Normal Gastric Mucosa Research Articles

The Correlation Between Mutant p53 Protein Expression and Cell Atypia in Early Differentiated Gastric Adenocarcinoma.

ObjectiveThis study aims to explore the correlation between the expression of mutant p53 protein and cellular atypia in early differentiated gastric adenocarcinoma (DGA).MethodsA total of 107 cases of early DGA samples resected by endoscopic submucosal dissection (ESD) were collected from the Pathology Department of Beijing Friendship Hospital from January 2018 to December 2019. The EnVision two-step immunohistochemical method was used to detect the expression of mutant p53 protein in these cancer tissues, and the correlation with cell atypia was analyzed.ResultsIn early DGA tissues, the expression rate of mutant p53 protein was significantly higher than in normal gastric mucosa (P < 0.01). However, the expression of mutant p53 protein was not correlated to age or gender (P > 0.05) but to the location of the tumor, depth of invasion, and degree of differentiation (P < 0.01). The expression of mutant p53 protein was closely correlated to cell atypia. Furthermore, this was weakly positive in low-grade atypical adenocarcinoma but strongly positive or negative in high-grade atypical adenocarcinoma, and there was a significant difference between these two (P < 0.01).ConclusionMutant p53 protein is highly expressed in early DGA, which can be used as an auxiliary index for the diagnosis of early gastric cancer. The different expression patterns of mutant p53 protein in high-grade and low-grade atypical gastric cancers suggest that these may have different genetic changes.

Histologic Study of the Esophagogastric Junction of Organ Donors Reveals Novel Glandular Structures in Normal Esophageal and Gastric Mucosae.

INTRODUCTION:Whether cardiac mucosa at the esophagogastric junction is normal or metaplastic is controversial. Studies attempting to resolve this issue have been limited by the use of superficial pinch biopsies, abnormal esophagi resected typically because of cancer, or autopsy specimens in which tissue autolysis in the stomach obscures histologic findings.METHODS:We performed histologic and immunohistochemical studies of the freshly fixed esophagus and stomach resected from 7 heart-beating, deceased organ donors with no history of esophageal or gastric disease and with minimal or no histologic evidence of esophagitis and gastritis.RESULTS:All subjects had cardiac mucosa, consisting of a mixture of mucous and oxyntic glands with surface foveolar epithelium, at the esophagogastric junction. All also had unique structures we termed compact mucous glands (CMG), which were histologically and immunohistochemically identical to the mucous glands of cardiac mucosa, under esophageal squamous epithelium and, hitherto undescribed, in uninflamed oxyntic mucosa throughout the gastric fundus.DISCUSSION:These findings support cardiac mucosa as a normal anatomic structure and do not support the hypothesis that cardiac mucosa is always metaplastic. However, they do support our novel hypothesis that in the setting of reflux esophagitis, reflux-induced damage to squamous epithelium exposes underlying CMG (which are likely more resistant to acid-peptic damage than squamous epithelium), and proliferation of these CMG as part of a wound-healing process to repair the acid-peptic damage could result in their expansion to the mucosal surface to be recognized as cardiac mucosa of a columnar-lined esophagus.

A Deep Learning Convolutional Neural Network Can Differentiate Between Helicobacter Pylori Gastritis and Autoimmune Gastritis With Results Comparable to Gastrointestinal Pathologists.

Pathology studies using convolutional neural networks (CNNs) have focused on neoplasms, while studies in inflammatory pathology are rare. We previously demonstrated a CNN that differentiates reactive gastropathy, Helicobacter pylori gastritis (HPG), and normal gastric mucosa. To determine whether a CNN can differentiate the following 2 gastric inflammatory patterns: autoimmune gastritis (AG) and HPG. Gold standard diagnoses were blindly established by 2 gastrointestinal (GI) pathologists. One hundred eighty-seven cases were scanned for analysis by HALO-AI. All levels and tissue fragments per slide were included for analysis. The cases were randomized, 112 (60%; 60 HPG, 52 AG) in the training set and 75 (40%; 40 HPG, 35 AG) in the test set. A HALO-AI correct area distribution (AD) cutoff of 50% or more was required to credit the CNN with the correct diagnosis. The test set was blindly reviewed by pathologists with different levels of GI pathology expertise as follows: 2 GI pathologists, 2 general surgical pathologists, and 2 residents. Each pathologist rendered their preferred diagnosis, HPG or AG. At the HALO-AI AD percentage cutoff of 50% or more, the CNN results were 100% concordant with the gold standard diagnoses. On average, autoimmune gastritis cases had 84.7% HALO-AI autoimmune gastritis AD and HP cases had 87.3% HALO-AI HP AD. The GI pathologists, general anatomic pathologists, and residents were on average, 100%, 86%, and 57% concordant with the gold standard diagnoses, respectively. A CNN can distinguish between cases of HPG and autoimmune gastritis with accuracy equal to GI pathologists.

