Astrocyte-elevated gene-1 (AEG-1) plays an important role in diverse cancers and its up-regulation is associated with poor survival of patients. However, the status of AEG-1 expression and its significance in gastric cancer are still unclear. In this study, the expression of AEG-1 was studied in different gastric cancer cell lines and gastric cancer tissues. Expression of AEG-1 was significantly higher in gastric cancer tissues than that in normal tissues. Overexpression of AEG-1 was found in 62.9% of gastric cancers and significantly associated with TNM stage and Ki-67 proliferation index (P < 0.01). For survival study, overexpression of AEG-1 was significantly associated with poor survival (P < 0.01). Further multivariate analysis suggested that AEG-1 overexpression was an independent prognostic factor for the disease. We demonstrated that inhibition of AEG-1 expression by specific siRNA clearly inhibited SGC-7901 cell growth and enhanced cell apoptosis (P < 0.01). Inhibition of AEG-1 reduced phosphorylation of AKT and glycogen synthase kinase (GSK)-3β (Ser 9) and decreased the level of β-catenin, lymphoid enhancer binding factor 1 (LEF1), and Cyclin D1. This indicated that AEG-1 may play a role in Wnt/β-catenin-mediated cancer progression. Taken together, overexpression of AEG-1 could be a useful prognostic factor in patients with gastric cancer. Targeted inhibition of AEG-1 may provide a novel therapeutic strategy for gastric cancer.

To synthesize the available data on the association between metabolic syndrome and all-cause mortality, we conducted a meta-analysis of prospective cohort studies. We performed a literature search using Medline, EMBASE and Cochrane Library from 2001 to December 2009, with no restrictions. We included studies if they were prospective, had an assessment of metabolic syndrome at baseline and risk of all-cause mortality. We recorded several characteristics for each study. We extracted relative risks (RR) and 95% confidence intervals (CI) and pooled them using fixed or random effects models. We performed sensitivity analysis, and assessed heterogeneity and publication bias. A total of 21 studies including 372,411 participants were included in our meta-analysis. 18,556 deaths from any cause occurred during a mean follow-up of 11.5 years. Individuals with the metabolic syndrome, compared to those without, had an increased mortality from all causes (pooled RR 1.46; 95% CI 1.35-1.57). The RR of all-cause mortality associated with metabolic syndrome was higher in studies using the National Cholesterol Education Program Adult Treatment Panel (NCEP) than the revised NCEP criteria (RR: 1.45 vs. 1.25; P = 0.0002). Metabolic syndrome is an important risk factor for all-cause mortality. The diagnosis and treatment of the underlying risk factors for the metabolic syndrome should be an important strategy for the reduction of all-cause mortality associated with metabolic syndrome in the general population.

The aim of this study was to detect mixed lineage kinase domain-like protein (MLKL) expression in gastric cancer (GC) and to analyze its association with the prognosis of GC patients. Immunohistochemical staining, Western blotting, and quantitative reverse-transcriptase polymerase chain reaction were performed to detect MLKL tissue expression in 117 GC patients. Clinicopathological characteristics and survival data were retrospectively analyzed to discover the clinical importance of MLKL expression. The chi-square test was used to analyze the relationship between MLKL expression and the clinicopathological characteristics. Survival curves were plotted by using the Kaplan-Meier method and compared using the log-rank test. Survival data were evaluated using univariate and multivariate Cox regression analyses. The expression of MLKL mRNA was significantly higher in adjacent normal samples than in the tumor tissues (P = 0.003). Clinicopathological analysis showed that MLKL expression was significantly correlated with age (P = 0.013), histologic type (P = 0.049), differentiation grade (P < 0.001), depth of invasion (P = 0.022), and lymph node metastasis (P = 0.003). Low MLKL expression was significantly associated with decreased overall survival (median 29 months vs. 56 months, P < 0.001). Multivariate analysis suggested that MLKL expression might be an independent prognostic indicator (HR = 0.645, 95 % CI, 0.446-1.165, P = 0.002) for GC patients. In conclusion, our findings provide evidence that MLKL might serve as a candidate tumor suppressor and a potential prognostic biomarker for GC.

The log odds of positive lymph nodes (LODDS) was defined as the log of the ratio between the number of positive lymph nodes and the number of negative lymph nodes, which is a novel and promising nodal staging system for gastric cancer. Here, we aimed to compare the prognostic effect of pN, lymph node ratio (LNR) and LODDS. The association between overall survival and pN, LNR and LODDS was retrospectively analysed. The discriminatory ability and monotonicity of gradients (linear trend χ 2 score), homogeneity ability (likelihood ratio test) and prognostic stratification ability (Akaike information criterion [AIC] and receiver operating characteristic [ROC] curve) were compared among three lymph node staging systems. The pN, LNR and LODDS were all identified as independent prognostic factors for gastric cancer patients in the multivariate analysis. LODDS showed the best prognostic performance (linear trend χ 2 score 266.743, likelihood ratio χ 2 test score 427.771, AIC value 5670.226, area under the curve (AUC) 0.793), followed by LNR and pN. In patients with different levels of retrieved lymph nodes (≤10, 11–14, 15–25 and >25), LODDS was the most powerful for prognostic prediction and discrimination of the heterogeneity among the subgroups. Significant differences in survival were observed among patients in different LODDS subgroups after being classified according to the pN and LNR classifications. LODDS appears to be a more powerful system for predicting the overall survival of gastric cancer patients, as compared to LNR and pN, and may serve as an alternative nodal staging system for gastric cancer.

