• Helicobacter pylori
• gastric cancer
• gastric epithelial cells
• infection
• innate immunity
• mucosal immunology

• Immunity, Innate
• Humans
• Helicobacter Infections/immunology
• Helicobacter Infections/complications
• Helicobacter Infections/microbiology
• Helicobacter pylori/immunology
• Helicobacter pylori/pathogenicity
• Stomach Neoplasms/immunology
• Stomach Neoplasms/microbiology
• Carcinogenesis/immunology
• Animals

• 2022YFC3602103 National Key Research and Development Program of China
• 2022-PUMCH-C-063 National High Level Hospital Clinical Research Funding
• 2022-PUMCH-B-024 National High Level Hospital Clinical Research Funding
• ZK108000 National Key Clinical Specialist Construction Project

• Clinical significance
• Disease diagnosis
• LAMB3
• Signaling pathway
• Therapeutic target
• Upregulated gene

• Humans
• Neoplasms/pathology
• Neoplasms/genetics
• Neoplasms/metabolism
• Kalinin
• Animals
• Cell Adhesion Molecules/metabolism
• Cell Adhesion Molecules/genetics
• Signal Transduction
• Clinical Relevance

• Chemotherapy
• Deficient mismatch repair
• Gastric cancer
• Immunotherapy
• Microsatellite instability-high

• Humans
• Microsatellite Instability
• Stomach Neoplasms/genetics
• Stomach Neoplasms/therapy
• Stomach Neoplasms/pathology
• DNA Mismatch Repair/genetics
• Immune Checkpoint Inhibitors/therapeutic use
• Biomarkers, Tumor/genetics
• Prognosis

• Disulfidptosis-related genes
• Glutamine mediated energy metabolism
• NRP1
• Prognosis
• Stomach adenocarcinoma

• 2021MD703842 the China Postdoctoral Science Foundation

• E-cadherin
• gastric cancer
• intestinal type of gastric cancer
• liver kinase B1
• mouse models of cancer
• phosphatase and tensin homolog
• phosphoinositide 3-kinase signaling pathway

• MOST 110-2314-B-110 -003 -MY3 the Ministry of Science and Technology, Taiwan ROC

• EMT gastric cancer progression Snail Twist

• Humans
• Cadherins/metabolism
• Carcinoma
• Nuclear Proteins/metabolism
• Snail Family Transcription Factors/genetics
• Stomach Neoplasms/pathology
• Transcription Factors/genetics

• DNA methylation
• TNS4
• cell migration
• cell proliferation
• gastric cancer

• Humans
• Cell Line, Tumor
• DNA Methylation
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• Helicobacter Infections/genetics
• Helicobacter pylori/metabolism
• Stomach Neoplasms/genetics
• Stomach Neoplasms/pathology
• Tensins/genetics
• Tensins/metabolism

• R155-2014-4184 Lundbeckfonden (Lundbeck Foundation)
• NNF22OC0071681 Novo Nordisk Fonden (Novo Nordisk Foundation)

• GEO database
• Gastric intestinal metaplasia
• biomarker
• cBioPortal database
• gastric cancer

• Helicobacter pylori
• animal model
• cancer
• gastric cancer

Gastric cancer (GC) is a common gastrointestinal tumor. Gastric precancerous lesions (GPL) are the last pathological stage before normal gastric mucosa transforms into GC. However, preventing the transformation from GPL to GC remains a challenge. Traditional Chinese medicine (TCM) has been used to treat gastric disease for millennia. A series of TCM formulas and active compounds have shown therapeutic effects in both GC and GPL. This article reviews recent progress on the herbal drugs and pharmacological mechanisms of TCM in preventing the transformation from GPL to GC, especially focusing on anti-inflammatory, anti-angiogenesis, proliferation, and apoptosis. This review may provide a meaningful reference for the prevention of the transformation from GPL to GC using TCM.

