with the risk.