Transduced caudal-type homeobox (CDX) 2/CDX1 can induce growth inhibition on CDX-deficient gastric cancer by rapid intestinal differentiation.

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.

Atrophic gastritis and enlarged gastric folds diagnosed by double-contrast upper gastrointestinal barium X-ray radiography are useful to predict future gastric cancer development based on the 3-year prospective observation.

BACKGROUND: Double-contrast upper gastrointestinal barium X-ray radiography (UGI-XR) is the standard gastric cancer screening method in Japan. Atrophic gastritis and enlarged gastric folds are considered the two major features of Helicobacter pylori-induced chronic gastritis, but the clinical meaning of evaluating them by UGI-XR has not been elucidated. METHODS: We analyzed healthy UGI-XR examinees without a history of gastrectomy, previous Helicobacter pylori eradication and usage of gastric acid suppressants. RESULTS AND CONCLUSIONS: Of the 6433 subjects, 1936 (30.1 %) had atrophic gastritis and 1253 (19.5 %) had enlarged gastric folds. During the 3-year prospective observational follow-up, gastric cancer developed in seven subjects, six of whom (85.7 %) had atrophic gastritis with H. pylori infection and five of whom (71.4 %) had enlarged gastric folds with H. pylori infection. The Kaplan-Meier method with log-rank testing revealed that both UGI-XR-based atrophic gastritis (p = 0.0011) and enlarged gastric folds (p = 0.0003) are significant predictors for future gastric cancer incidence.

Comparative analysis of upper gastrointestinal endoscopy, double-contrast upper gastrointestinal barium X-ray radiography, and the titer of serum anti-Helicobacter pylori IgG focusing on the diagnosis of atrophic gastritis.

BACKGROUND: Upper gastrointestinal endoscopy (UGI-ES) and double-contrast upper gastrointestinal barium X-ray radiography (UGI-XR) are two major image-based methods to diagnose atrophic gastritis, which is mostly induced by Helicobacter pylori infection. However, there have been few studies directly comparing them. METHODS: Atrophic gastritis was evaluated using the data of 962 healthy subjects who underwent UGI-ES and UGI-XR within 1 year. RESULTS AND CONCLUSION: Based on UGI-ES and UGI-XR, 602 subjects did not have atrophic gastritis and 254 subjects did have it. Considering UGI-ES-based atrophic gastritis as the standard, sensitivity and specificity of UGI-XR-based atrophic gastritis were 92.0 % (254/276) and 92.8 % (602/649), respectively. The seven-grade Kimura-Takemoto classification of UGI-ES-based atrophic gastritis showed a strong and significant association with the four-grade UGI-XR-based atrophic gastritis. Sensitivity and specificity of serum anti-Helicobacter pylori IgG to detect UGI-ES/UGI-XR-based atrophic gastritis were 89.4 % (227/254) and 99.8 % (601/602), indicating that atrophic gastritis can be overlooked according to serum anti-Helicobacter pylori IgG alone.

Trend and risk factors of diverticulosis in Japan: age, gender, and lifestyle/metabolic-related factors may cooperatively affect on the colorectal diverticula formation.

BACKGROUND: Despite the marked increase of diverticulosis, its risk factors have not been adequately elucidated. We therefore aim to identify significantly associated factors with diverticulosis. We also aim to investigate the present state of diverticulosis in Japan. METHODS: We reviewed the medical records from 1990 to 2010 that included the data of consecutive 62,503 asymptomatic colonoscopy examinees from the general population in Japan. Most recent 3,327 examinees were analyzed with 16 background factors. RESULTS: Among the 62,503 subjects (47,325 men and 15,178 women; 52.1 ± 9.2 years old), diverticulosis was detected in 11,771 subjects (18.8%; 10,023 men and 1,748 women). The incidences of diverticulosis in 1990-2000 and 2001-2010 were respectively 13.0% (3,771 of 29,071) and 23.9% (8,000 of 33,432): the latter was much higher than the former in all age groups and for both genders. Considering the anatomical locations of colorectal diverticula, left-sided ones have markedly increased with age but not significantly changed with times. Univariate analyses of the 3,327 subjects showed significant association of diverticulosis with four basic factors (age, sex, body mass index, blood pressure), three life style-related factor (smoking, drinking, severe weight increase in adulthood), and two blood test values (triglyceride, HbA1c). The multiple logistic analysis calculating standardized coefficients (ß) and odds ratio (OR) demonstrated that age (ß = 0.217-0.674, OR = 1.24-1.96), male gender (ß = 0.185, OR = 1.20), smoking (ß = 0.142-0.200, OR = 1.15-1.22), severe weight increase in adulthood (ß = 0.153, OR = 1.17), HbA1c (ß = 0.136, OR = 1.15), drinking (ß = 0.109, OR = 1.11), and serum triglyceride (ß = 0.098, OR = 1.10) showed significantly positive association with diverticulosis whereas body mass index and blood pressure did not. CONCLUSIONS: The large-scale data of asymptomatic colonoscopy examinees from the general population from 1990 to 2010 indicated that the prevalence of diverticulosis is still increasing in Japan. Age, male gender, smoking, severe weight increase in adulthood, serum HbA1c, drinking, and serum triglyceride showed significant positive association with diverticulosis.

