Hedgehog signaling-related genomics signature for the accurate progress and prognosis prediction in gastric cancer.

The Hedgehog pathway is thought to be closely associated with the progression of GC; however, a specific link between the Hedgehog pathway on the prognosis and immune infiltration of gastric cancer is still lacking. This study collected Hedgehog pathway-related genes. The Hedgehog pathway-related pattern were identified by consensus cluster analysis. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) were used to identify the biological functions which were significantly altered between predefined Cluster1 and Cluster2 in consensus clustering. The risk model of gastric cancer based on Hedgehog signaling pathway was constructed by univariate and multivariate COX regression, and the nomogram was constructed. The results showed that there were significant differences in the expression of Hedgehog pathway-related genes between the two groups. In addition, the constructed risk model was significantly correlated with the clinical prognosis and immune cell infiltration level of patients with gastric cancer. The model effectively predicted the efficacy of chemotherapy in GC patients and the sensitivity of drug treatment between groups. We systematically revealed the mechanism of Hedgehog pathway in gastric cancer and selected biomarkers with biological significance from a new perspective, providing potential direction for the treatment of gastric cancer.

Association between FAS-1377 G/A polymorphism and susceptibility to gastric cancer: evidence from a meta-analysis.

Previous studies published to evaluate the association between FAS-1377 G/A polymorphism and susceptibility to gastric cancer provided inconclusive outcomes. To derive a more precise estimation on this association, a meta-analysis of published case-control studies was performed. Eligible studies up to November 13, 2012 were identified from PubMed, Wanfang Medicine database, and Web of Science. Nine studies with a total of 2,086 cases and 2,701 controls were finally included into this meta-analysis. Overall, there was an obvious association between FAS-1377 G/A polymorphism and susceptibility to gastric cancer (for AA versus GG: odds ratio (OR) = 1.38; 95 % confidence interval (CI) 1.00-1.91, P = 0.05; for AA versus GA/GG: OR = 1.28; 95 %CI 1.07-1.53, P = 0.006). After excluding studies with low quality, there was no between-study heterogeneity, and there was still an obvious association between FAS-1377 G/A polymorphism and susceptibility to gastric cancer (for AA versus GG: OR = 1.25; 95 %CI 1.02-1.52, P = 0.03; for AA versus GA/GG: OR = 1.27; 95 %CI 1.05-1.53, P = 0.01). Subgroup analyses by ethnicity showed that the association above was still obvious in Asians, but the association was still unclear in Caucasians owing to the limited sample. In summary, this meta-analysis suggests that the FAS-1377 G/A polymorphism is associated with susceptibility to gastric cancer, especially in Asians. More studies from Caucasians are needed to provide further evidence for the possible association in Caucasians.

Roles of endoplasmic reticulum stress and autophagy on H2O2­induced oxidative stress injury in HepG2 cells.

Endoplasmic reticulum stress (ERS) can be induced by a variety of physiological and pathological factors including oxidative stress, which triggers the unfolded protein response to deal with ERS. Autophagy has been hypothesized to be a means for tumor cells to increase cell survival under conditions of hypoxia, metabolic stress and even chemotherapy. Although they may function independently from each other, there are also interactions between responses to oxidative stress injury induced by pathologic and pharmacological factors. The aim of the present study was to investigate the effects of ERS and autophagy on H2O2­induced oxidative stress injury in human HepG2 hepatoblastoma cells. It was demonstrated that exposure of HepG2 cells to H2O2 decreased cell viability and increased reactive oxygen species (ROS) levels in a dosage­dependent manner. In addition, apoptosis and autophagy rates were elevated and reduced following cell exposure to H2O2 + the ERS inducer Tunicamycin (TM), and to H2O2 + the ERS inhibitor Salubrinal (SAL), compared with the cells treated with H2O2 alone, respectively. Further studies revealed that TM enhanced the expression of ERS­related genes including glucose­regulated protein­78/binding immunoglobulin protein, inositol­requiring kinase­I and activating transcription factor 6 and C/EBP­homologous protein 10, which were attenuated by SAL compared with cells exposed to H2O2 alone. The data from the present study also demonstrated that LC3II/LC3­I and p62, members of autophagy­related genes, were increased and decreased in cells treated with H2O2 + TM compared with cells treated with H2O2, respectively, indicating that autophagy was stimulated by ERS. Furthermore, a reduction in the levels of pro caspase­3 and pro caspase­9, and elevation level of caspase­12 were observed in cells exposed to H2O2 + TM compared with cells treated with H2O2, respectively, suggesting apoptosis induced by H2O2 was enhanced by ERS or autophagy triggered by H2O2. The above results suggest that the ERS inducer may be a potential target for pharmacological intervention targeted to ERS or autophagy to enhance oxidative stress injury of tumor cells induced by antitumor drugs.

MiR-449c inhibits gastric carcinoma growth.

AIMS: Gastric carcinoma (GC) is among the leading causes of cancer-related deaths in China. Growing evidence indicates that dysregulation of miRNAs contributes to GC development. Although it has been shown that miR-449c acts as a tumor suppressor in lung cancer, the role of miR-449c in GC remains unclear. MAIN METHODS: Here, we analyzed miR-449c levels in GC tissues and cell lines by RT-qPCR. We also overexpressed and inhibited miR-449c by transfecting miRNA mimics and antisense oligonucleotides (ASO), respectively. Cell growth was analyzed by MTT assay, and cell apoptosis was evaluated by FACS analysis. MiR-449c target genes were predicted using bioinformatics algorithms and confirmed by a dual luciferase reporter assay. KEY FINDINGS: We detected lower miR-449c levels in GC tissues; the low miR-449c levels correlated with low survival rate. Overexpression of miR-449c inhibited cell growth and promoted apoptosis, while depletion of miR-449c increased cell growth and suppressed apoptosis. Moreover, the 3' UTR of MET, an oncogene that activates tumor cell growth, appeared to be targeted by miR-449c. SIGNIFICANCE: Together, we showed that the reduced miR-449c levels in GC tissues promote GC growth, which possibly contributes to the low survival rate of GC patients. Mechanistically, miR-449c may target MET to suppress GC cell growth.