Expression and prognostic significance of thrombospondin gene family in gastric cancer.

Thrombospondins (THBSs) are glycoproteins expressed in the extracellular matrix (ECM) and have critical roles in tumor development and metastasis. However, the diverse expression patterns and prognostic roles of distinct THBS genes in gastric cancer have not been fully elucidated. In the current study, we aimed to investigate the expression patterns of THBSs in gastric cancer (GC) and determine whether they are prognostic markers for this malignancy. mRNA expression status and genetic mutations of THBS family members were performed by using ONCOMINE, UCSC Xena browser, GEPIA, and cBioPortal databases. Prognostic values and function enrichment analysis of the members were assessed via Kaplan-Meier plotter and Metascape. we found that the mRNA expression of THBS1, THBS2, THBS4, and COMP were higher in patients with GC tissues than those in normal gastric mucosa and there was no difference in the mRNA expression of THBS3 between GC and normal tissue. Survival analysis revealed that mRNA levels of THBSs were strongly related to worse OS in GC patients (P<0.05). Overexpression of THBSs indicated poor OS in stage III/IV GC and high expression of THBS1, THBS3, THBS4, and COMP were related to worse OS in stage II GC. Bioinformatics analysis revealed a better understanding the value of THBS family members in GC and suggest that THBSs might serve as potential prognostic biomarkers for GC.

Autophagic Heterogeneity in Gastric Adenocarcinoma.

Background and AimGastric/gastroesophageal junction (GEJ) adenocarcinoma is a heterogeneous disease, with various etiologies and with tumors encompassing a spectrum of histologic and molecular subtypes. “Autophagy” includes two related but distinct homeostatic processes that promote cell survival under adverse conditions, namely macro- and chaperone-mediated autophagy. There is increasing evidence of the roles autophagy may play in tumorigenesis.MethodsAutophagic pathways were examined in the context of the heterogeneity intrinsic to gastric/GEJ adenocarcinoma, utilizing immunohistochemistry targeting specific proteins within the pathways (p62, LAMP2A, LC3B). We examined whole sections of normal and dysplastic gastric mucosa, as well as a tissue microarray of adenocarcinomas.ResultsDysplastic gastric epithelium was marked by frequent nuclear p62 and aberrant LAMP2A expression compared to normal. Examining the pattern of LC3B/cytoplasmic p62 immuno-reactivity in gastric adenocarcinoma demonstrated a predominant pattern of LC3BHigh/p62High staining (56/86, 65.1%), which has been previously associated with active, but impaired macroautophagy. There were no statistically significant associations seen between LC3B/cytoplasmic p62 staining patterns with tumor grade, histotype, or approximated TCGA molecular subtype. LAMP2A and nuclear p62 and staining patterns were also heterogeneous across the cohort, but with no statistically significant associations seen. The prognostic significance of the three proteins was limited, however high nuclear p62 levels were associated with worse overall survival (log-rank p-value = 0.0396).ConclusionOur data demonstrate the dynamic nature of autophagic proteins in the gastric epithelium, and we expand the biological heterogeneity observed in gastric/GEJ adenocarcinoma to include autophagy.

Identification of hub genes and pathways in the development of gastric cancer by gene co‑expression network analysis.

