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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. 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. 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. The frequency of NI is high in GC patients and increases with disease progression. NI is related to poor survival in GC patients who underwent curative gastrectomy and provides independent prognostic value for young and lymph node metastasis negative patients. [ABSTRACT FROM AUTHOR]

Background: Abnormal glycosylation of proteins has been identified in almost all types of cancers and is closely related to the cancer progression, metastasis, and survival of cancer patients. This study was to explore the values of serum tumor abnormal protein (TAP), an abnormal glycochain protein, in the diagnosis and prognosis of gastric cancer (GC). Methods: A total of 335 GC patients were included as the study group, and another 335 subjects served as the control group. Tumor abnormal protein expression was compared between the 2 groups. Correlation analysis was used to assess the correlations of TAP with clinicopathological factors. Gastric cancer patients were divided into training set and test set at a ratio of 2:1. Univariate and multivariate Cox regression analyses in training set were used to evaluate the prognostic significance of TAP in GC patients and explore the independent risk factors for overall survival (OS) and disease-free survival (DFS) to establish a prognostic model, followed by testing of the model. According to the median of TAP, 335 GC patients were divided into 2 groups to plot the survival curves of OS and DFS. Results: Tumor abnormal protein expression in the study group was significantly higher than in the control group. Taking the best cut-off value of TAP (110.128 μm2) as the diagnostic criteria for GC, the sensitivity and specificity of TAP were 83.58% and 97.61%, respectively, and the area under the receiver operating characteristics (ROC) curve was 0.935, which was not inferior to computed tomography (CT). Tumor abnormal protein expression was an independent risk factor for OS and DFS. The prognostic predictive value of TAP was better than that of pathological stage in GC patients. The model with TAP was effective in predicting prognosis. Conclusion: Tumor abnormal protein is an effective indicator for early screening and prognostic evaluation of GC and can also assist the clinical diagnosis and treatment of GC. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) ranks third in mortality among all cancers worldwide. Circular RNAs (circRNAs) play an important role in the occurrence and development of gastric cancer. Forkhead box P2 (FOXP2), as a transcription factor, is closely associated with the development of many types of tumours. However, the regulatory network between FOXP2 and circRNAs remains to be explored. In our study, circST3GAL6 was significantly downregulated in GC and was associated with poor prognosis in GC patients. Overexpression of circST3GAL6 inhibited the malignant behaviours of GC cells, which was mediated by inducing apoptosis and autophagy. In addition, we demonstrated that circST3GAL6 regulated FOXP2 through the mir‐300 sponge. We further found that FOXP2 inhibited MET Proto‐Oncogene (MET), which was the initiating factor that regulated the classic AKT/mTOR pathway of autophagy. In conclusion, our results suggested that circST3GAL6 played a tumour suppressive role in gastric cancer through miR‐300/FOXP2 axis and regulated apoptosis and autophagy through FOXP2‐mediated transcriptional inhibition of the MET axis, which may become a potential target for GC therapy. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy can significantly improve the disease‐free survival and overall survival of patients with advanced gastric cancer (GC). 5‐fluorouracil (5‐FU) is frequently applied in the clinic, acting as a first‐line chemotherapy drug of advanced GC, which could be used alone or combining platinum drugs. However, its efficacy is significantly attenuated by chemoresistance, which is associated with patients' poor survival. Recently, there is evidence suggesting that dysregulation of autophagy may contribute to drug resistance in cancer, and circular RNAs (circRNAs) also take part in chemoresistance. However, whether circRNAs participate in 5‐FU chemoresistance through autophagy remains largely unknown. Methods: RNA sequencing technologies and bioinformatics analysis were performed in GC. Sanger sequencing, Actinomycin D assay and RNase R assay confirmed the circular structure of circular CPM (circCPM). Various cell line models and animal models were used to explore related functions in vitro and in vivo. Quantitative Real‐time PCR (qRT‐PCR), fluorescence in situ hybridization, ribonucleic acid; (RNA) pulldown assays, RNA binding protein immunoprecipitation assays and Luciferase reporter assays were applied to explore involved pathways. Results: circCPM was up‐regulated in 5‐FU resistant GC cell lines and tissue. Moreover, high circCPM expression is positively associated with poor survival. Silencing circCPM greatly improved chemosensitivity in vitro and in vivo. Mechanistically, it directly binds to miR‐21‐3p in the cytoplasm and therefore increases the expression of PRKAA2, contributing to the activation of autophagy and chemoresistance. Conclusion: Our results reveal that circCPM has a crucial role in regulating GC autophagy and 5‐FU resistance by targeting PRKAA2. It may function as a new theory basis for assessing the curative effect of GC and reversing 5‐FU chemoresistance. [ABSTRACT FROM AUTHOR]