• Gastric cancer
• Gastric precancerous lesions
• Traditional Chinese medicine
• Formulas
• Pharmacological mechanism
• Inflammation-cancer transformation

The tumor microenvironment (TME) in gastric cancer (GC) has been shown to be important for tumor control but the specific characteristics for GC are not fully appreciated. We generated an atlas of 166,533 cells from 10 GC patients with matched paratumor tissues and blood. Our results show tumor-associated stromal cells (TASCs) have upregulated activity of Wnt signaling and angiogenesis, and are negatively correlated with survival. Tumor-associated macrophages and LAMP3⁺ DCs are involved in mediating T cell activity and form intercellular interaction hubs with TASCs. Clonotype and trajectory analysis demonstrates that Tc17 (IL-17⁺CD8⁺ T cells) originate from tissue-resident memory T cells and can subsequently differentiate into exhausted T cells, suggesting an alternative pathway for T cell exhaustion. Our results indicate that IL17⁺ cells may promote tumor progression through IL17, IL22, and IL26 signaling, highlighting the possibility of targeting IL17⁺ cells and associated signaling pathways as a therapeutic strategy to treat GC.

Gastric cancer can vary in tumour stage and immune cell involvement. Here the authors compare gene expression in immune cell types from the blood and the tumour site from GC patients using single cell and TCR sequencing and show that IL17⁺CD8⁺ T cells have a phenotype related to that seen with exhausted cells.

Claudin (CLDN) is a tight junction protein found in human epithelial cells and its altered expression is known to be associated with the progression of gastric cancer. We aimed to investigate the differential expression of CLDN-4 in early gastric cancer (EGC) according to its clinicopathological characteristics. We enrolled 53 patients with EGC who underwent surgical gastric resection from January 2007 to December 2018. The staining intensity of the tumor cells was scored as 0–3, and the percentage of staining was scored as 0–5; high expression was defined if the intensity plus percentage score was 7 or 8, and low expression was defined if the score was 0–6. Among the 53 patients, 16 (30.2%) showed low CLDN-4 expression, while 37 (69.8%) had high CLDN-4 expression. High CLDN-4 expression was significantly associated with intestinal-type EGC (low: 12.5% vs. high: 56.8%, p = 0.003), open-type atrophic change (low: 60.0% vs. high: 90.9%, p = 0.011), and the presence of synchronous tumors (0 vs. 32.4%, p = 0.010), and all 12 EGCs with synchronous tumors showed high CLDN-4 expression. However, expression of CLDN-3, a typical intestinal phenotype CLDN, was neither correlated with CLDN-4 expression nor associated with synchronous tumors. Taken together, high CLDN-4 expression may be considered as an auxiliary tool for screening synchronous tumors in patients with EGC.

• claudin-4
• early gastric cancer
• synchronous neoplasms

• bile acid
• bile reflux
• gastric carcinogenesis
• microbiome

• Animals
• Bile Reflux/complications
• Bile Reflux/pathology
• Carcinogenesis/metabolism
• Gastritis/complications
• Gastritis/pathology
• Gastrointestinal Microbiome
• Humans
• Interleukin-6/metabolism
• Lipopolysaccharides
• Mice
• Stomach Neoplasms/etiology
• Stomach Neoplasms/metabolism
• Taurodeoxycholic Acid/metabolism

• 81772530 National Natural Science Foundation of China
• 81974073 National Natural Science Foundation of China
• 82170833 National Natural Science Foundation of China
• 82122012 National Natural Science Foundation of China
• 21ZR1448800 Natural Science Foundation of Shanghai
• National Natural Science Foundation of China
• Natural Science Foundation of Shanghai

Intestinal metaplasia (IM) is considered a key pivot point in the Correa model of gastric cancer (GC). It is histologically subtyped into the complete and incomplete subtypes, the latter being associated with a greater risk of progression. However, the clinical utility of IM subtyping remains unclear, partially due to the absence of reliable defining biomarkers.

Based on gene expression data and existing literature, we selected CD10 and Das1 as candidate biomarkers to distinguish complete and incomplete IM glands in tissues from patients without GC (IM-GC) and patients with GC (IM + GC). Immunohistochemical staining of individually subtyped IM glands was scored after blinding by two researchers using tissue belonging to both IM-GC and IM + GC patients. Whole tissue Das1 staining was further assessed using digital image quantification (cellSens Dimension, Olympus).

