Xueyuan Cao

Roles of cyclooxygenase‐2 and microsomal prostaglandin E synthase‐1 expression and β‐catenin activation in gastric carcinogenesis in N‐methyl‐N‐nitrosourea‐treated K19‐C2mE transgenic mice

K19‐C2mE transgenic (Tg) mice, simultaneously expressing cyclooxygenase‐2 (COX‐2) and microsomal prostaglandin E synthase‐1 (mPGES‐1) in the gastric mucosa under the cytokeratin 19 gene promoter, were here treated with N‐methyl‐N‐nitrosourea (MNU) and inoculated with Helicobacter pylori (H. pylori) to investigate gastric carcinogenesis. Wild‐type (WT) and Tg mice undergoing MNU treatment frequently developed tumors in the pyloric region (100% and 94.7%, respectively); multiplicity in Tg was higher than that in WT (P < 0.05) with H. pylori infection. Larger pyloric tumors were more frequently observed in Tg than in WT (P < 0.05). In addition, Tg developed fundic tumors, where WT did not. No gastric tumors were observed without MNU treatment. Transcripts of TNF‐α, iNOS, IL‐1β, and CXCL14 were up‐regulated with H. pylori infection in both genotypes and were also increased more in Tg than in WT within H. pylori‐inoculated animals. Immunohistochemical analysis demonstrated significantly greater β‐catenin accumulation in pyloric tumors, compared with those in the fundus (P < 0.01) with mutations of exon 3; 18.2% and 31.6% in MNU‐alone and MNU + H. pylori‐treated WT, whereas 21.4% and 62.5% was observed in the Tg, respectively; the latter significantly higher (P < 0.05), suggesting the role of H. pylori in Wnt activation. In conclusion, K19‐C2mE mice promoted gastric cancer in both fundic and pyloric regions. Furthermore β‐catenin activation may play the important role of pyloric carcinogenesis especially in H. pylori‐infected Tg. Induction of various inflammatory cytokines in addition to overexpression of COX‐2/mPGES‐1 could be risk factors of gastric carcinogenesis and may serve as a better gastric carcinogenesis model. (Cancer Sci 2008; 99: 2356–2364)

Enhanced recovery after surgery with laparoscopic radical gastrectomy for stomach carcinomas

AIM To study the efficacy of the enhanced recovery after surgery (ERAS) program in laparoscopic radical gastrectomy for stomach carcinomas. METHODS From June 2010 to December 2012, 61 gastric cancer patients who underwent laparoscopic-assisted radical gastrectomy with D2 lymphadenectomy at First Hospital of Jilin University were enrolled in this randomized controlled trial. (Clinical Trials.gov, registration ID: NCT01955096). The subjects were divided into the ERAS program group and the conventional control group. The clinical characteristics, recovery variables, and complications of patients were analyzed. RESULTS The time to first ambulation, oral food intake, and time to defecation were significantly shorter in the ERAS group (n = 30), compared to the conventional group (n = 31; P = 0.04, 0.003, and 0.01, respectively). The postoperative hospital stay was less in the ERAS group (6.8 ± 1.1 d) compared to the conventional group (7.7 ± 1.1 d) (P = 0.002). There was no significant difference in postoperative complications between the ERAS (1/30) and conventional care groups (2/31) (P = 1.00). There were no readmissions or mortality during the 30-d follow-up period. CONCLUSION The ERAS program is associated with a shorter hospital stay in gastric cancer patients undergoing laparoscopic radical gastrectomy. The ERAS protocol is useful in the treatment of gastric cancer.

Canolol Inhibits Gastric Tumors Initiation and Progression through COX-2/PGE2 Pathway in K19-C2mE Transgenic Mice

4-vinyl-2, 6-dimethoxyphenol (canolol) is an antioxidant phenolic compound extracted from crude canola oil. In current research, K19-C2mE transgenic mice, developing hyperplastic tumors spontaneously in the glandular stomach, were used to study the mechanisms involved in the anti-inflammation and anti-tumor effects of canolol. Tg mice receiving canolol diet had a reduced tumor incidence, to 41.2%, compared with Non-treatment Tg mice, 77.8% of which had gastric tumor (P=0.002). Besides that, the mean tumor diameter was decreased from 6.5mm to 4.5mm (P<0.001) after canolol administration. COX-2/PGE2 pathway is known to play pivotal role in inflammation-induced gastric tumorigenesis. The neutrophils and lymphocytes infiltration was suppressed significantly, and the mRNA levels of the proinflammatory cytokines COX-2, IL-1β and IL-12b were also downregulated in gastric mucosa. Additionally, immunohistochemical analysis showed that COX-2, EP2, Gαs and β-catenin, key factors involving in PGE2 signal transduction, were positive staining with higher H scores in Non-treatment Tg mice, while the expressions were suppressed significantly by 0.1% canolol (P<0.001). In addition, tumor-suppressor miR-7 was reactivated after canolol administration, and COX-2 was showed to be a functional target of miR-7 to suppress the tumor progression. In conclusion, canolol could inhibit the gastritis-related tumor initiation and progression, and the suppression effect was correlated with the blocking up of canonical COX-2/PGE2 signaling pathway and might be regulated by miR-7.