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BackgroundSonic hedgehog (SHH) plays critical roles in cell growth and development. Tumor cells express SHH, which can promote cell proliferation and epithelial-to-mesenchymal transition. However, the autocrine SHH pathway has not been described in gastric cancer. The aim of this study was to explore molecular mechanisms underlying autocrine SHH signaling in gastric cancer cells.MethodsSHH expression was assessed using immunohistochemistry and the results were compared with clinicopathologic parameters, including survival. Using gastric cancer cell lines, we measured SHH mRNA and protein expression, and studied the effects of SHH signaling on cell proliferation and SHH secretion. We also studied the effects of an inhibitor of PLC-γ1 on phosphorylation of phospholipase Cγ1 and extracellular signal-regulated kinases (ERK)1/2.ResultsSHH protein expression in gastric cancer tissue was significantly higher compared with that in normal gastric tissue (P < 0.001), and the increased expression was significantly associated with pT staging (P = 0.004), pN staging (P = 0.018), pM staging (P = 0.006), and pTNM staging (P < 0.001). In multivariate analyses, overall survival in gastric cancer was significantly shorter in cases with high SHH expression (HR = 1.734, 95 % CI: 1.109–2.713, P = 0.016). The AGS and SGC-7901 gastric cancer cell lines expressed SHH mRNA and protein. In these cell lines, SHH promoted carcinogenesis through activation of the PLCγ1-ERK1/2 pathway, resulting in increased cell proliferation and survival.ConclusionsIncreased SHH expression is associated with shorter survival in gastric cancer patients, and SHH could represent a useful biomarker or therapeutic target for this disease.

Aim. CD44 and Sonic Hedgehog (Shh) signaling are important for gastric cancer (GC). However, the clinical impact, survival, and recurrence outcome of CD44, Shh, and Gli1 expressions in GC patients following radical resection have not been elucidated. Patients and Methods. CD44, Shh, and Gli1 protein levels were quantified by immunohistochemistry (IHC). The association between CD44, Shh, and Gli1 expression and clinicopathological features or prognosis of GC patients was determined. The biomarker risk score was calculated by the IHC staining score of CD44, Shh, and Gli1 protein. Results. The IHC positive staining of CD44, Shh, and Gli1 proteins was correlated with larger tumour size, worse gross type and histological type, and advanced TNM stage, which also predicted shorter overall survival (OS) and disease-free survival (DFS) after radical resection. Multivariate analysis indicated the Gli1 protein and Gli1, CD44 proteins were predictive biomarkers for OS and DFS, respectively. If biomarker risk score was taken into analysis, it was the independent prognostic factor for OS and DFS. Conclusions. CD44 and Shh signaling are important biomarkers for tumour aggressiveness, survival, and recurrence in GC.

The aim of this study was to detect forkhead box L1 (FOXL1) expression in gastric cancer (GC) and to analyze its association with the prognosis of GC patients. Immunohistochemical staining, Western blotting, and quantitative reverse transcriptase polymerase chain reaction were performed to detect FOXL1 tissue expression in 109 GC patients. Clinicopathological characteristics and survival data were retrospectively analyzed to discover the clinical importance of FOXL1 expression. The chi-square test was used to analyze the relationship between FOXL1 expression and the clinicopathological characteristics. Survival curves were plotted by using the Kaplan-Meier method and compared using the log-rank test. Survival data were evaluated using univariate and multivariate Cox regression analyses. The expression of FOXL1 messenger RNA (mRNA) was significantly higher in adjacent normal samples than in the tumor tissues (P = 0.043). Clinicopathological analysis showed that FOXL1 expression was significantly correlated with depth of invasion (P = 0.017), lymph node metastasis (P = 0.019), and distant metastasis (P = 0.047). FOXL1-negative as opposed to the FOXL1-positive patients had lower 5-year overall survival (14.06 vs. 37.78 %, P < 0.001). Multivariate analysis suggested that FOXL1 expression might be an independent prognostic indicator (hazard ratio = 0.307, 95 % confidence interval, 0.187-0.505; P < 0.001) for GC patients. In conclusion, our findings provide evidence that FOXL1 might serve as a candidate tumor suppressor and a potential prognostic biomarker for GC.