Across both cohorts CD10 stained the IM brush border and was shown to have a high sensitivity (87.5% and 94.9% in IM-GC and IM + GC patients respectively) and specificity (100.0% and 96.7% respectively) with an overall AUROC of 0.944 for complete IM glands. By contrast Das1 stained mainly goblet cells and the apical membrane of epithelial cells, mostly of incomplete IM glands with a low sensitivity (28.6% and 29.3% in IM-GC and IM + GC patients respectively) but high specificity (98.3% and 85.1% respectively) and an overall AUROC of 0.603 for incomplete IM glands. A combined logistic regression model showed a significant increase in AUROC for detecting complete IM glands (0.955 vs 0.970). Whole tissue digital quantification of Das1 staining showed a significant association with incomplete IM compared to complete IM, both in IM-GC and in IM + GC patients (p = 0.016 and p = 0.009 respectively, Mann–Whitney test and unpaired t test used). Additionally, complete IM in IM + GC patients exhibited significantly more Das1 staining than in IM-GC patients (p = 0.019, Mann–Whitney test).

These findings suggest that CD10 is an outstanding biomarker for complete IM and Das1 may be useful as a secondary biomarker for IM glands at greater risk of progression irrespective of IM subtype. Overall, the clinical use of these biomarkers could lead to improved patient stratification and targeted surveillance.

The online version contains supplementary material available at 10.1186/s12876-022-02268-z.

• Biomarkers
• CD10
• Das1
• Digital quantification
• Gastric cancer
• Gene expression profiling
• Immunohistochemistry
• Intestinal metaplasia subtypes
• Logistic regression model
• Risk of progression

• FGFR2
• Lauren classification
• chemotherapy
• claudin 18.2
• diffuse-type
• gastric cancer

• cancer
• gastrointestinal disorders
• pathology
• probiotic
• therapy

Diffuse gastric carcinoma (DGC) is characterized by poorly cohesive cells, highly invasive growth patterns, poor prognosis and resistance to the majority of available systemic therapeutic strategies. It has been previously reported that the Wnt/β-catenin signaling pathway serves a prominent role in the tumorigenesis of gastric carcinoma. However, the mechanism underlying the dysregulation of this pathway in DGC has not been fully elucidated. Therefore, the present study aimed to investigate the expression profiles of Wnt antagonists, secreted frizzled-related protein 1 (SFRP1) and secreted frizzled-related protein 3 (SFRP3), and dishevelled protein family members, dishevelled segment polarity protein 2 (DVL2) and dishevelled segment polarity protein 3 (DVL3), in DGC tissues. The association between the expression levels of these factors and the clinicopathological parameters of the patients was determined. Protein and mRNA expression levels in 62 DGC tumor tissues and 62 normal gastric mucosal tissues obtained from patients with non-malignant disease were measured using immunohistochemical and reverse transcription-quantitative PCR (RT-qPCR) analysis. Significantly lower protein expression levels of SFRP1 (P<0.001) and SFRP3 (P<0.001), but significantly higher protein expression levels of DVL2 (P<0.001) and DVL3 (P<0.001) were observed in DGC tissues compared with in control tissues by immunohistochemistry. In addition, significantly lower expression levels of SFRP1 (P<0.05) and higher expression levels of DVL3 (P<0.05) were found in in DGC tissues compared with those in normal gastric mucosal tissues using RT-qPCR. According to correlation analysis between the SFRP1, SFRP3, DVL2 and DVL3 protein expression levels and the clinicopathological characteristics of patients with DGC, a statistically significant correlation was found between the SFRP3 volume density and T stage (r=0.304; P=0.017) and between the SFRP3 volume density and clinical stage (r=0.336; P=0.008). In conclusion, the findings of the present study suggested that the Wnt signaling pathway components SFRP1, SFRP3, DVL2 and DVL3 may be aberrantly expressed in DGC tissues, implicating their possible role in the development of this malignant disease. The present data also revealed a positive relationship between SFRP3 protein expression and the clinical and T stage of DGC.