BACKGROUND: Genetic polymorphisms are believed to represent a key aspect of predisposition to gastric cancer (GC). Therefore, considering the important role of Cathepsin B (CTSB) in promoting cancer onset and development, it could be very worthful to explore the function of CTSB-related genetic polymorphisms in GC. OBJECTIVE: In this study, we investigated the correlation of CTSB-related polymorphisms (rs9009A>T, rs6731T>C, rs1293303G>C, rs1874547C>T, rs3779659C>T, rs17814426C>T and rs148669985C>T) with GC risk and prognosis in a case-control study of 994 cases and 1000 controls. METHODS: All tag single nucleotide polymorphisms (SNPs) were genotyped by polymerase chain reaction-ligase detection reaction (PCR-LDR) sequencing technology. RESULTS: The results indicated rs9009, rs6731 and rs17814426 correlated with decreased risks of GC (HR = 0.97, p < 0.001; HR = 0.86, P = 0.019; HR = 0.85, P = 0.017; respectively). Stratification analysis further showed rs17814426 variant genotypes correlated with earlier T stage (p = 0.044). In addition, GC patients carrying the C allele of rs6371 had better overall prognosis (HR = 0.62, 95%CI = 0.44–0.88). CONCLUSION: Our results firstly suggested the importance of CTSB-related polymorphisms on GC which could predict GC risk and prognosis. [ABSTRACT FROM AUTHOR]

So far, many existing evidences indicate that microRNAs (miRNA) are closely associated with the tumorigenesis and progression of various tumors. It has been reported that miR-1301-3p is abnormally expressed in several malignant tumors. However, the role of miR-1301-3p in gastric cancer (GC) remains unclear and is worth studying. Through qRT-PCR, the expression of miR-1301-3p and SIRT1 were detected in GC tissues and cells. The cell proliferation and cell cycle were measured through CCK-8 assay and clone formation assay. Dual luciferase reporter assay was used to determine the target of miR-1301-3p. Though tumorigenesis assay, we monitored the effect of miR-1301-3p on GC cell growth in vivo. miR-1301-3p was upregulated in GC tissues and cells in our study. Overexpression of miR-1301-3p accelerated GC cell proliferation, cell cycle progression and tumorigenesis. Notably, altering the expression miR-1301-3p caused deregulation of Cyclin D1, CDK4, c-Myc and P21. Furthermore, SIRT1 was the direct target of miR-1301-3p by luciferase reporter assay. After transfecting with miR-1301-3p inhibitor, we found that knockdown of SIRT1 could enhance the ability of proliferation. Our results identify miR-1301-3p as a novel potential therapeutic target that is associated with the tumorigenesis and progression of gastric cancer. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is one of the most deadly malignancies at global scale, and is particularly common in eastern Asia. MicroRNA‐5683 (miR‐5683) was confirmed to be downregulated in GC by analyzing data from the Cancer Genome Atlas. We packaged miR‐5683‐mimics and miR‐5683‐inhibitors into lentivirus vectors and transfected them into GC cells. MiR‐5683 expression and possible target genes were detected by employing quantitative real‐time polymerase chain reaction. In vitro, cell proliferation and apoptosis were analyzed using CCK‐8, colony formation assay, and flow cytometric assay. We verified the direct interaction between miR‐5683 and the possible downstream target gene pyruvate dehydrogenase kinase 4 (PDK4) through luciferase reporter assay. The role of miR‐5683 in vivo was explored by injecting stably transfected GC cells subcutaneously into nude mice. Here we show that miR‐5683 was downregulated in GC and the decreased level of miR‐5683 enhances GC cell proliferation and impairs apoptosis. Tumor oncogene PDK4, which is associated with GC overall survival and disease‐free survival, has been identified as the target gene of miR‐5683. Besides, we demonstrate that the inhibition of miR‐5683 promotes glycolysis by upregulating the PDK4 expression, thus leading to GC progression. Our study determines that miR‐5683 represses GC glycolysis and progression through targeting PDK4. MiR‐5683 overexpression may thus become a new treatment strategy for GC. [ABSTRACT FROM AUTHOR]