There are many risk factors for gastric cancer (GC), including chronic atrophic gastritis, which involves multiple genes and signaling pathways. Weighted gene co-expression network analysis (WGCNA) was performed on GSE111762 to construct free-scale gene co-expression networks and identified four significant modules that consisted of blue, dark orange, dark red and dark violet. In each module, genes with the most connectivity were selected as hub genes, including G antigen 12J (GAGE12J) in blue, proline, histidine and glycine rich 1 (PHGR1) in dark orange, DNA polymerase gamma 2, accessory subunit (POLG2) in dark red and collagen type XXI alpha 1 chain (COL21A1) in dark violet. The transcription level of COL21A1 and GAGE12J was up-regulated in atrophic gastritis vs normal gastric mucosa, but down-regulated in GC vs atrophic gastritis. PHGR1 was consistently down-regulated from normal gastric mucosa to GC, while POLG2 was up-regulated. Gene set enrichment analysis (GSEA) was then conducted to study the biological functions of hub genes in the development of GC. It showed that multiple tumorigenesis-related pathways were enriched, including peroxisome, DNA repair and KRAS signaling pathway in COL21A1, IL6-JAK-STAT3, epithelial mesenchymal transition (EMT) and TNFα-NF-κB signaling pathway in PHGR1, MYC targets, E2F targets and angiogenesis in POLG2 and peroxisome, Notch signaling pathway and androgen response in GAGE12J. The identified four genes, especially for COL21A1, PHGR1 and POLG2, were important in GC tumorigenesis and affected many cancer-related pathways.

FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma

Claudin 18.2 (CLDN18.2) is contained within normal gastric mucosa epithelial tight junctions; upon malignant transformation, CLDN18.2 epitopes become exposed. Zolbetuximab, a chimeric monoclonal antibody, mediates specific killing of CLDN18.2-positive cells through immune effector mechanisms. The FAST study enrolled advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients (aged ≥18 years) with moderate-to-strong CLDN18.2 expression in ≥40% tumour cells. Patients received first-line epirubicin+ oxaliplatin+ capecitabine (EOX, arm 1, n= 84) every 3 weeks (Q3W), or zolbetuximab+ EOX (loading dose, 800 mg/m2 then 600 mg/m2 Q3W) (arm 2, n= 77). Arm 3 (exploratory) was added after enrolment initiation (zolbetuximab+ EOX 1000 mg/m2 Q3W, n= 85). The primary endpoint was progression-free survival (PFS) and overall survival (OS) was a secondary endpoint. In the overall population, both PFS [hazard ratio (HR)= 0.44; 95% confidence interval (CI), 0.29-0.67; P < 0.0005] and OS (HR= 0.55; 95% CI, 0.39-0.77; P < 0.0005) were significantly improved with zolbetuximab+ EOX (arm 2) compared with EOX alone (arm 1). This significant PFS benefit was retained in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells (HR= 0.38; 95% CI, 0.23-0.62; P < 0.0005). Significant improvement in PFS was also reported in the overall population of arm 3 versus arm 1 (HR= 0.58; 95% CI, 0.39-0.85; P= 0.0114) but not in high CLDN18.2-expressing patients; no significant improvement in OS was observed in either population. Most adverse events (AEs) related to zolbetuximab+ EOX (nausea, vomiting, neutropenia, anaemia) were grade 1-2. Grade ≥3 AEs showed no substantial increases overall (zolbetuximab+ EOX versus EOX alone). In advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients expressing CLDN18.2, adding zolbetuximab to first-line EOX provided longer PFS and OS versus EOX alone. Zolbetuximab+ EOX was generally tolerated and AEs were manageable. Zolbetuximab 800/600 mg/m2 is being evaluated in phase III studies based on clinical benefit observed in the overall population and in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells.

A case of early autoimmune gastritis with characteristic endoscopic findings

Significant atrophic gastritis in the fundic gland region is a well-known endoscopic finding observed in autoimmune gastritis (AIG). The endoscopic features of early AIG have not been reported. Iron deficiency, vitamin B12 deficiency, anemia, or neurological symptoms may not be observed in the early stages of AIG, and it may thus be difficult to diagnose early AIG based on clinical findings. We treated a 50-year-old Japanese female whose condition was suspected to be early AIG. The endoscopic findings showed normal gastric pyloric gland mucosa, and diffuse reddened and edematous gastric fundic gland mucosa. Pathologically, local infiltration of lymphocytes and decrease of parietal cells was present in a deep part of the gastric fundic gland mucosa. Blood tests showed that the titer of parietal cell antibody (PCA) was 1:320 and the gastrin level was 820 pg/ml. We determined that the patient had AIG because she also had Hashimoto’s disease, the PCA titer was high, the serum gastrin level was slightly increased, and inflammation was observed only in the gastric body on the endoscopic images. To the best of our knowledge, this is the first case report of endoscopic findings that suggest early AIG, before atrophic changes were observed.