Polyglycolic acid sheets and fibrin glue decrease the risk of bleeding after endoscopic submucosal dissection of gastric neoplasms (with video).

BACKGROUND: The prevention of bleeding after endoscopic submucosal dissection (ESD) for gastric neoplasms is still an important problem. OBJECTIVE: To investigate the efficacy and safety of a shielding method that uses polyglycolic acid (PGA) sheets and fibrin glue to prevent post-ESD bleeding in high-risk patients. DESIGN: A nonrandomized trial with historical control subjects. SETTING: A single academic hospital in Japan. PATIENTS: From July 2013 to February 2014, 45 ESD-induced ulcers in 41 patients with a high risk of bleeding were enrolled in a study group. Forty-one consecutive ESD-induced ulcers in 37 control subjects with a high risk of bleeding were treated in 2013 before the first enrollment. INTERVENTIONS: We placed PGA sheets on the mucosal defect and fixed with fibrin glue in the study group. MAIN OUTCOME MEASUREMENTS: The post-ESD bleeding rate. RESULTS: The post-ESD bleeding occurred at a rate of 6.7% in the study group (3/45 lesions) and 22.0% in the historical control group (9/41 lesions). There was a significant difference in the post-ESD bleeding rate between the 2 groups (P = .041). LIMITATIONS: A nonrandomized trial with historical control subjects; a single-center analysis; small sample size. CONCLUSIONS: The endoscopic tissue shielding method with PGA sheets and fibrin glue appears to be promising for the prevention of post-ESD bleeding. ( CLINICAL TRIAL REGISTRATION NUMBER: UMIN000011058.).

Polyglycolic acid sheets with fibrin glue can prevent esophageal stricture after endoscopic submucosal dissection.

BACKGROUND AND STUDY AIMS: Suitable techniques for the prevention of stricture formation after esophageal endoscopic submucosal dissection (ESD) are still lacking. We investigated the efficacy of polyglycolic acid (PGA) sheets with fibrin glue to prevent post-ESD stricture. PATIENTS AND METHODS: We conducted a pilot study on a total of eight consecutive patients who underwent esophageal ESD that left a mucosal defect of more than three-quarters of the esophageal circumference. PGA sheets were attached to the defect with fibrin glue immediately after the completion of ESD. The primary endpoint was the incidence of post-ESD stricture. The secondary endpoints were the number of sessions of endoscopic balloon dilation (EBD) required to resolve any stricture and the rate of complications. RESULTS: There were no adverse events related to the use of PGA sheets and fibrin glue. Post-ESD stricture occurred in 37.5 % of the subjects and 0.8 ± 1.2 sessions of EBD were required. CONCLUSION: The use of PGA sheets and fibrin glue after esophageal ESD is a novel method that radically decreases the incidence of esophageal stricture and the number of EBD sessions subsequently required. University Hospital Medical Network Clinical Trial Registry (UMIN000011058).

Associated factors of atrophic gastritis diagnosed by double-contrast upper gastrointestinal barium X-ray radiography: a cross-sectional study analyzing 6,901 healthy subjects in Japan.