Objectives: The PHD Finger Protein 19 (PHF19), as a sub-component of polycomb repressive complex 2 (PRC2), has been identified to be associated with various biological processes. Aberrant expression of PHF19 has implicated in several cancer types. This study aims to investigate its function and clinical significance in gastric cancer for the first time. Methods: The expression of PHF19 was evaluated by quantitative real-time PCR (qRT-PCR) and immunohistochemistry. PHF19 was silenced by small interference RNAs and lentiviral particles in gastric cancer cells. Then cell growth was measured by CCK-8 assays, colony formation and in a mouse model. Transwell and wound healing assays were performed to detect cell migration. Western blot analysis was used to explore the downstream signaling factors in PHF19-silenced cells, xenograft tumors and gastric cancer samples. Results: PHF19 was frequently upregulated in gastric cancer tissues compared with adjacent normal stomach tissues and this upregulation was correlated with tumor cell differentiation and poor outcome of gastric cancer patients. Functionally, the silencing of PHF19 in gastric cancer cells led to decreased cell growth and migration. Stable knockdown of PHF19 inhibited the tumorigenicity of gastric cancer cells in nude mice model. Western blot results demonstrated that phosphorylated AKT and ERK were reduced upon PHF19 downregulation, implying the two signaling pathways possibly mediate the oncogenic roles of PHF19. Conclusions: We identified PHF19 as an oncogene candidate and provided a new potential drug target for gastric cancer. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is one of the most common causes of cancer‐related death worldwide, and outstanding biomarkers for therapeutic targets or predicting GC survival are still lacking. Increasing evidence indicated that nucleolar and spindle associated protein 1 (NUSAP1) involved in regulating the progression of various cancers; however, its specific role in GC remained unclear. In this study, we found that NUSAP1 was upregulated in the GC tissues and cell lines via analysing data from The Cancer Genome Atlas (TCGA), gene expression omnibus (GEO), qRT‐PCR, and western blot assays. Patients with high NUSAP1 expression levels showed shorter free‐progression survival (FPS), larger tumour size, and higher lymphatic metastasis rate compared with those with low NUSAP1 expression. Further functional experiments revealed knockdown of NUSAP1 could inhibit the growth, migration, and invasion of GC cells in vitro and vivo. Additionally, silencing NUSAP1 induced G0/G1 phase arrest, apoptosis, and suppressed the epithelial‐mesenchymal transition (EMT) process. Finally, we performed gene set enrichment analysis (GSEA) and observed NUSAP1 was positive with mTORC1 signalling pathway, which was verified by the subsequent immunoblotting. In conclusion, our findings suggested that NUSAP1 contributed to GC progression and may act as a potential therapeutic target for GC. Significance of the study: Our results firstly illuminated that NUSAP1 expression was significantly upregulated in GC tissues and predicted poor FPS. Silencing it could attenuate GC progression via inhibiting mTORC1 signalling pathway. Hence, NUSAP1 may act as a promising therapy target for GC. [ABSTRACT FROM AUTHOR]