• DVL2
• DVL3
• SFRP1
• SFRP3
• Wnt signaling pathway
• diffuse gastric carcinoma

Intestinal type of gastric cancer (IGC) is the largest subtype of gastric cancer (GC) by Lauren classification. The purpose of this present study was to construct a prognostic signature for IGC patients, based on the high-grade dysplasia (HGD) and IGC tissues, to improve and enhance the prognostic accuracy.

The microarray datasets and associated clinical characteristics of HGD and IGC were obtained from the Gene Expression Omnibus (GEO) database. Based on the differential expression analysis between HGD and IGC, the prognostic-related differential expression genes (DEGs) were identified in a training set by univariate COX regression analysis. The least absolute shrinkage and selection operator (LASSO) regression was used to construct an optimal prognostic signature. The enrichment analysis was performed by using Gene Set Enrichment Analysis (GSEA). The performance of the nomogram was assessed by the calibration curve and concordance index (C-index). The results were validated by using a testing set.

We identified 35 prognostic-related DGEs in the training set. The nine-gene signature was established by LASSO analysis. The nine-gene signature was an independent risk factor in both the training and testing sets. The areas under the curve (AUC) values of receiver operating characteristic (ROC) analysis were 0.733 and 0.700 for the training and testing sets, respectively. In GSEA analysis, the gene expression in high-risk group was enriched in hedgehog signaling, epithelial mesenchymal transition, and angiogenesis. The nomogram for IGC showed good performance with C-index of 0.81 (95% CI: 0.76-0.86) and 0.70 (95% CI: 0.63-0.77) in the training and testing sets, respectively.

We identified and verified a nine-gene signature for the prognostic prediction of IGC patients, which might identify subgroups of IGC patients and select more suitable therapeutic options.

• Aurora kinase A
• Biomarker
• Gastric cancer
• Kinesin family member C1

• E2F family
• Helicobacter pylori
• RB-E2F pathway
• gastric cancer
• p53
• pocket protein

• Duodenogastric reflux
• Gastric stump cancer
• Mice, inbred C57BL

• Gastric cancer
• claudin-4
• differentiation
• precancerous lesions of gastric carcinoma
• treatment

• Gastric cancer
• ITGA2
• Metaplasia
• Tumor suppressor
• miR-30a

• Animals
• Apoptosis
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Carcinogenesis/genetics
• Carcinogenesis/metabolism
• Carcinogenesis/pathology
• Cell Movement
• Cell Proliferation
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Integrin alpha2/genetics
• Integrin alpha2/metabolism
• Intestinal Neoplasms/genetics
• Intestinal Neoplasms/metabolism
• Intestinal Neoplasms/pathology
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Nude
• MicroRNAs/genetics
• Prognosis
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays

• RO1 DK071590 NIDDK NIH HHS
• P30 DK058404 NIDDK NIH HHS
• RO1 DK101332 NIDDK NIH HHS
• I01 BX000930 BLRD VA
• IS1 BX003097 BLRD VA
• R01 DK071590 NIDDK NIH HHS
• R01 DK101332 NIDDK NIH HHS

Globally, gastric carcinoma (GC) is one of the most commonly encountered malignancies and is the second highest contributor to cancer mortality. Lapatinib is a potent, orally-bioavailable small-molecule inhibitor of both epidermal growth factor receptor and human epidermal growth factor receptor-2 tyrosine kinases, and is administered to treat GC. However, a large proportion of patients either develop resistance to or do not respond to lapatinib, often because the treatment activates alternative signaling pathways. It is, therefore, vital to identify the key pathways which mediate resistance to lapatinib treatment.