BACKGROUND: Double-contrast upper gastrointestinal barium X-ray radiography (UGI-XR) is one of the most widely conducted gastric cancer screening methods. It has been executed to find gastric cancer, but has not been usually executed to detect premalignant atrophic mucosa of stomach. To understand the meaning of UGI-XR-based atrophic gastritis, we analyzed its association with several causative factors including Helicobacter pylori (HP) infection. METHODS: We evaluated 6,901 healthy adults in Japan. UGI-XR-based atrophic gastritis was diagnosed based on the irregular shape of areae gastricae and its expansion in the stomach. RESULTS: Of the 6,433 subjects with no history of HP eradication and free from gastric acid suppressants, 1,936 were diagnosed as UGI-XR-based atrophic gastritis (mild: 234, moderate: 822, severe: 880). These were univariately associated with serum HP IgG and serum pepsinogen I/II ratio with statistical significance. The multiple logistic analysis calculating standardized coefficients (ß) and odds ratio (OR) demonstrated that serum HP IgG (ß = 1.499, OR = 4.48), current smoking (ß = 0.526, OR = 1.69), age (ß = 0.401, OR = 1.49), low serum pepsinogen I/II ratio (ß = 0.339, OR = 1.40), and male gender (ß = 0.306, OR = 1.36) showed significant positive association with UGI-XR-based atrophic gastritis whereas drinking and body mass index did not. Among the age/sex/smoking/drinking-matched 227 pairs derived from chronically HP-infected and successfully HP-eradicated subjects, UGI-XR-based atrophic gastritis was detected in 99.1% of the former but in only 59.5% of the latter subjects (p<0.0001). Contrastively, UGI-XR-based atrophic gastritis was detected in 13 of 14 HP-positive proton pump inhibitor users (92.9%) and 33 of 34 HP-positive histamine H2-receptor antagonist users (97.1%), which are not significantly different from gastric acid suppressant-free subjects. CONCLUSIONS: The presence of UGI-XR-based atrophic gastritis is positively associated with Helicobacter pylori infection, current smoking, age, decreased serum pepsinogen I/II ratio, and male gender. Eradication of Helicobacter pylori seems to superficially improve UGI-XR-based atrophic gastritis whereas intake of gastric acid suppressants does not.

The Gateway Reflex, which is mediated by the inflammation amplifier, directs pathogenic immune cells into the CNS.

The brain-blood barrier (BBB) tightly limits immune cell migration into the central nervous system (CNS), avoiding unwanted inflammation under the normal state. However, immune cells can traverse the BBB when inflammation occurs within the CNS, suggesting a certain signal that creates a gateway that bypasses the BBB might exist. We revealed the inflammation amplifier as a mechanism of this signal, and identified dorsal vessels of the fifth lumber (L5) spinal cord as the gateway. The inflammation amplifier is driven by a simultaneous activation of NF-κB and STATs in non-immune cells, causing the production of a large amount of inflammatory chemokines to open the gateway at L5 vessels. It was found that the activation of the amplifier can be modulated by neural activation and artificially operated by electric pulses followed by establishment of new gateways, Gateway Reflex, at least in mice. Furthermore, genes required for the inflammation amplifier have been identified and are highly associated with various inflammatory diseases and disorders in the CNS. Thus, physical and/or pharmacological manipulation of the inflammation amplifier holds therapeutic value to control neuro-inflammation.

Gli regulates MUC5AC transcription in human gastrointestinal cells.

MUC5AC is a well-known gastric differentiation marker, which has been frequently used for the classification of stomach cancer. Immunohistochemistry revealed that expression of MUC5AC decreases accompanied with increased malignant property of gastric mucosa, which further suggests the importance of MUC5AC gene regulation. Alignment of the 5'-flanking regions of MUC5AC gene of 13 mammal species denoted high homology within 200 bp upstream of the coding region. Luciferase activities of the deletion constructs containing upstream 451 bp or shorter fragments demonstrated that 15 bp region between -111 and -125 bp plays a critical role on MUC5AC promoter activity in gastrointestinal cells. We found a putative Gli-binding site in this 15 bp sequence, and named this region a highly conserved region containing a Gli-binding site (HCR-Gli). Overexpression of Gli homologs (Gli1, Gli2, and Gli3) clearly enhanced MUC5AC promoter activity. Exogenous modulation of Gli1 and Gli2 also affected the endogenous MUC5AC gene expression in gastrointestinal cells. Chromatin immunoprecipitation assays demonstrated that Gli1 directly binds to HCR-Gli: Gli regulates MUC5AC transcription via direct protein-DNA interaction. Conversely, in the 30 human cancer cell lines and various normal tissues, expression patterns of MUC5AC and Gli did not coincide wholly: MUC5AC showed cell line-specific or tissue-specific expression whereas Gli mostly revealed ubiquitous expression. Luciferase promoter assays suggested that the far distal MUC5AC promoter region containing upstream 4010 bp seems to have several enhancer elements for gene transcription. In addition, treatments with DNA demethylation reagent and/or histone deacetylase inhibitor induced MUC5AC expression in several cell lines that were deficient in MUC5AC expression. These results indicated that Gli is necessary but not sufficient for MUC5AC expression: namely, the multiple regulatory mechanisms should work in the distal promoter region of MUC5AC gene.