Research on the relationship between RAGE and its ligand HMGB1, and prognosis and pathogenesis of gastric cancer with diabetes mellitus.

To investigate the relationship between the expression of receptor for advanced glycation end products (RAGE) and high-mobility group box-1 (HMGB1) and the clinical and pathological parameters and prognosis of the patients with gastric cancer (GC) with diabetes mellitus (DM). 30 normal gastric mucosa, 30 tissues with GC, 90 tissues with GC and DM and their clinical data were collected. The expression levels of RAGE and HMGB1 were detected by immunohistochemistry. Kaplan-Meier survival curve was used to analyze the relationship between the expression levels of RAGE and HMGB1 and the 5-year survival rate. MTT and cell scratch assays were used to detect the effects of knockdown RAGE and HMGB1 on the proliferation and migration of BGC-823 cells. Real-Time PCR was used to detect the regulation of RAGE and HMGB1 on PTBP-1, and Spearman correlation analysis was performed to analyze the correlation between RAGE and HMGB1 and Polyprimidine tract protein (PTBP-1). Compared with the normal gastric mucosa group, the expression levels of RAGE and HMGB1 were significantly higher in the GC group, GC with DM group. The expression of RAGE and HMGB1 was related with lymph node metastasis, TNM staging, and tumor invasion (p<0.05). Age, TNM stage, tumor infiltration depth, the expression of RAGE and HMGB1 were related with prognosis of patients with GC and DM (p<0.05). Tumor infiltration depth, the expression of RAGE and HMGB1 could affect the 5-year survival rate of patients with GC and DM (p<0.05). Knockdown RAGE and HMGB1 increased the expression of PTBP-1, and RAGE and HMGB1 were negatively regulated with PTBP-1. RAGE and HMGB1 are independent risk factors for the prognosis of patients with GC with DM. RAGE and HMGB1 may regulate the expression of PTBP-1 and inhibit the glycolysis of cells, which may affect the cell proliferation and migration of GC.

Chronic gastritis according to age and Helicobacter pylori in Thailand: histopathological patterns

Objectives We aimed to evaluate the histopathological characteristics of chronic gastritis in dyspeptic patients without visible mucosal lesions in different age groups and different biopsy sites. Methods Patients who underwent upper endoscopy for the investigation of dyspepsia as the sole indication were recruited. We selected data from patients without visible mucosal lesions for the study. Gastric biopsy specimens were evaluated by Update Sydney classification according to age, Helicobacter pylori (Hp), and biopsy sites. Results A total of 626 patients were retrospectively studied. 58.2% had histopathological features of chronic gastritis, while 41.8% had normal gastric mucosa. The prevalence of glandular atrophy, intestinal metaplasia, and Hp infection was 36.7, 19.3 and 36.6%. Complete and incomplete metaplasia was found to be 17.0 and 2.2%. The mean score of chronic inflammation, neutrophil activity, glandular atrophy, and intestinal metaplasia was significantly higher in the antrum than in the corpus. The positivity of gastritis increases with age; however, Hp positivity decreased considerably with advanced age. Concerning gastritis’s topography, antral-predominant gastritis and corpus-predominant gastritis increased with age. The prevalence of glandular atrophy and intestinal metaplasia markedly increased with age, especially after age 50. Gastric atrophy and intestinal metaplasia were significantly higher in patients positive for Hp than in negative patients. Conclusion Overall chronic gastritis is common in dyspeptic patients without visible lesions. Prevalence, grading, and severity of chronic gastritis increase with age and Hp infection. Temporal changes of the gastric mucosa are caused by aging rather than by Hp alone.

Helicobacter pylori induces epithelial-mesenchymal transition in gastric carcinogenesis via the AKT/GSK3β signaling pathway.