The lapatinib sensitivity-related genes were extracted from the CellMiner database (version 2.2) using “NCI-60 Analysis Tools”. The differentially expressed genes (DEGs) in gastric cancer were derived from The Cancer Genome Atlas (TCGA) database, the protein-protein interaction (PPI) network was derived from the Human Protein Reference Database (HPRD), and the Database for Annotation, Visualization and Integrated Discovery (DAVID) facilitated the functional analysis. The cell function was tested by CCK-8 cell viability assay, colony formation assay, acridine orange/ethidium bromide (AO/EB) staining, and Transwell assay.

The functional linkage networks of lapatinib sensitivity were constructed. Two modules were identified, and pathway analysis indicated that these modules were involved in several pathways, including the neuroactive ligand-receptor interaction network and the Rap1 signaling pathway. Finally, the breast cancer anti-estrogen resistance 1 (BCAR1) gene was selected for further study with lapatinib-resistant SUN216 cells (SUN216/LR). We found the expression of BCAR1 was upregulated in SUN216/LR cells compared to SUN216 cells. The IC50 of lapatinib in SUN216/LR cells was reduced upon BCAR1 knockdown, as measured by a CCK-8 assay. A clonogenic assay showed fewer SUN216/LR colonies with BCAR1 knockdown and lapatinib treatment.

In brief, we efficiently identified those crucial modules highly related to lapatinib sensitivity in GC by using a topological network method. BCAR1 was identified as a potentially critical gene that plays a role in lapatinib sensitivity, and experiments confirmed that BCAR1 might contribute to lapatinib resistance in GC. These results provide further insight into the molecular basis of lapatinib sensitivity and may offer novel strategies for the future treatment of GC.

• Gastric carcinoma (GC)
• apoptosis
• functional linkage network
• sensitivity

The protective property of propolis across a wide spectrum of diseases has long been realized, yet the anti-tumor efficacy of this bioactive substance from Philippine stingless bees has remained poorly understood. Here, we showed the tumor-suppressing potential of crude ethanolic extract of Philippine stingless bee propolis (EEP) in in vitro models of gastric cancer highlighting the first indication of remarkable subtype specificity towards differentiated-type human gastric cancer cell lines but not the diffuse-type. Mechanistically, this involved the profound modulation of several cell cycle related gene transcripts, which correlated with the prominent cell cycle arrest at the G0/G1 phase. To reinforce our data, a unique differentiated-type gastric cancer model, A4gnt KO mice, together with age-matched 60 week-old C57BL/6 J mice were randomly assigned to treatment groups receiving distilled water or EEP for 30 consecutive days. EEP treatment induced significant regression of gross and histological lesions of gastric pyloric tumors that consistently corresponded with specific transcriptional regulation of cell cycle components. Also, the considerable p21 protein expression coupled with a marked reduction in rapidly dividing BrdU-labeled S-phase cells unequivocally supported our observation. Altogether, these findings support the role of Philippine stingless bee propolis as a promising adjunct treatment option in differentiated-type gastric cancer.

• Helicobacter pylori
• cation transport regulator 1
• gastric cancer
• parietal cells
• secretary canaliculi

Treatment of advanced gastric cancer patients with current standard chemotherapeutic agents frequently results in resistance, leading to poor overall survival. However, there has been no success in developing strategies to overcome it. We showed the expression levels of both β-catenin and RAS were significantly increased and correlated in tissues of 756 gastric cancer (GC) patients and tissues of primary- and acquired-resistance patient-derived xenograft tumors treated with 5-fluorouracil and oxaliplatin modulated with leucovorin (FOLFOX). On the basis of our previous studies, where small molecules to suppress colorectal cancer (CRC) via degrading both β-catenin and RAS were developed, we tested the effectiveness of KYA1797K, a representative compound functioning by binding axin, in the growth of GC cells. The efficacy test of the drugs using gastric tumor organoids of Apc^1638N mice showed that the CD44 and ALDH1A3 cancer stem cell markers were induced by FOLFOX, but not by KYA1797K. KYA1797K also efficiently suppressed tumors generated by re-engrafting the FOLFOX-resistant patient-derived xenograft (PDX) tumors, which also showed resistance to paclitaxel. Overall, the small-molecule approach degrading both β-catenin and RAS has potential as a therapeutic strategy for treating GC patients resistant to current standard chemotherapies.