It was investigated that TP73-AS1(TP73 antisense RNA 1) could function as an oncogene in gastric cancer (GC). The expression and function of long noncoding RNAs (lncRNAs) could be impacted by single nucleotide polymorphisms (SNPs), which are related to cancer susceptibility and prognosis. This study was to reveal the association between lncRNAs TP73-AS1 polymorphisms (rs1181865 A > G, rs9800 G > C, rs3737589 A > G, rs2298222 G > A, rs7515164 C > A) and GC in 1000 GC cases and 1000 controls in a Chinese Han population. Rs3737589 G allele had significant associations with the increasing risk of GC (G vs. A: p =.005). Rs3737589 variant genotypes (AG + GG) were related to an increased risk of GC in the elder population (age ≥60), females, nonsmokers, nondrinkers, individuals living in urban, and individuals without family history of GC in stratified analyses. Rs3737589 variant genotypes (AG + GG) were related to the advanced depth of tumor invasion (T3 + T4). Besides, we found that GC patients with AG or GG genotype of rs3737589 had poorer overall survival (OS) than those with AA genotype (p <.05). Our findings showed that the lncRNA TP73-AS1 rs3737589 polymorphism might increase the risk of GC, and rs3737589 polymorphism could be a potential biomarker to predict the prognosis of GC patients. [ABSTRACT FROM AUTHOR]

Background: The objective of this study is to identify independent risks and protective factors and to construct a mortality prediction model for gastrectomy in the Chinese population. Study design: This is a population-based prospective cohort at an institutional level. Seventy-two participating hospitals reported their annual gastrectomy data between 2014 and 2016, while 44 variables covering the institution and surgical information were included in the analysis. We used R software to encode and complete data pre-processing. The first difference model was applied to build the risk model. Data from 2014 and 2015 were assigned to risk model development, while data from 2016 was used for validation. Results: In the included centers with 94,277 gastric cancer cases, the in-hospital mortality rate was 0.32%. The regression model revealed that provinces with low-middle GDP, hospitals with annual gastrectomy volume between 100 and 500, greater volume of urgent surgeries performed, larger proportion of males, and a higher proportion of liver metastasis were independent risk factors for mortality following gastric surgeries, while higher laparoscopic resection volume, greater volume of distal gastrectomy with B2 reconstruction, and larger proportion of palliative surgery were independent protective factors (p < 0.05, respectively). In the prediction test, the mean square error of the training set was 0.948, while that of the test set was 0.728, demonstrating the effectiveness of this model. Conclusions: We constructed the first mortality risk prediction model for gastric cancer surgery in the Chinese population. The identified risk factors will help with the therapy selection, while further informing Chinese medical policy decision-makers. [ABSTRACT FROM AUTHOR]

Objectives: Gastric cancer (GC) is one of the most common cancers in the world, causing a large number of deaths every year. The Slit‐Robo signalling pathway, initially discovered for its critical role in neuronal guidance, has recently been shown to modulate tumour invasion and metastasis in several human cancers. However, the role of Slit‐Robo signalling and the molecular mechanisms underlying its role in the pathogenesis of gastric cancer remains to be elucidated. Materials and methods: Slit2, Robo1 and USP33 expressions were analysed in datasets obtained from the Oncomine database and measured in human gastric cancer specimens. The function of Slit2‐Robo1‐USP33 signalling on gastric cancer cells migration and epithelial‐mesenchymal transition (EMT) was studied both in vitro and in vivo. The mechanism of the interaction between Robo1 and USP33 was explored by co‐IP and ubiquitination protein analysis. Results: The mRNA and protein levels of Slit2 and Robo1 are lower in GC tissues relative to those in adjacent healthy tissues. Importantly, Slit2 inhibits GC cell migration and suppresses EMT process in a Robo‐dependent manner. The inhibitory function of Slit2‐Robo1 is mediated by ubiquitin‐specific protease 33 (USP33) via deubiquitinating and stabilizing Robo1. USP33 expression is decreased in GC tissues, and reduced USP33 level is correlated with poor patient survival. Conclusions: Our study reveals the inhibitory function of Slit‐Robo signalling in GC and uncovers a role of USP33 in suppressing cancer cell migration and EMT by enhancing Slit2‐Robo1 signalling. USP33 represents a feasible choice as a prognostic biomarker for GC. [ABSTRACT FROM AUTHOR]