Helicobacter pylori (H. pylori) is a main risk factor for gastric cancer (GC). Epithelial-mesenchymal transition (EMT) is involved in the development and progression of H. pylori-associated GC. However, the exact molecular mechanism of this process remains unclear. The AKT/GSK3β signaling pathway has been demonstrated to promote EMT in several types of cancer. The present study investigated whether H. pylori infection induced EMT, and promoted the development and metastasis of cancer in the normal gastric mucosa, and whether this process was dependent on AKT activation. The expression levels of the EMT-associated proteins, including E-cadherin and N-cadherin, were determined in 165 gastric mucosal samples of different disease stages by immunohistochemical analysis. The expression levels of E-cadherin, N-cadherin, AKT, phosphorylated (p-)AKT (Ser473), GSK3β and p-GSK3β (Ser9) were further determined in H. pylori-infected Mongolian gerbil gastric tissues and cells co-cultured with H. pylori by immunohistochemical analysis and western blotting. The results indicated that the expression levels of the epithelial marker E-cadherin were decreased, whereas the expression levels of the mesenchymal marker N-cadherin were increased during gastric carcinogenesis. Their expression levels were associated with H. pylori infection. Furthermore, H. pylori infection resulted in downregulation of E-cadherin expression and upregulation of N-cadherin expression in Mongolian gerbils and GES-1 cells. In addition, an investigation of the associated mechanism of action revealed that p-AKT (Ser473) and p-GSK3β (Ser9) were activated in GES-1 cells following co-culture with H. pylori. Furthermore, following pretreatment of the cells with the AKT inhibitor VIII, the expression levels of E-cadherin, N-cadherin, p-AKT and p-GSK3β did not show significant differences between GES-1 cells that were co-cultured with or without H. pylori. The levels of p-AKT and p-GSK3β were increased in H. pylori-infected Mongolian gerbils. In conclusion, the present study demonstrated that H. pylori infection activated AKT and resulted in the phosphorylation and inactivation of GSK3β, which in turn promoted early stage EMT. These effects were AKT-dependent. This mechanism may serve as a prerequisite for GC development.

Relationship Between the Expression of S100P in Gastric Cancer Tissue and Clinical Pathology

Purpose: Discuss the diagnosis value and action mechanism of S100P for gastric cancer and the influence of S100P in tumor metastasis. Method: Collect 100 cases of gastric cancer tissues diagnosed as per histopathology by our hospital, apply immunohistochemistry method, test the positive expression condition of S100P protein, compare with 100 cases of control tissue specimens, and analyze the relationship between S100 protein expression condition in gastric cancer tissue and clinical pathology. Result: the positive rate (51.0%) of S100P in gastric cancer tissue is significantly lower than chronic atrophic gastritis with atypical hyperplasia, superficial gastritis and normal gastric mucosa (P<0.001 or P<0.05), while the difference between gastric cancer group and group of chronic atrophic gastritis with atypical hyperplasia has no statistic significance (P>0.05). The difference of positive rate of S100P in gastric cancer tissue with gender, age, tumor size, tumor position and Lauren typing has no statistic significance. In well differentiated adenocarcinoma, moderately differentiated adenocarcinoma, poorly differentiated adenocarcinoma and adenocarcinoma anaplastic, the positive rate (80.56%) of S100P of the three groups has significant difference (χ²=13.912, P=0.001). The positive rate of S100P which doesn’t invade serosa is significantly higher than the positive rate (34.38%, χ²=19.662, P<0.001) of S100P invading serosa and invading beyond the serosa, and the difference of positive rate of S100P of Phase I, Phase II, Phase III and Phase IV also has statistic difference (χ²=13.347, P=0.004), the positive rate (73.17%) of localized S100P protein is significantly higher than the positive rate (35.59%, χ²=13.669, P<0.001) of invasive type; the positive rate (74.42%) of S100P without lymph node metastasis is significantly higher than the positive rate (33.33%, χ²=15.020, P<0.001) with lymph node metastasis. Conclusion: the positive rate of S100P protein in gastric cancer tissue is significantly lower than the para-carcinoma tissue; the lower the differentiation degree is, the deeper the invasion is; the patients who have later TNM staging and Borrmanntyping, and lymph node metastasis have lower positive rate of S100P protein, which indicates that the low expression of S100P protein participates in the occurrence, development, invasion and metastasis of gastric cancer, and is an independent dangerous factor affecting the patients’ prognosis.

Overexpression of TC2N is associated with poor prognosis in gastric cancer.