Evaluation of preferable insertion routes for esophagogastroduodenoscopy using ultrathin endoscopes.

AIM: To evaluate the discomfort associated with esophagogastroduodenoscopy (EGD) using an ultrathin endoscope through different insertion routes. METHODS: This study (January 2012-March 2013) included 1971 consecutive patients [male/female (M/F), 1158/813, 57.5 ± 11.9 years] who visited a single institute for annual health checkups. Transnasal EGD was performed in 1394 patients and transoral EGD in 577. EGD-associated discomfort was assessed using a visual analog scale score (VAS score: 0-10). RESULTS: Multivariate analysis revealed gender (M vs F: 4.02 ± 2.15 vs 5.06 ± 2.43) as the only independent predictor of the VAS score in 180 patients who underwent EGD for the first time; whereas it revealed gender (M vs F 3.60 ± 2.20 vs 4.84 ± 2.37), operator, age group (A: < 39 years; B: 40-49 years; C: 50-59 years; D: 60-69 years; E: > 70 years; A/B/C/D/E: 4.99 ± 2.32/4.34 ± 2.49/4.19 ± 2.31/3.99 ± 2.27/3.63 ± 2.31), and type of insertion as independent predictors in the remaining patients. Subanalysis for gender, age group, and insertion route revealed that the VAS score decreased with age regardless of gender and insertion route, was high in female patients regardless of age and insertion route, and was low in males aged over 60 years who underwent transoral insertion. CONCLUSION: Although comprehensive analysis revealed that the insertion route may not be an independent predictor of the VAS score, transoral insertion may reduce EGD-associated discomfort in elderly patients.

Categorization of upper gastrointestinal symptoms is useful in predicting background factors and studying effects and usages of digestive drugs.

BACKGROUND: There have been very few reports assessing the relationship between various upper gastrointestinal (GI) symptoms or evaluating each individual upper GI symptom separately. METHODS: Based on the answers to Frequency Scale for the Symptoms of GERD from a large-scale population of healthy adults in Japan, a hierarchical cluster analysis was performed to categorize the typical 12 upper GI symptoms. The associations between the 12 symptoms and 13 background factors were systematically analyzed among the 18,097 digestive drug-free subjects, 364 proton-pump inhibitor (PPI) users, and 528 histamine H2-receptor antagonist (H2RA) users. RESULTS: The derived relationship between the 12 upper GI symptoms suggests the five symptom categories: heartburn (2), dyspepsia (4), acid regurgitation (3), pharyngo-upper esophageal discomfort (2), and fullness while eating (1). Among the digestive drug-free subjects, inadequate sleep, weight gain in adulthood, NSAID use, meals immediately prior to sleep, and frequent skipping of breakfast showed significant positive association with most upper GI symptoms. Compared to the digestive drug-free subjects, significantly associated factors for PPI and H2RA users are respectively different in "4 of 5" and "5 of 5" symptoms in heartburn and acid regurgitation categories, "1 of 2" and "1 of 2" symptoms in pharyngo-upper esophageal discomfort category, and "0 of 5" and "3 of 5" symptoms in dyspepsia and fullness while eating categories. These differences between digestive drug-free subjects and gastric acid suppressant users seem to correlate with our experiences in clinical situations: heartburn and acid regurgitation category symptoms are effectively controlled with PPI and H2RA whereas other category symptoms are not. CONCLUSIONS: The 12 upper GI symptoms can be classified into five categories, which are statistically associated with various background factors. The differences of associated factors between digestive drug-free subjects and digestive drug users may be useful in studying the drug effects upon diverse upper GI symptoms.