CD44 but not CD24 expression is related to poor prognosis in non-cardia adenocarcinoma of the stomach

BackgroundRecent studies have focused on the diagnostic and prognostic significance of CD24 and CD44 expression in human cancers. This study aimed to explore changes in CD44 and CD24 expression levels in patients with gastric cancer and to assess their prognostic values.MethodsCD44 and CD24 expression levels were investigated immunohistochemically in tumor samples from 290 patients with non-cardia gastric adenocarcinoma, of whom 77 had paired adjacent normal gastric mucosa. CD24 and CD44 mRNA levels were determined by quantitative polymerase chain reaction in 34 patients. Serum anti-Helicobacter pylori IgG was detected by enzyme-linked immunosorbent assay. Relationships between CD44 and CD24 protein expression levels and tumor parameters were analyzed and their prognostic values were evaluated by Cox proportional hazards models.ResultsCD24 and CD44 expression levels were significantly higher in patients with gastric cancer compared with those in paired controls (45.5% vs. 0.0%, and 61.0% vs. 0.0%, P < 0.001). Among 290 patients, the overall survival rate was significantly higher in CD44(−) compared with CD44(+) patients (log-rank test, P = 0.035). However, there was no significant correlation between CD24 expression and overall survival time (log-rank test, P = 0.115). Multivariate regression analysis indicated that positive CD44 expression (P = 0.029), TNM staging (P < 0.001), and lymphovascular invasion (P = 0.016), but not CD24 expression (P = 0.065), were independent prognostic factors in gastric cancer.ConclusionsIndividual expression of CD44 was associated with poor survival in patients with gastric carcinoma.

Polymorphism of DNA Methyltransferase 3b and Association with Development and Prognosis in Gastric Cancer

Objective DNA methyltransferase 3b (DNMT3b) plays an important role in abnormal methylation during tumorigenesis. Polymorphism of the DNMT3b gene may influence DNMT3b activity and be associated with cancer risk. This study aimed to investigate the association between single nucleotide polymorphisms (SNPs) of the DNMT3b gene and susceptibility and prognosis of gastric cancer. Methods Four hundred and forty-seven histologically-confirmed gastric cancer cases, 111 gastric atrophy cases and 961 tumor-free controls were enrolled into the study. Five tag SNPs (rs6119954, rs1569686, rs4911107, rs4911259 and rs8118663) of the DNMT3b gene were genotyped by TaqMan assay. DNMT3b expression was evaluated in 104 cancer tissues by immunohistochemistry method. Results The median follow-up time for 422 gastric patients with prognosis information was 55.1 (51.8–58.5) month. We found that individuals with the rs1569686 variant genotype (TG/GG) were significantly associated with poor prognosis in gastric cancer compared to those carrying the TT genotype (HR = 1.43, 95%CI: 1.02–1.99). This trend was more evident in the long-term survival of gastric cancer. Similar results were observed for the G allele carriers of rs4911107 and T allele carriers of rs4911259 as these two sites were in complete linkage disequilibrium with rs1569686. The rs8118663 GG carriers tended to live shorter than AA/AG genotype (HR = 2.72, 95%CI: 1.45–5.12) in patients living longer than 2.0 years. None of the five SNPs was associated with the risks of gastric cancer or gastric atrophy. And no relationship was found between each of the five SNPs and DNMT3b expression. Conclusions This study provides evidence that DNMT3b polymorphisms may predict long-term survival of gastric cancer. However, further studies are needed to reveal the underlying biological roles of DNMT3b polymorphism.

Association of the miR-146a rs2910164 polymorphism with gastric cancer susceptibility and prognosis.

AIM Single nucleotide polymorphisms in miRNA-coding region may be involved in the development or progression of gastric cancer (GC). MATERIALS & METHODS Six SNPs (miR-146a rs2910164, miR-196a2 rs11614913, miR-27a rs895819, miR-423 rs6505162, miR-608 rs4919510, miR-149 rs2292832) were genotyped in 898 histologically confirmed GC cases and 992 controls in this hospital-based case-control study. RESULTS The G/G genotype of rs2910164 was associated with reduced risk of GC (odds ratio: 0.76, 95% CI: 0.60-0.97; p = 0.024). Meanwhile, in 838 GC cases receiving radical tumorectomy, cases bearing the G/G genotype of rs2910164 had shorter survival time comparing to cases with C/C or C/G genotype (hazard ratio: 1.36, 95% CI: 1.04-1.78, p = 0.023). CONCLUSION rs2910164 of miR-146a is associated with GC.