• chemotherapy resistance
• degradation of both β-catenin and RAS
• gastric cancer
• gastric cancer patient-derived xenograft

• HI3C2162 Korea Health Industry Development Institute

• carcinogenesis
• dysplasia/intraepithelial neoplasia
• minute gastric carcinoma
• mutation profiling

• CDX1
• EMT
• EZH2
• H3K27me3
• recurrent miscarriages
• trophoblast

• Adenocarcinoma/genetics
• Apoptosis/genetics
• Cell Line, Tumor
• Cell Proliferation/genetics
• Clustered Regularly Interspaced Short Palindromic Repeats/genetics
• Cyclooxygenase 2/genetics
• Dinoprostone/genetics
• Gene Expression Regulation, Enzymologic/genetics
• Gene Expression Regulation, Neoplastic
• Helicobacter Infections/genetics
• Humans
• Hydroxyprostaglandin Dehydrogenases/genetics
• Methylation
• MicroRNAs/genetics
• Promoter Regions, Genetic/genetics
• Prospective Studies
• Retrospective Studies
• Stomach Neoplasms/genetics
• Transfection/methods

Background: Gastric cancer (GC), one of the most common cancers worldwide, is highly malignant and fatal. Ras-related protein in brain 31 (RAB31), a member of the RAB family of oncogenes, participates in the process of carcinogenesis and cancer development; however, its role in GC progression is unknown.

Methods: In our study, 90 pairs of tissue microarrays were used to measure the levels of RAB31 protein by immunochemistry, and 22 pairs of fresh tissue were used to measure the levels of RAB31 mRNA by quantitative PCR. We also investigated the effects of RAB31 on tumor growth both in vitro and in vivo.

Results: RAB31 was overexpressed in GC tissues, and its overexpression predicted poor survival in patients. In a nude mouse model, depletion of RAB31 inhibited tumor growth. In vitro, silencing of RAB31 suppressed cell viability, promoted cell cycle arrest, enhanced apoptosis, and affected the expression of cell cycle and apoptotic proteins; these effects were mediated by glioma-associated oncogene homolog 1 (GLI1). Co-immunoprecipitation and immunofluorescence assays confirmed that RAB31 interacted with GLI1. In addition, luciferase reporter assays and Western blotting showed that microRNA-30c-2-3p modulated the RAB31/GLI1 pathway by targeting the 3′-untranslated region of RAB31.

Conclusions: Collectively, these data show that RAB31 is regulated by microRNA-30c-2-3p, and functions as an oncogene in GC tumorigenesis and development by interacting with GLI1. Therefore, targeting the miR-30c-2-3p/RAB31/GLI1 axis may be a therapeutic intervention for gastric cancer.

• GLI1
• RAB31
• gastric cancer
• miR-30c-2-3p
• prognosis
• proliferation

Intestinal metaplasia induced by ectopic expression of caudal‐type homeobox (CDX)2 and/or CDX1 (CDX) is frequently observed around gastric cancer (GC). Abnormal expression of CDX is also observed in GC and suggests that inappropriate gastrointestinal differentiation plays essential roles in gastric tumorigenesis, but their roles on tumorigenesis remain unelucidated. Publicly available databases show that GC patients with higher CDX expression have significantly better clinical outcomes. We introduced CDX2 and CDX1 genes separately into GC‐originated MKN7 and TMK1 cells deficient in CDX. Marked suppression of cell growth and dramatic morphological change into spindle‐shaped flat form were observed along with induction of intestinal marker genes. G0‐G1 growth arrest was accompanied by changed expression of cell cycle‐related genes but not with apoptosis or senescence. Microarray analyses additionally showed decreased expression of gastric marker genes and increased expression of stemness‐associated genes. Hierarchical clustering of 111 GC tissues and 21 non‐cancerous gastric tissues by selected 18 signature genes based on our transcriptome analyses clearly categorized the 132 tissues into non‐cancer, “CDX signature”‐positive GC, and “CDX signature”‐negative GC. Gene set enrichment analysis indicated that “CDX signature”‐positive GC has lower malignant features. Immunohistochemistry of 89 GC specimens showed that 50.6% were CDX2‐deficient, 66.3% were CDX1‐deficient, and 44.9% were concomitant CDX2/CDX1‐deficient, suggesting that potentially targetable GC cases by induced intestinal differentiation are quite common. In conclusion, exogenous expression of CDX2/CDX1 can lead to efficient growth inhibition of CDX‐deficient GC cells. It is based on rapidly induced intestinal differentiation, which may be a future therapeutic strategy.