Background: Tac2-N (TC2N) is a tandem C2 domain-containing protein, acting as a novel oncogene or suppressor in different kinds of cancers. However, the status of TC2N expression and its significance in gastric cancer (GC) is still unclear. The present study is aimed to elucidate the clinicopathological significance and prognostic value of TC2N level in GC.Methods: We used sequencing data from the Cancer Genome Atlas (TCGA) database to analyze TC2N expression in GC by UALCAN database and Gene Expression Profiling Interactive Analysis tools (GEPIA). TC2N expression level in 12 pairs of fresh GC tissues and adjacent nontumorous tissues was detected by quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) and Western blot (WB) assays. Immunohistochemical (IHC) staining was used to detect TC2N protein expression in Paraffin-embedded tissues in our center. In vitro proliferation, migration and invasion assays were used to evaluate the effect of TC2N on functional capability of gastric cancer cells. LinkedOmics was used to identify gene expressions associated with TC2N.Results: The mRNA and protein expression of TC2N in gastric cancer were both significantly higher than normal gastric mucosa. It was also elevated in gastric cancer cells compared with normal gastric epithelium cell. In vitro assays suggested that TC2N facilitated proliferation, migration and invasion of gastric cancer cells. Bioinformatic analysis showed a widespread impact of TC2N on the transcriptome and a strong interaction with tumor associated genes. We also found that TC2N was an independent prognostic factor for long-term survival in GC patients and its high expression was evidently associated with poor overall survival and recurrence-free survival.Conclusions: Our results show that high level of TC2N correlates with poor prognosis in patients with gastric cancer and promotes the development of gastric cancer. Thus, TC2N expression can serve as a prognostic biomarker for patients with gastric cancer.

Endoskopik Atrofik Gastrit Görünümünün Histopatolojik Karşılığının Değerlendirilmesi: Sistematik İnceleme

Objective: Atrophic gastritis (AG), which is defined as the loss of gastric glands, can be precancerous. The objective of this study is examination of histopathological correlation of our patients with AG, considered according to endoscopic findings and determination of the other concomitant pathological findings. Material and Methods: Biopsy was performed in the atrophic areas and/or different areas on a total of 201 patients during gastroscopic evaluation due to the pre-diagnosis of AG between 2013 and 2014 in our clinic. Their pathological evaluation was performed and the cases of these patients were examined retrospectively. Endoscopic diagnosis of AG was made based on observation of the gastric mucosa as pale compared to the normal gastric mucosa and the separation of this area from the normal gastric mucosa, which can be defined as an endoscopic atrophic border with the prominence of submucosal thin vascular structures. Diagnosis of AG was pathologically defined as loss of glands. Results: The average age of the total 201 patients, who were 133 (67%) women and 68 (33%) men, was 69 years. Endoscopic and histological AG correlation in the whole group was 63 (31%). Considering the gastric localisation of the cases with confirmed diagnosis of AG in histopathological examination; it was determined that 89% affect the proximal, 9% the distal and 2% the distal and proximal together. Intestinal metaplasia (IM) was accompanied in 68% of cases with chronic active gastritis (21%) and neuroendocrine cell hyperplasia (NEHD) (14%). Chronic active gastritis was detected in 32% and IM 17% in cases without histopathological AG. While Helicobacter pylori positivity was 6% in those with histopathologically AG, it was 24% in those without AG (p=0.003). When evaluated in terms of accompanying pathological findings, NEHD, IM and lymphoid follicle hyperplasia were found with a higher rate in patients with histopathologically AG, and found statistically significant. Conclusion: Pathological examination must be performed if AG is suspected in endoscopy. While IM and NECH were more commonly concomitantly observed in patients with AG in pathological examination, the rate of H. Pylori was lower compared to the patients who did not have AG.

Influence of Inducing Factors on the Pathogenicity of Dysplastic Gastric Carcinoma

Gastric cancer is a kind of gastric epithelial dysplasia and adenoma. At present, it is recognized that the formation process of gastric cancer is normal gastric mucosa chronic atrophic gastritis (Ag) - intestinal metaplasia (IM) - dysplasia gastric cancer. In addition to genetic factors, environmental factors such as microorganisms, nutrients and drugs in the stomach can affect the formation of dysplasia by changing the stomach. In this paper, the influence of inducing factors on the pathogenicity of dysplastic gastric cancer was discussed.