Trefoil Factor 1 (TFF1, also named pS2), which serves as the gastrointestinal mucosal protector, is known as gastric‐specific tumor suppressor gene. However, the genetic variants of TFF1 are still not well studied. In our study, we aim to explore the effects of tagging single nucleotide polymorphisms (tagSNPs) of TFF1 on risk and prognosis of gastric cancer. Seven tagSNPs of TFF1 gene were first analyzed in the discovery set, which was consisted of 753 cases and 950 cancer‐free controls. Then, the validation set (940 cases and 1,042 controls) was used for further evaluation. Moreover, we also tested the relation between these tagSNPs and prognosis of gastric cancer (GC). A series of experiments were performed to investigate the underlying mechanisms. We found that rs3761376 AA in the promoter region of TFF1, could reduce the expression of TFF1 by affecting the binding affinity of estrogen receptor 1 (ESR1, ERα), and thereby increased the risk of GC (1.29, 1.08–1.53). Moreover, the rs3761376 AA genotype was also found associated with worse prognosis among patients receiving 5‐FU based chemotherapy after surgery (1.71, 1.18–2.48). Further functional assays demonstrated that TFF1 could increase the chemosensitivity of 5‐FU by modulating NF‐κB targeted genes. These results identified the effect of rs3761376 on TFF1 expression, which accounted for the correlation with susceptibility and prognosis of GC; and this genetic variant may be a potential biomarker to predict the risk and survival of GC. [ABSTRACT FROM AUTHOR]

Background/Aims: There is little published data on the role of FOXP3 in gastric cancer. Methods: FOXP3 expression and localization in gastric cancer tissues and cells were examined by immunohistochemistry, RT-PCR, flow cytometry, western blot, and laser confocal microscopy. CCK8, plate clone, wound healing, and transwell insert assays were performed for gastric cancer cells. Potential molecules and signaling pathways were screened using high-throughput transcriptome sequencing. Results: FOXP3 expression in gastric cancer tissues was higher than that in para-carcinoma tissues. It was restricted to the cytoplasm of para-carcinoma tissues, but was observed in the cytoplasm or/and nuclei of gastric cancer tissues. FOXP3 expression was positively correlated with pathological grading, and was detected in gastric cancer and GES-1 cells, where it was expressed in the cytoplasm alone, or in both the cytoplasm and the nucleus. FOXP3 overexpression promoted cell proliferation, migration, and invasion, while FOXP3 knockdown suppressed these effects. Furthermore, RT-PCR and ELISA confirmed that FOXP3 upregulation resulted in increased TGF-β expression and secretion in gastric cancer cells. Conclusion: FOXP3 expression was associated with degree of gastric cancer differentiation. In addition, upregulated and ectopic tumoral FOXP3 can promote gastric cancer proliferation, migration, and invasion, partly through the TGF-β pathway. [ABSTRACT FROM AUTHOR]

The zinc finger protein 143 (ZNF143) is a transcription factor, which regulates many cell cycle-associated genes. ZNF143 expressed strongly in multiple solid tumors. However, the influence of ZNF143 on gastric cancer (GC) remains largely unknown. In this study, we investigated the ZNF143 mRNA level in GC tissues and cells by quantitative real-time PCR (qRT-PCR). The protein expression of ZNF143 in GC cells, and the signaling pathway proteins were detected by Western blotting. Transwell assay and wound healing assay were performed to explore the effects of ZNF143 for the migration ability of GC cells in vitro. We also performed the tail vein injection in nude mice with GC cells to explore the impact of ZNF143 on GC metastasis in vivo. ZNF143 was overexpressed in specimens of GC compared with adjacent normal tissues and increased more significantly in GC tissues of patients who had lymph node metastasis. Ectopic overexpression of ZNF143 enhanced GC migration, whereas ZNF143 knockdown suppressed this effect in vitro. In vivo, ZNF143 knockdown reduced distant metastasis of GC cells in nude mice. In addition, overexpression of ZNF143 reduced the expression of epithelial cell marker (E-cadherin) and induced the expression of mesenchymal cell marker (N-cadherin,Vimentin), Snail and Slug. We also found that ZNF143 enhanced GC cell migration by promoting the process of EMT through PI3K/AKT signaling pathway. In general, our findings show that ZNF143 expressed strongly in GC and enhanced migration of GC cells in vitro and in vivo. It is conceivable that ZNF143 could be a therapeutic genetic target for GC treatment. [ABSTRACT FROM AUTHOR]