• CDX
• gastric cancer
• hierarchical clustering
• intestinal differentiation
• transcriptome

Helicobacter pylori (H. pylori) infection is a well-established risk factor for the development of gastric cancer (GC), one of the most common and deadliest neoplasms worldwide. H. pylori infection induces chronic inflammation in the gastric mucosa that, in the absence of treatment, may progress through a series of steps to GC. GC is only one of several clinical outcomes associated with this bacterial infection, which may be at least partially attributed to the high genetic variability of H. pylori. The biological mechanisms underlying how and under what circumstances H. pylori alters normal physiological processes remain enigmatic. A key aspect of carcinogenesis is the acquisition of traits that equip preneoplastic cells with the ability to invade. Accumulating evidence implicates H. pylori in the manipulation of cellular and molecular programs that are crucial for conferring cells with invasive capabilities. We present here an overview of the main findings about the involvement of H. pylori in the acquisition of cell invasive behavior, specifically focusing on the epithelial-to-mesenchymal transition, changes in cell polarity, and deregulation of molecules that control extracellular matrix remodeling.

• Helicobacter pylori
• Plasminogen activation system
• Invasion
• Epithelial-to-mesenchymal transition
• Cell polarity
• Gastric carcinogenesis

Achaete-scute homolog 2 (ASCL2), a basic helix-loop-helix transcription factor, serves an essential role in the maintenance of adult intestinal stem cells and the growth of gastric cancer (GC). However, the function of ASCL2 in the metastasis of GC is poorly understood. The present study aimed to evaluate the effect of ASCL2 expression on gastric tumor metastasis. ASCL2 protein expression was detected in 32 cases of gastric metastasis and its relevant primary tumors using western blotting and immunohistochemistry. The data suggested that the expression of ASCL2 was highest in metastatic tumors, among adjacent normal tissues, primary gastric tumors and gastric metastatic tumors. Furthermore, ASCL2-overexpressing GC cell lines MKN1-ASCL2 and SNU16-ASCL2 were established. An in vitro assay suggested that microRNA 223 (miR223) expression was downregulated following ASCL2 overexpression, and that the expression of the epithelium-associated protein E-cadherin was significantly decreased, while a series of mesenchyme-associated proteins, including zinc finger E-box-binding homeobox 1 (Zeb-1), twist-related protein 1, integrin, vimentin, 72 kDa type IV collagenase and matrix metalloproteinase-9 were upregulated in ASCL2-overexpressing cells. Overexpression of miR223 attenuated the epithelial-mesenchymal transition (EMT)-promoting effect induced by ASCL2 expression. In addition, the results of the chromatin immunoprecipitation and luciferase reporter gene assays indicated that ASCL2 was able to interact with the promoter of pre-miR223, and to inhibit the maturation of miR223, which may interact with the 3′ untranslated region of Zeb-1 and inhibit EMT in tumor cells. The results of the present study demonstrated that ASCL2 was able to downregulate the expression level of miR223, contribute to EMT and promote gastric tumor metastasis, which indicated that ASCL2 may serve as a therapeutic target in the treatment of GC.