Is gastric mapping needed in the endoscopy of dyspeptic patients?

Our study aimed to determine the prevalence of intestinal metaplasia in dyspeptic patients who underwent upper GI endoscopy. Intestinal metaplasia, which is defined as the replacement of normal gastric mucosa by metaplastic intestinal epithelium, has been described as a premalignant gastric lesion. Six hundred two consecutive patients with dyspeptic symptoms who had undergone upper GI endoscopy were included in the study. For all patients, gastric mapping was performed to determine the presence of intestinal metaplasia. All histologic samples were reported according to the updated Sydney classification. Total of 61.3% of the patients were female. The mean age of the patients was 46±15 years. The overall prevalence of intestinal metaplasia was 22%. The distribution of intestinal metaplasia in the stomach was 15.1% in the antrum, 4.3% in the body, and 2.6% in the antrum and body together. Also, the prevalence of intestinal metaplasia in the age group of under 40 years was 9.5% and in patients over 40 years it was 29.5%.. The results of this study have shown that more than one-fifth of the patients with dyspepsia have intestinal metaplasia. This indicates that gastric mapping in patients with dyspepsia may lead to the detection of precancerous lesions especially after the age of 40.

LncRNA UCA1 Enhances Cisplatin Resistance by Regulating CYP1B1-mediated Apoptosis via miR-513a-3p in Human Gastric Cancer.

BackgroundChemoresistance contributes to treatment failure of gastric cancer (GC) patients but the molecular mechanism of chemoresistance in GC is still unclear. Long-chain noncoding RNA (lncRNA) urothelial cancer associated 1 (UCA1) is associated with resistance to chemotherapy drugs.MethodsWe detected the expression of UCA1 in 53 pairs of GC tumor tissue and adjacent normal tissue, human normal gastric mucosa cells (GES-1) and human GC cells (HGC-27, SNU-5, AGS, SGC-7901, and NCI-N87) using RT-qPCR. Small RNA interference technology was used to knock down the expression of UCA1 in gastric cancer cells. CCK8 solution was used to detect cell viability. Flow cytometry was used to detect apoptosis, and Western blotting was used to detect protein expression.ResultsUCA1 was highly expressed in GC tissues and cells, and knockdown of UCA1 increased chemosensitivity to cisplatin by inducing cell apoptosis. Furthermore, UCA1 promoted CYP1B1 expression by binding to miR-513a-3p in human GC cells in vitro, and UCA1/CYP1B1 expression was negatively related to miR-513a-3p expression, while UCA1 expression was positively related to CYP1B1 expression in human GC tissues. Moreover, overexpression of miR-513a-3p or knockdown of CYP1B1 increased chemosensitivity to cisplatin, and knockdown of miR-513a-3p or overexpression of CYP1B1 decreased chemosensitivity to cisplatin by inducing cell apoptosis in human GC cells. Importantly, overexpression of CYP1B1 reduced chemosensitivity to cisplatin which increased by knockdown of UCA1, and knockdown of CYP1B1 increased chemosensitivity to cisplatin which decreased by knockdown of miR-513a-3p in human GC cells.ConclusionThe lncRNA UCA1/miR-513a-3p/CYP1B1 axis regulates cisplatin resistance in human GC cells; hence, it is a potential target for treating chemoresistance in GC.

Expression of the Body-Weight Signaling Players: GDF15, GFRAL and RET and their clinical relevance in Gastric Cancer.

The existence, the functional role and clinical relevance of GDF15 and its signaling through a GFRAL/RET-dependent complex in gastric cancer (GC) and other human tumors remain to be elucidated, despite the widespread recognition of obesity as an important cancer-predisposing factor. Therefore, we aimed to analyze the expression levels of GDF15, GFRAL and RET in GC tissues in relation to each other and clinicopathological features, including patient survival, in order to establish a potential implication of the body-weight signaling pathway in the pathology and clinical outcome of GC. Protein expression was examined by immunohistochemistry on tissue microarrays containing 104 and 30 consecutive GC and normal gastric mucosa samples, whereas gene expression data for The Cancer Genome Atlas cohort of 413 GC patients were obtained from public sources. We found that the protein expression of GDF15, GFRAL and RET was significantly elevated and positively correlated in our set of GC tissues, which was reflected in their tendency to be overexpressed in low-grade and intermediate-grade tumors rather than high-grade ones. No other relationships between the expression status of the examined proteins and clinicopathological characteristics of GC patients were found. Through in silico data analysis, we showed that high GDF15 expression was associated with better overall survival (OS) of GC patients, whereas the opposite was true for high levels of GFRAL or RET. Specifically, GFRAL and RET emerged as independent prognostic factors associated with poor OS. Furthermore, high combined expression of the three markers: GDF15+GFRAL+RET was significantly associated with reduced OS, and it was an independent prognostic factor of borderline significance in terms of OS, when adjusted for covariates. If validated in large-scale studies, the individual and combined expression of GDF15, GFRAL and RET may provide significant clinical implications for the prognosis prediction of GC patients.