The muscarinic receptor M3 is an acetylcholine receptor that regulates the activity of numerous fundamental central and peripheral nervous system functions. Recent studies have identified the activation of the M3 receptor in several cancers; however, the role of M3 in human gastric cancer (GC) remains largely unknown. In this study, we demonstrated that the M3 receptor was overexpressed in human GC tissues and was correlated with the cancer stage and with lymph node metastasis. In vitro, the M3 receptor enhanced the proliferation induced by acetylcholine in human GC cells, whereas the knockdown of M3 by a small hairpin RNA (shRNA) inhibited cell proliferation. Furthermore, M3 knockdown caused G2/M phase cell cycle arrest and induced apoptosis in human GC cells. In vivo, M3 knockdown suppressed tumorigenesis and promoted apoptosis in GC xenografts. In addition, we also detected the secretion of acetylcholine (ACh) by human GC cells and observed the co-expression of the M3 receptor and choline acetyltransferase (ChAT), the enzyme necessary for acetylcholine synthesis, in human GC tissues and cells. Taken together, our findings support an oncogenic role for the M3 receptor in gastric cancer, suggesting that M3 antagonists may serve as potential adjuvants to GC therapies. Further study of the underlying molecular mechanism could also lead to the identification of novel therapeutic targets for improved treatment of GC. [ABSTRACT FROM AUTHOR]

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. 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. 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 steroid receptor coactivator–dependent manner. Functionally, we found that FGFR4 protected against H pylori -induced DNA damage and cell death. Our findings demonstrated a link between infection, inflammation, and FGFR4 activation, where a feedforward activation loop between FGFR4 and STAT3 is established via steroid receptor coactivator 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. [Display omitted] Helicobacter pylori infection is a key step driving a novel tumorigenic feedforward signaling loop linking infection, inflammation, and fibroblast growth factor receptor 4 activation in gastric cancer. [ABSTRACT FROM AUTHOR]

Objective: To expand the current knowledge on the feasibility and safety of laparoscopic total gastrectomy (LTG) for gastric cancer in comparison with open total gastrectomy (OTG). Background: Additional studies comparing laparoscopic versus open total gastric resection have been published, and it is necessary to update the meta-analysis of this subject. Methods: Original articles compared LTG and OTG for gastric cancer, which published in English from January 1990 to July 2013 were searched in PubMed, Embase, and Web of Knowledge by two reviewers independently. Operative time, blood loss, harvested lymph nodes, proximal resection margin, analgesic medication, first flatus day, first oral intake, postoperative hospital stay, postoperative complications, hospital mortality, 5-year overall survival (OS) and disease-free survival (DFS) were compared using STATA version 10.1. Results: 17 studies were selected in this analysis, which included a total of 2313 patients (955 in LTG and 1358 in OTG). LTG showed longer operative time, less blood loss, fewer analgesic uses, earlier passage of flatus, quicker resumption of oral intake, earlier hospital discharge, and reduced postoperative morbidity. The number of harvested lymph nodes, proximal resection margin, hospital mortality, 5-year OS and DFS were similar. Conclusion: LTG had the benefits of less blood loss, less postoperative pain, quicker bowel function recovery, shorter hospital stay and lower postoperative morbidity, at the price of longer operative time. There were no statistical differences in lymph node dissection, resection margin, hospital mortality, and long-term outcomes, which indicated the similar oncological safety with OTG. A positive trend was indicated towards LTG. So LTG can be performed as an alternative to OTG by the experienced surgeons in high-volume centers. Whereas, due to the relative small sample size of long-term outcomes and lack of randomized control trials, more studies are required. [ABSTRACT FROM AUTHOR]