Evaluation of a new image-enhanced endoscopic technology using band-limited light for detection of esophageal squamous cell carcinoma.

BACKGROUND: The aim of the present study was to evaluate the clinical utility of a new image-enhanced endoscopy (IEE) technology called optical enhancement imaging (OEI-1, -2, -3) by quantitatively evaluating diagnostic performance in superficial esophageal squamous cell carcinoma (SCC) in order to facilitate detection and characterization of gastrointestinal tumors. PATIENTS AND METHODS: The study involved 10 esophageal SCC resected endoscopically at our hospital. Ex vivo observation of the boundary area between normal and SCC was done using each mode (white light image [WLI], OEI-1, OEI-2, and OEI-3) with and without magnification. The additional effect of OEI on WLI was evaluated by calculating the color difference (expressed as ΔE94 ) between SCC and normal epithelium, and that between the intraepithelial papillary capillary loop (IPCL) and inter-vascular background coloration (IVBC). RESULTS: Mean ΔE94 values between SCC and normal epithelium for WLI, OEI-1, OEI-2, and OEI-3 were 9.37 ± 4.64, 13.82 ± 4.46,13.26 ± 4.73, and 16.44 ± 4.83, respectively; the corresponding values between IPCL and IVBC were 17.57 ± 10.17, 29.32 ± 9.95, 25.41 ± 11.72, and 23.71 ± 11.58, respectively. Compared with WLI, all OEI exhibited significant additional effect on ΔE94 . Furthermore, we found significant additional effect of OEI-3 in observing SCC and normal epithelium, and of OEI-1 in observing IPCL and IVBC, compared with other OEI. CONCLUSION: These results suggest that OEI improves endoscopic detection and characterization of esophageal SCC compared with WLI. Moreover, the data indicate that OEI-3 is useful for detection and OEI-1 is useful for characterization of esophageal SCC.

Background factors of reflux esophagitis and non-erosive reflux disease: a cross-sectional study of 10,837 subjects in Japan.

BACKGROUND: Despite the high prevalence of gastroesophageal reflux disease (GERD), its risk factors are still a subject of controversy. This is probably due to inadequate distinction between reflux esophagitis (RE) and non-erosive reflux disease (NERD), and is also due to inadequate evaluation of adjacent stomach. Our aim is therefore to define background factors of RE and NERD independently, based on the evaluation of Helicobacter pylori infection and gastric atrophy. METHODS: We analyzed 10,837 healthy Japanese subjects (6,332 men and 4,505 women, aged 20-87 years) who underwent upper gastrointestinal endoscopy. RE was diagnosed as the presence of mucosal break, and NERD was diagnosed as the presence of heartburn and/or acid regurgitation in RE-free subjects. Using GERD-free subjects as control, background factors for RE and NERD were separately analyzed using logistic regression to evaluate standardized coefficients (SC), odds ratio (OR), and p-value. RESULTS: Of the 10,837 study subjects, we diagnosed 733 (6.8%) as RE and 1,722 (15.9%) as NERD. For RE, male gender (SC = 0.557, OR = 1.75), HP non-infection (SC = 0.552, OR = 1.74), higher pepsinogen I/II ratio (SC = 0.496, OR = 1.64), higher BMI (SC = 0.464, OR = 1.60), alcohol drinking (SC = 0.161, OR = 1.17), older age (SC = 0.148, OR = 1.16), and smoking (SC = 0.129, OR = 1.14) are positively correlated factors. For NERD, HP infection (SC = 0.106, OR = 1.11), female gender (SC = 0.099, OR = 1.10), younger age (SC = 0.099, OR = 1.10), higher pepsinogen I/II ratio (SC = 0.099, OR = 1.10), smoking (SC = 0.080, OR = 1.08), higher BMI (SC = 0.078, OR = 1.08), and alcohol drinking (SC = 0.076, OR = 1.08) are positively correlated factors. Prevalence of RE in subjects with chronic HP infection and successful HP eradication denotes significant difference (2.3% and 8.8%; p<0.0001), whereas that of NERD shows no difference (18.2% and 20.8%; p = 0.064). CONCLUSIONS: Significantly associated factors of NERD are considerably different from those of RE, indicating that these two disorders are pathophysiologically distinct. Eradication of Helicobacter pylori may have disadvantageous effects on RE but not on NERD.