Polymorphisms of the DNA Methyltransferase 1 Gene Predict Survival of Gastric Cancer Patients Receiving Tumorectomy.

DNA methyltransferase 1 (DNMT1) plays a pivotal role in maintaining DNA methylation status. Polymorphisms of DNMT1 may modify the role of DNMT1 in prognosis of gastric cancer (GC). Our aim was to test whether polymorphisms of DNMT1 gene were associated with overall survival of GC. Four hundred and forty-seven GC patients who underwent radical tumorectomy were enrolled in the study. Five tagging SNPs (rs10420321, rs16999593, rs2228612, rs2228611, and rs2288349) of the DNMT1 gene were genotyped by TaqMan assays. Kaplan-Meier survival plots and Cox proportional hazard regression were used to analyze the associations between SNPs of DNMT1 and survival of GC. Patients carrying rs2228611 GA/AA genotype tended to live longer than those bearing the GG genotype (HR 0.68, 95% CI: 0.51–0.91, P = 0.007). Further multivariate Cox regression analysis showed that rs2228611 was an independent prognostic factor (GA/AA versus GG: OR 0.67, 95% CI 0.49–0.91, P = 0.010). Nevertheless, other SNPs did not show any significant associations with survival of GC. Polymorphisms of the DNMT1 gene may affect overall survival of GC. The SNP rs2228611 has the potentiality to serve as an independent prognostic marker for GC patients.

Predictive Value of MiR-219-1, MiR-938, MiR-34b/c, and MiR-218 Polymorphisms for Gastric Cancer Susceptibility and Prognosis

Gastric cancer (GC) is one of the most prominent global cancer-related health threats. Genes play a key role in the precise mechanisms of gastric cancer. SNPs in mi-RNAs could affect mRNA expression and then affect the risk and prognosis of GC. Firstly, we have decided to perform a case-control study which included 897 GC patients and 992 controls to evaluate the association of miR-219-1 rs213210, miR-938 rs2505901, miR-34b/c rs4938723, and miR-218 rs11134527 polymorphisms with gastric cancer susceptibility. Secondly, among the 897 GC patients above, 755 cases underwent a radical operation, without distant metastasis and with negative surgical margins included in the survival analysis to evaluate the association of the four SNPs above with gastric cancer prognosis. The C/T or C/C genotypes of rs213210 were related to a lower GC risk (OR = 0.76, 95% CI: 0.62–0.93, P = 0.009) compared to the T/T genotype. Rs11134527 in miR-218 was associated with GC survival, and the G/A and G/G genotypes of rs11134527 resulted in a decreased risk of death when compared with the A/A genotype (HR = 0.75, 95% CI: 0.61–0.95, P = 0.016). This study found that miR-219-1 rs213210 polymorphism was associated with GC susceptibility and rs11134527 in miR-218 was positively correlated with GC prognosis.

Anticancer effects of 4-vinyl-2,6-dimethoxyphenol (canolol) against SGC-7901 human gastric carcinoma cells

Gastric cancer remains the fourth most commonly diagnosed cancer and is the second leading cause of cancer-related mortality worldwide. The aim of this study was to investigate the effects of canolol on the proliferation and apoptosis of SGC-7901 human gastric cancer cells and its relevant molecular mechanisms. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to observe the effect of canolol on the proliferation of SGC-7901 human gastric adenocarcinoma cells. The results showed that SGC-7901 cells exhibited a marked dose-dependent reduction in the proliferation rate. The survival rate of the cells was 88.86±1.58% at 50 μmol/l, decreasing to 53.73±1.51% at 800 μmol/l (P<0.05). By contrast, canolol had no significant toxicity on the human gastric mucosal epithelial cell line GES-1. The vivid images of cell morphology using an inverted microscope provided confirmation of the MTT assay. Treatment of SGC-7901 cells with canolol resulted in apoptosis demonstrated by flow cytometry. Furthermore, canolol downregulated the mRNA levels of COX-2, but had no significant effect on the mRNA expession of the Bax and Bcl-2 genes. These findings suggest that canolol has potential to be developed as a new natural anti-gastric carcinoma agent.

Interaction between Helicobacter pylori and host genetic variants in gastric carcinogenesis

Helicobacter pylori (H. pylori) is the definite carcinogen of gastric cancer. H. pylori infection induces chronic inflammation, causes DNA damage and aberrant methylation of genes and these pathways are involved in H. pylori-related gastric carcinogenesis. Polymorphisms of the genes involved in these pathways could alter susceptibility to gastric cancer. In this mini review, we focused on the role of polymorphisms in these genes on the susceptibility to gastric cancer, with a particular emphasis on their possible interactions with H. pylori infection. We found that many studies on this theme did not simultaneously report H. pylori infection and the interactions remained inconclusive.