Abstract: Regular use of aspirin (ASA) could reduce the risk of gastric cancer although the precise mechanism remains unclear. Down-regulation of survivin may be one of the cyclooxygenase-independent mechanisms whereby ASA induces apoptosis of gastric cancer cell. In this study, we investigated the effect of ASA on the growth, apoptosis and survivin expression of gastric cancer cell line SGC7901. The survival of cells treated with 3.0 and 10.0 mmol/L ASA for 24 h was decreased by 44.6% and 88.5%, respectively. ASA at 3.0 mmol/L inhibited the viability of SGC7901 cells in a time-dependent manner. Apoptosis analysis showed similar results with MTT assay. ASA at 3.0 and 10.0 mmol/L decreased the mRNA transcript levels of survivin and reduced survivin protein levels in SGC7901 cells also in a time-dependent manner. Our findings indicated that ASA inhibited the proliferation of SGC7901 by suppressing survivin at both the transcriptional and translational level. [Copyright &y& Elsevier]

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. • Muscarinic receptor M3 on gastric cancer (GC)-derived sEVs regulates their absorption by neuronal cells. • sEV-circVAPA promotes neural invasion of GC by reducing the SLIT2 expression of neuronal cells. • sEV-circVAPA decreases SLIT2 transcription by miR-548p/TGIF2 and inhibits SLIT2 translation via eIF4G1 in neuronal cells. [ABSTRACT FROM AUTHOR]

The most studied genetic polymorphisms associated with gastric cancer (GC) risk are located in protein-coding genes. However, these sited in long noncoding RNA (lncRNA) are not adequately explored yet. Here, we designed a case-control study of 848 cases and 880 controls to investigate the associations of polymorphisms (rs61396151, rs1059307, rs11961028, rs9351065) in lncRNA SNHG5 with the risk and prognosis of GC. The results indicate rs61396151 associated with decreased risk of GC (OR = 0.78, 95% CI = 0.62–0.96), but there were no correlations observed with the clinicopathological features of GC (P > 0.05). However, the CA genotype of rs61396151 was correlated with poor overall survival rate in a multivariate cox regression model (HR = 1.91, P = 0.040), but it was reversed with adjustment for age, gender and TNM stage (HR = 1.35, P = 0.213). Collectively, our results highlight the importance of SNHG5-related polymorphisms to GC susceptibility and prognosis. • This study investigated the association of SNHG5 polymorphisms with the susceptibility and prognosis to gastric cancer. • Polymorphism rs61396151 of SNHG5 was associated with decreased risk to gastric cancer. • The variant genotype of rs61396151 predicted poor overall survival of gastric cancer patients. [ABSTRACT FROM AUTHOR]

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 m6A-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. In the study, "TRIM29 promotes antitumor immunity through enhancing IGF2BP1 ubiquitination and subsequent PD-L1 downregulation in gastric cancer," we explored for the first time the role of the E3 ubiquitin ligase TRIM29 in antitumor T-cell immunity and showed that this role is dependent on the IGF2BP1/PD-L1 signaling axis. • Through a gastric cancer cell-T cell co-culture model, we found that TRIM29 enhanced anti-tumor T cell immunity. Further exploring its molecular mechanism, we confirmed that TRIM29 induces K48-linked ubiquitination degradation of the IGF2BP1 K440 and K450 sites through its C-terminal structural domain binding to the KH3/4 structural domain of IGF2BP1, which further mediates the effect of IGF2BP1 in a 3′UTR- and m6A-dependent manner on the PD-L1 mRNA stability and expression. • In animal models with different immune systems, we also found that specific antagonism of TRIM29 could synergize with PD-1 monoclonal antibody to exert anti-tumor effects, and clinical samples also verified that the expression of TRIM29 in gastric cancer was significantly correlated with the infiltration of CD8+ T-cells and the overall survival of gastric cancer patients. • This study provides new ideas for the immunotherapy of gastric cancer, and TRIM29 may be a potential prognostic predictor and therapeutic target for gastric cancer patients. The expression of TRIM29 can improve the prediction accuracy of PD-L1 histochemical scores, a predictive target for the efficacy of immunotherapy in gastric cancer, and the combination of TRIM29 specific antagonist and PD-1 monoclonal antibody can enhance the efficacy of immunotherapy for gastric cancer by increasing the activity of CD8+ T-cells. The combination of TRIM29-specific antagonist and PD-1 monoclonal antibody can improve the immunotherapeutic effect of gastric cancer by enhancing CD8+ T cell activity. [ABSTRACT FROM AUTHOR]