Infiltration of Immunoinflammatory Cells and Related Chemokine/Interleukin Expression in Different Gastric Immune Microenvironments.

Gastric mucosal immune microenvironment plays an important role in the occurrence and development of diseases such as inflammation and cancer. In the present study, single-sample gene set enrichment analysis (ssGSEA) was used to evaluate the expression of cytokines and the degree of immune cell infiltration in four different gastric mucosa tissues from normal gastric mucosa, simple gastritis, and atrophic gastritis to gastric cancer. Here, we show the immune microenvironments of these four gastric mucosae were significantly different. From inflammation to gastric cancer, most immunoinflammatory cells showed a downward trend such as central memory CD4 T cell. Instead, several cells showed an upward trend such as macrophage. Additionally, we found some chemokines/interleukins were illustrated to be low expressed (or highly expressed) in precancerous stage and highly expressed (or low expressed) in postcancerous stage, which demonstrated an opposite expression characteristic in pre-/postcancerous stage.

HTRA3 Is a Prognostic Biomarker and Associated With Immune Infiltrates in Gastric Cancer.

HtrA serine peptidase 3 (HTRA3) participates in multiple signal pathways and plays an important regulatory role in various malignancies; however, its role on prognosis and immune infiltrates in gastric cancer (GC) remains unclear. The study investigated HTRA3 expression in tumor tissues and its association with immune infiltrates, and determined its prognostic roles in GC patients. Patients with GC were collected from the cancer genome atlas (TCGA). We compared the expression of HTRA3 in GC and normal gastric mucosa tissues with Wilcoxon rank sum test. And logistic regression was used to evaluate the relationship between HTRA3 and clinicopathological characters. Gene ontology (GO) term analysis, Gene set enrichment analysis (GSEA), and single-sample Gene Set Enrichment Analysis (ssGSEA) was conducted to explain the enrichmental pathways and functions and quantify the extent of immune cells infiltration for HTRA3. Kaplan-Meier analysis and Cox regression were performed to evaluate the correlation between HTRA3 and survival rates. A nomogram, based on Cox multivariate analysis, was used to predict the impact of HTRA3 on prognosis. High HTRA3 expression was significantly correlated with tumor histological type, histological grade, clinical stage, T stage, and TP53 status (P < 0.05). HTRA3-high GC patients had a lower 10-year progression-free interval [PFI; hazard ratio (HR): 1.46; 95% confidence interval (CI): 1.02–2.08; P = 0.038], disease-specific survival (DSS; HR: 1.65; CI: 1.08–2.52; P = 0.021) and overall survival (OS; HR: 1.59; CI: 1.14–2.22; P = 0.006). Multivariate survival analysis showed that HTRA3 was an independent prognostic marker for PFI (HR: 1.456; CI: 1.021–2.078; P = 0.038), DSS (HR: 1.650; CI: 1.079–2.522; P = 0.021) and OS [hazard ratio (HR): 1.590; 95% confidence interval (CI):1.140–2.219; P = 0.006]. The C-indexes and calibration plots of the nomogram based on multivariate analysis indicated an effective predictive performance for GC patients. GSEA showed that High HTRA3 expression may activate NF-κB pathway, YAP1/WWTR1/TAZ pathway, and TGFβ pathway. There was a negative correlation between the HTRA3 expression and the abundances of adaptive immunocytes (T helper cell 17 cells) and a positive correlation with abundances of innate immunocytes (natural killer cells, macrophages etc.). HTRA3 plays a vital role in GC progression and prognosis and could be a moderate biomarker for prediction for survival after gastrectomy.