Narrow band imaging with magnification can pick up esophageal squamous cell carcinoma more efficiently than lugol chromoendoscopy in patients after chemoradiotherapy.

Aim. Little is known about the usefulness of narrow band imaging (NBI) for surveillance of patients after chemoradiotherapy for esophageal neoplasia. Its usefulness in detecting esophageal squamous cell carcinoma (SCC) or high-grade intraepithelial neoplasia (HGIN) in these patients was retrospectively compared to Lugol chromoendoscopy. Patients and Methods. We assessed the diagnostic ability of NBI with magnification based on the biopsy specimens obtained from iodine-unstained lesions. Seventy-two iodine-unstained lesions were biopsied and consecutively enrolled for this study. The lesions were divided into NBI positive and NBI negative. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of NBI with magnification and PPV of Lugol chromoendoscopy was calculated using histological assessment as a gold standard. Results. Forty-six endoscopic examinations using NBI with magnification followed by Lugol chromoendoscopy were performed to 28 patients. The prevalence of SCC and HGIN was 21.4%. Sensitivity, specificity, PPV, NPV, and accuracy of NBI were 100.0%, 98.5%, 85.7%, 100%, and 98.6%, respectively. On the contrary, PPV of Lugol chromoendoscopy were 8.3%. Compared to Lugol chromoendoscopy, NBI with magnification showed equal sensitivity and significantly higher PPV (P < 0.0001). Conclusion. NBI with magnification would be able to pick up esophageal neoplasia more efficiently than Lugol chromoendoscopy in patients after chemoradiotherapy.

Cathepsin E is a marker of gastric differentiation and signet-ring cell carcinoma of stomach: a novel suggestion on gastric tumorigenesis.

Gastric cancer (GC) presents various histological features, though the mechanism underlying its diversity is seldom elucidated. It is mainly classified into well differentiated tubular adenocarcinoma (tub1), moderately differentiated tubular adenocarcinoma (tub2), poorly differentiated adenocarcinoma (por), signet-ring cell carcinoma (sig), mucinous adenocarcinoma (muc), and papillary adenocarcinoma (pap). By screening, we found cathepsin E (CTSE) expresses universally in sig-type, occasionally in por-type, and rarely in tub1/tub2-type GC cell lines. In surgically-resected specimens, CTSE was immunostained in 50/51 sig-type (98.0%), 3/10 tub1-type (30.0%), 7/18 tub2-type (38.9%), 15/26 por-type (57.7%), 4/10 pap-type (40.0%), and 0/3 muc-type (0.0%) GC. In endoscopically-resected specimens, 6/7 sig-type (85.7%), 7/52 tub1-type (13.7%), 5/12 tub2-type (41.7%), 2/7 pap-type (28.6%) GC and 0/6 adenoma (0.0%) expressed CTSE. For non-malignant tissues, CTSE is universally expressed in normal fundic, pyloric, and cardiac glands of stomach, but hardly in other digestive organs. In the precancerous intestinal metaplasia of stomach, CTSE is mostly observed in mixed gastric-and-intestinal type and deficient in solely-intestinal type. CTSE expression is positively correlated with gastric marker MUC5AC (p<0.0001) and negatively correlated with intestinal marker MUC2 (p = 0.0019). For sig-type GC, in both tumors and background mucosa, expression of MUC5AC and CTSE is high whereas that of MUC2 is low, indicating that sig-type GC reflects the features of background mucosa. For gastric adenoma and tub1/tub2-type GC, more undifferentiated tumors tend to show higher expression of CTSE with MUC5AC and lower expression of MUC2 in tumors, but they tend to present lower expression of CTSE, MUC5AC and MUC2 in background mucosa. These suggest that more malignant gastric adenocarcinoma with stronger gastric and weaker intestinal properties tend to arise from background mucosa with decreased both gastric and intestinal features. In conclusion, CTSE is a marker of both gastric differentiation and signet-ring cell carcinoma, which should shed light on the mechanism of gastric tumorigenesis.