Increasing evidence indicates that microRNAs (miRNAs) play an important role in various tumors by regulating downstream target genes and diverse signaling pathways. Herein, we confirmed miR-1265 expression in gastric cancer (GC) using the Cancer Genome Atlas (TCGA) database and assessed the level of miR-1265 expression in clinical specimens and cell lines. We found that miR-1265 expression was negatively correlated with tumor size. Further functional analysis revealed that miR-1265 suppresses cellular proliferation and autophagy while inducing apoptosis in GC cells. A luciferase reporter assay was used to identify an miR-1265 targeted gene, calcium binding protein 39 (CAB39), which is an essential upstream regulator in the AMPK-mTOR signaling pathway. Upregulation or downregulation of CAB39 expression reversed the effects of miR-1265 overexpression or inhibition, respectively. Notably, the knockdown of autophagy-related gene 12 (ATG12) impaired the effects of miR-1265 inhibition or CAB39 overexpression in GC. MiR-1265 also suppressed the growth of GC cells in vivo and that of human gastric organoids. Altogether, our results show that miR-1265 suppresses GC progression and oncogenic autophagy by reducing CAB39 expression and regulating the AMPK-mTOR signaling pathway. Therefore, miR-1265 may represent a potential therapeutic target for GC. [ABSTRACT FROM AUTHOR]

Cisplatin (CDDP) resistance is a major clinical problem associated with poor prognosis in gastric cancer (GC) patients. In this study, we performed integrated analysis of TCGA data from microRNAs (miRNAs) expression matrix of GC patients who received CDDP-based chemotherapy with GEO dataset which contains differential miRNAs expression profiles in CDDP-resistant and -sensitive cell lines. We identified miR-148a-3p downregulation as a key step involved in CDDP resistance. Using a cohort consisting 105 GC patients who received CDDP-based therapy, we found that miR-148a-3p downregulation was associated with a decrease in patients' disease-free survival (DFS, P = 0.0077). A series of experiment data demonstrated that: 1) miR-148a-3p was downregulated in CDDP-resistant GC cell lines; 2) miR-148a-3p reconstitution sensitized CDDP-resistant cells to CDDP treatment through promoting mitochondrial fission and decreasing AKAP1 expression level; 3) AKAP1 played a novel role in CDDP resistance by inhibiting P53-mediated DRP1 dephosphorylation; 4) miR-148a-3p reconstitution in CDDP-resistant cells inhibits the cyto-protective autophagy by suppressing RAB12 expression and mTOR1 activation. Taken together, our study demonstrates that miR-148a-3p could be a promising prognostic marker or therapeutic candidate for overcoming CDDP resistance in GC. [ABSTRACT FROM AUTHOR]

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. • MSCs improved the stemness and chemoresistance of GC cells and accounted for poor prognosis of GC. • MSCs and NPRA formed a positive loop in GC. • MSCs promoted the stemness and chemoresistance through NPRA-mediated FAO. • NPRA could protect Mfn2 against protein degradation and promote its mitochondrial localization, thus improving FAO. • NPRA could be a potential target of chemotherapy in GC. [ABSTRACT FROM AUTHOR]