• biomarker
• diagnosis
• gastric cancer
• microRNA
• prognosis

The cellular components and function of the gastrointestinal epithelium exhibit distinct characteristics depending on the region, e.g., stomach or intestine. How these region-specific epithelial characteristics are generated during development remains poorly understood. Here, we report on the involvement of the helix-loop-helix inhibitor Id2 in establishing the specific characteristics of the intestinal epithelium. Id2^−/− mice developed tumors in the small intestine. Histological analysis indicated that the intestinal tumors were derived from gastric metaplasia formed in the small intestine during development. Heterotopic Id2 expression in developing gastric epithelium induced a fate change to intestinal epithelium. Gene expression analysis revealed that foregut-enriched genes encoding Irx3 and Irx5 were highly induced in the midgut of Id2^−/− embryos, and transgenic mice expressing Irx5 in the midgut endoderm developed tumors recapitulating the characteristics of Id2^−/− mice. Altogether, our results demonstrate that Id2 plays a crucial role in the development of regional specificity in the gastrointestinal epithelium.

• Id2
• Irx transcription factor
• cancer
• cell differentiation
• cell fate specification
• endoderm
• gastric mucosa
• intestinal development
• intestinal epithelium
• tumorigenesis

Non-ampullary duodenal adenoma with activation of Wnt/β-catenin signalling is common in familial adenomatous polyposis (FAP) patients, whereas sporadic non-ampullary adenoma is uncommon. The adenoma-carcinoma sequence similar to colon cancer is associated with duodenal tumors in FAP, but not always in sporadic tumors. We obtained 37 non-ampullary duodenal tumors, including 25 adenomas and 12 adenocarcinomas, were obtained from biopsies and endoscopic resections. We performed immunohistochemistry for β-catenin, the hallmark of Wnt activation, and aldehyde dehydrogenase 1 (ALDH1), a putative cancer stem cell marker. In non-ampullary lesions, abnormal nuclear localization of β-catenin was observed in 21 (84.0%) of 25 adenomas and 4 (33.3%) of 12 adenocarcinomas. In the proximal duodenum, nuclear β-catenin was less frequent in both adenomas and adenocarcinomas. Gastric duodenal metaplasia (GDM) was observed only in the proximal duodenum. All adenomas with GDM were the gastric foveolar and pyloric gland types, and showed only membranous β-catenin. The intestinal-type adenomas had nuclear β-catenin in the proximal and distal duodenum. ALDH1-positive cells were more frequent in adenocarcinomas than adenomas. Nuclear β-catenin accumulation frequently occurred in ALDH1-positive cells in adenoma, but not in adenocarcinoma. In the non-ampullary proximal duodenum, Wnt/β-catenin pathway activation was more closely associated with adenomas than adenocarcinomas, and while it might cooperate with ALDH1 in adenoma, it does not in adenocarcinoma. The pathogenesis thus may differ between sporadic adenoma and adenocarcinoma of non-ampullary duodenal lesions, especially in the proximal and distal duodenum.

• beta-catenin
• duodenal neoplasms

Ever since its initial discovery in Drosophila, hedgehog signaling has been linked to foregut development, The mammalian genome expresses three Hedgehog paralogues, sonic hedgehog (Shh), Indian Hedgehog, and desert hedgehog. In the mucosa of the embryonic and adult foregut, Shh expression is the highest. It has now become clear that hedgehog signaling is of pivotal importance in gastric homeostasis. Aberrant activation of hedgehog signaling is associated with a range of pathological consequences including various cancers. Also in gastric cancer, clinical and preclinical data support a role of Hedgehog signaling in neoplastic transformation, and gastrointestinal cancer development, also through cancer stroma interaction. Technological advance are facilitating monitoring Hedgehog signaling broadening options for the more efficient screening of individuals predisposed to eventually developing gastric cancer and targeting Hedgehog signaling may provide opportunities for prophylactic therapy once atrophic gastritis develops. Nevertheless, convincing evidence that Hedgehog antagonists are of clinically useful in the context of gastric cancer is still conspicuously lacking. Here we analyze review the role of Hedgehog in gastric physiology and the potential usefulness of targeting Hedgehog signaling in gastric cancer.

• patched
• precision medicine
• receptors
• smoothened receptor
• zinc finger protein GLI1